High-Dose Chemotherapy and Autologous Bone Marrow
`Support as Consolidation After Standard-Dose Adjuvant
`Therapy for High-Risk Primary Breast Cancer
`
`By William P. Peters, Maureen Ross, James J. Vredenburgh, Barry Meisenberg, Lawrence B. Marks, Eric Winer,
`Joanne Kurtzberg, Robert C. Bast, Jr, Roy Jones, Elizabeth Shpall, Katherine Wu, Gary Rosner, Colleen Gilbert,
`Barbara Mathias, David Coniglio, William Petros, |. Craig Henderson, Larry Norton, Raymond B. Weiss,
`Daniel Budman, and David Hurd
`
`Purpose: We studied high-dose cyclophosphamide,
`cisplatin, and carmustine (CPA/cDDP/BCNU) with autol-
`ogous bone marrow support (ABMS) as consolidation af-
`ter standard-dese adjuvant chemotherapy treatmentof
`primary breast cancer involving 10 or more axillary
`lymph nodes.
`Patients and Methods: One hundred two womenwith
`stageIIA, IIB, IIIA, or IIIB breast cancer involving 10 or
`more lymph nodesat surgery were registered; 85 were
`eligible, treated, and assessable. Patients were treated
`with four cycles of standard-dose cyclophosphamide,
`doxorubicin, and fluorouracil (CAF), followed by high-
`dose CPA/cDDP/BCNU with ABMS.
`
`Results: Actuarial event-free survival for the study pa-
`tients at a median follow-up of 2.5 years is 72% (95%
`confidence interval, 56% to 82%). Comparison to three
`
`historical or concurrent Cancer and Leukemia Group B
`(CALGB) adjuvant chemotherapytrials selected for similar
`patients showed event-free survival at 2.5 years to be be-
`tween 38% and 52%.Therapy-related mortality was 12%;
`pulmonary toxicity of variable severity occurred in 31%
`of patients. Quality-of-life evaluationsindicate that patients
`are functioning well without major impairments.
`Conclusion: High-dose consolidation with CPA/cDDP/
`BCNU and ABMSafter standard-dose CAF results in a
`decreased frequency of relapse in patients with high-
`tisk primary breast cancer compared with historical se-
`ries at the median follow-up of 2.5 years. Evaluation in
`a prospective, randomized trial is warranted and cur-
`rently underway.
`J Clin Oncol 11:1132-1143. © 1993 by American So-
`ciety of Clinical Oncology.
`
`DJUVANT CHEMOTHERAPY has been demon-
`strated to produce modest but consistent improve-
`ments in long-term disease-free and overall survival in
`patients with primary breast cancer.'! These improvements
`are achieved with chemotherapy programsthat are not
`curative in metastatic disease. Further, there is increasing
`evidence both from retrospective analyses” and from pro-
`spective randomized clinicaltrials that dose intensification
`is sometimes associated with superior outcomes in
`metastatic** and primary breast cancer.” We have reported
`that high-dose cyclophosphamide,cisplatin, and carmus-
`tine (CPA/cDDP/BCNU)and autologous bone marrow
`support (ABMS) can produce frequent and rapid complete
`responses in metastatic breast cancer,® and that some of
`these responses are durable.* However, relapses occurred
`frequently and primarily at pretreatmentsites of bulk dis-
`
`
`From the Duke University Bone Marrow Transplant Program, De-
`partments of Medicine and Radiation Oncology, Duke University
`Medical Center, Durham NC; and the Cancer and Leukemia Group
`B, Lebanon, NH.
`Submitted December 9, 1992; accepted February 18, 1993.
`Supported in part by National Cancer Institute (Bethesda, MD)
`grants no. PO1-4774]-44 and CA-47577.
`Address reprint requests to William P. Peters, MD, PhD, Duke
`University Medical Center, 25101 Morris Building, DUMC Box 3961,
`Durham, NC 27710.
`© 1993 by American Society ofClinical Oncology.
`0732-183X/93/1106-0019$3.00/0
`
`ease. Further, the use of high-dose chemotherapy and au-
`tologous bone marrow transplantation as consolidation
`following standard-dose induction therapy has been re-
`ported byseveral groups, including our own, to augment
`the frequencyof complete responsesin patients with met-
`astatic breast cancer. However, these results were achieved
`with considerable treatment-related morbidity and mor-
`tality, although the rates of morbidity and mortality have
`recently been reduced.'*'*
`The prognosis for patients with extensive axillary lymph
`node involvementat the timeof presentation with primary
`breast cancer is poor, despite standard-dose adjuvant
`therapy. Analysis of treatment outcomesin patients with
`10 or more involved axillary lymph nodes indicates that
`between 55% and 87% ofpatients will relapse by 5 years
`and 70% to 90% will relapse by 10 years.'> Comparison
`to historical series in which adjuvant chemotherapy was
`not used indicates thatlittle, if any, impact of adjuvant
`therapy is seen in the first 4 years and that benefit from
`adjuvant therapy becomes apparent only after this time
`andis generally clinically modest,'* although statistically
`significant. Contemporary results from cooperative groups
`do not appear to improve meaningfully on these earlier
`results.
`
`Because of the inadequacy of standard adjuvant che-
`motherapy in high-risk primary breast cancer and the
`limitation of disease bulk in the use of high-dose che-
`motherapy for metastatic breast cancer, we chose to com-
`
`1132
`
`Journalof Clinical Oncology, Vol 11, No 6 (June), 1993: pp 1132-1143
`
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`Genentech Exhibit 2064
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`

`CHEMOTHERAPY WITH ABMS FOR BREAST CANCER
`
`1133
`
`bine these modalities in the treatment program reported
`here. The study reported here thus represents an evolution
`in treatmentstrategy for breast cancer by coupling a stan-
`dard-dose adjuvant chemotherapy regimen and high-dose
`consolidation with combination alkylating agents and
`ABMS. Wechose to use an adjuvant chemotherapy pro-
`gram (cyclophosphamide, doxorubicin and fluorouracil
`[CAF]) that has been widely used and is being simulta-
`neously evaluated in a cooperative group setting (Cancer
`and Leukemia Group B [CALGB] 8541) in a similar pa-
`tient population. Further, we used a high-dose chemo-
`therapy program of CPA/cDDP/BCNU,which has been
`extensively evaluated in both advanced and early meta-
`static breast cancer to characterize more carefully and
`control the expected toxicities of high-dose therapy.
`
`PATIENTS AND METHODS
`
`Patient Population
`Weentered 102 patients onto this trial between February 1987
`and January 1991. The patients presented here represent 85 eligible
`and assessable women whoreceived high-dose chemotherapy. Char-
`acteristics of the patients are listed in Table 1. Of the 11 eligible
`patients not transplanted, one waslost to follow-up and six of the
`remaining 10 had recurrence of breast cancer. All patients received
`high-dose therapy at the Duke University Medical Center and the
`sameentry and evaluation procedures were used throughoutthe study
`period. Between July 1987 and July 1989, 40 of the entered patients
`were simultaneously registered on a pilot protocol of identical design
`and conduct within the CALGB(protocol 8782); of these 40, 37 are
`assessable, two were not treated with high-dose consolidation for fi-
`nancial reasons, and one relapsed during CAFandis excluded from
`subsequent analyses. There were no importantdifferences between
`the CALGBsubset of patients and the remainder of patients; this
`report will describe the characteristics of the entire population sub-
`sequently.
`The median age for these 85 patients was 38 years (range, 23 to
`56). Ninety-five percent were between 25 and 50 years old; only three
`were older than 50 years. All patients were treated with a modified
`radical mastectomy, except one whoreceived a segmental resection.
`Thedistribution of patients by stage, numberofaxillary lymph nodes
`involved with cancer histologically, and hormone receptor charac-
`teristics of the primary tumoris listed in Table 1.
`
`Treatment Program
`Patients were eligible if they had histologically proven invasive
`breast cancer, stage II or III, which at mastectomy involved 10 or
`more axillary lymph nodes. Patients were excluded if they had a
`history of prior cancer or treatmentfor the breast cancer. Pretreatment
`evaluation requirements included history and physical examination;
`computed tomography of the head, chest, abdomen, and pelvis and
`bone scans showing no evidenceof cancer; rest and exercise left ven-
`triculography (ejection fraction > 45% at rest and < 5% decrease
`with exercise); pulmonary function testing (forced vital capacity,
`forced expiratory volume in | second, and diffusing capacity of the
`lung for carbon monoxide all > 60% of predicted); and bilateral
`bone marrowaspirations and biopsies showing no evidence of cancer
`
`Table 1. High-Dose CPA/cDDP/BCNU and ABMSfor StageIt/Ilt
`Breast Cancer Involving 10 or More Axillary Lymph Nodes
`Entire Duke
`Series Including
`8782
`
`CALGB
`8782"
`
`No. of patients entered
`Ineligible
`Treated before referral and evaluation
`Relapsed before starting treatment
`Nottransplanted
`ICRTP
`Hepatitis
`Psychotic
`Refused
`Relapsed during CAF induction
`Systemic relapse
`Local relapse
`Eligible and assessable
`Median age at surgery, years
`Surgical treatment
`Mastectomy
`Segmentectomy
`Stage
`WA
`IIB
`NIA
`B,
`No. of involved lymph nodes
`Median
`10-12
`13-15
`16-19
`over 20
`Hormonereceptorstatus
`ER-negative/PR-negative
`ER-negative/PR-positive
`ER-positive/PR-negative
`ER-positive/PR-positive
`
`40
`0
`Qo
`0
`2
`2
`
`1
`1
`0
`37
`38
`37
`37
`0
`
`9
`22
`5
`1
`
`13
`15
`9
`8
`5
`
`Ss
`2
`5
`15
`
`102
`4
`3
`1
`iB
`6
`1
`1
`3
`2
`1
`1
`85
`38
`85
`84
`1
`
`20
`44
`20
`1
`
`14
`28
`22
`25
`10
`
`34
`7
`10
`34
`
`Abbreviations: tCRTP, insurance companyrefused to pay; ER, estrogen
`receptor; PR, progesterone receptor.
`*CALGB 8782 represents a subsetof the entire Dukeseries. All patients
`in CALGB are includedin the entire Duke series.
`
`and cellularity greater than 20%. Evaluation andinitiation oftherapy
`were prescribed by protocol to be within 56 days of mastectomy;
`however, due to delays in evaluation and chemotherapy initiation,
`six patients received their first chemotherapy treatment from 58 to
`64 days after mastectomy. These were considered minor protocol
`violations and they are not excluded from analysis. The median time
`from mastectomyto first cycle of chemotherapy was 41 days (range,
`9 to 64).
`The treatment program involved the sequential use of an outpatient
`chemotherapy induction program of CAF followed by high-dose
`chemotherapy consolidation with CPA/cDDP/BCNU with ABMS,
`radiation therapy, and tamoxifen as shownin Fig |. All patients were
`treated with four cycles of CAF (cyclophosphamide 600 mg/m? day
`1, doxorubicin 60 mg/m?day 1, and fluorouracil 600 mg/m?days |
`and 8) with each cycle lasting 28 days. No patient had doses reduced
`from those prescribed by protocol; colony-stimulating factors (CSFs)
`were not administered during the CAF chemotherapy. Between the
`
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:68)(cid:86)(cid:70)(cid:82)(cid:83)(cid:88)(cid:69)(cid:86)(cid:17)(cid:82)(cid:85)(cid:74)(cid:3)(cid:69)(cid:92)(cid:3)(cid:53)(cid:72)(cid:83)(cid:85)(cid:76)(cid:81)(cid:87)(cid:86)(cid:3)(cid:39)(cid:72)(cid:86)(cid:78)(cid:3)(cid:82)(cid:81)(cid:3)(cid:49)(cid:82)(cid:89)(cid:72)(cid:80)(cid:69)(cid:72)(cid:85)(cid:3)(cid:21)(cid:20)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:26)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:21)(cid:20)(cid:25)(cid:17)(cid:20)(cid:27)(cid:24)(cid:17)(cid:20)(cid:24)(cid:25)(cid:17)(cid:19)(cid:21)(cid:27)
`Downloaded from ascopubs.org by Reprints Desk on November21, 2017 from 216.185.156.028
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`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`

`

`1134
`
`PETERS ET AL
`
`&=
`@ae
`«66
`28
`DAY 1
`
`
`= ” N
`
`~ 8o
`
`168
`
`203
`
`HOvHd.
`NaMeDaAT
`
`infusion [day +1]), cisplatin (55 mg/m?/d, days —6, —5, and —4)
`
`administered as a 72-hour continuousintravenousinfusion, and car-
`
`XRT |~>|TAM
`
`
`mustine (600 mg/m?) administered on day —3 as an intravenous
`infusion ata rate of 5 mg/m?/min, unless hypotension not responsive
`to fluid challenge (systolic blood pressure < 80 mm Hg) occurred,
`at which time the dose rate was reduced to 2.5 mg/m?/min.If hy-
`potension persisted, dopamine was begun andtitered to maintain a
`systolic blood pressure greater than 80 mm Hg. Ifpatients were more
`than 20% over ideal body weight, the administered doses of CPA/
`cDDP/BCNU in the high-dose portion ofthis program were calculated
`from the average ofthe surface areas based on actual and ideal body
`weight.
`Wehavepreviously reported that high-dose CPA/cDDP/BCNU
`induces a functional platelet defect, which is partially corrected by
`transfusion ofallogeneic platelets.'’ All patients were therefore trans-
`fused twice with single-donor pheresed platelets 24 hours after com-
`pletion ofchemotherapy (day — 2), regardless ofthe measured platelet
`count. Throughout the remainder of the treatment course, single-
`donorplatelets were administered to maintaina platelet count greater
`than 25,000/nL if possible.
`Daily cultures were performed for bacterial or fungal infection if
`a patients temperature was greater than 38.3°C not associated with
`blood products or amphotericin B administration. Febrile, neutro-
`penic patients were empirically treated with a standardized antibiotic
`protocol, which included, if indicated, empiric antifungal therapy;
`these patients continued to receive antibiotics until the granulocyte
`count was greater than 500/uL.
`
`T™>0
`
`1™>0
`
`7?0
`
`nN?>O M&HMSDSEBH
`
`
`
`
`
`
`Fig 1. Schema for treatment. BM harvest, bone marrow harvest;
`PBPC harvest, CSF-primed PBPC harvest; ABMT, autologous bone
`marrow transplant; CSF, colony-stimulating factor; XRT, radiation
`therapy to chest wall and draining lymph node regions; TAM, ta-
`moxifen 10 mgorally twice daily for 5 years.
`
`third and fourth cycles of CAF, a bulk bone marrow harvest was
`obtained under general anesthesia from the posterior iliac crest and
`processed as described later. Cellular and cytokine support evolved
`during the protocol and, in addition to bone marrow, 65 patients
`had CSF-primedperipheral-blood progenitor cells (PBPC) collected
`after the fourth cycle of CAF. CSF-priming and collection of PBPC
`required 9 days, and a washoutperiod of 5 days was allowed to elapse
`before initiation of high-dose chemotherapy. Patients were then ad-
`mitted to the next available bed in the transplant unit and were cared
`for in private rooms with positive-pressure, high-efficiency particle
`filtration (HEPA) air systems. During the high-dose consolidation
`phase of treatment, access to patient rooms required masks, gloves,
`gowns, and shoe covers; a low-bacterial, low-fungal content diet was
`prescribed.
`All patients had a triple-lumencentral venous catheter placed for
`access within 3 weeksofbeginning high-dose chemotherapy.Per unit
`policy, patients were transfused until a hematocrit greater than 42%
`was reached; hematocrit was maintained atthis level until leukocyte
`andplatelet recovery. Before initiation ofthe high-dose chemotherapy,
`bladderirrigation was begun with 1 L/h urologic saline containing 2
`mLof neomycin and polymixin B. This was continued until 24 hours
`after the last dose of cyclophosphamide to minimize hemorrhagic
`cystitis. Aggressive hydration with 5% dextrose/0.45% saline supple-
`mented with electrolytes at 200 to 250 mL/m7/h was used, and urine
`output replaced on a milliliter-for-milliliter basis throughout che-
`motherapy.If urine output fell below 200 mL/h, additional hydration
`was provided. An average 13,375 mL offluid was administered to
`patients on a daily basis between day —6 and day —3. High-dose
`chemotherapy was always begun between 8 AM and noon.
`The high-dose chemotherapy program was cyclophosphamide
`(1,875 mg/m?/d) administered as a |-hour intravenous infusion on
`3 successive days (days —6, —5, and —4 from day of bone marrow
`
`Cellular Support
`Bone marrow. All patients treated with high-dose CPA/cDDP/
`BCNU received ABMS.Bone marrow was collected when the leukocyte
`count was greater than 3,000/u—approximately 28 days after the
`third cycle ofCAF. Marrow was collected as described previously from
`the posterioriliac crests under general or regional anesthesia." A buffy-
`coat concentrate was prepared using a Cobe 2991 cell washer (Cobe
`Industries, Lakewood, CO), mixed with 20% autologous plasma, 20%
`TC-199 (GIBCO, GrandIsland, NY), and 10% sterile, nonpyrogenic
`dimethylsulfoxide (Research Laboratories Corp, Midvale, UT); the
`concentrate was frozen using a controlled-rate program technique. No
`bone marrow purging technique was used. Marrow was stored in the
`liquid phase ofnitrogen until administration. Bone marrow was thawed
`rapidly at 37°C in a water bath and infused over 10 minutes without
`further processing through the central venous catheter. A mean 0.76
`+ 0.39 X 10* nucleated cells per kilogram patient weight was infused
`(range, 0.32 to 2.3 X 10° nucleated cells per kilogram patient weight)
`(Table 2). Approximately one half of the harvested bone marrow was
`retained as a backupin case ofgraft failure. Four patients with persistent
`thrombocytopenia received their backup bone marrow 56, 77, 222,
`
`Table 2. Cellular and CSF Support
`Bone Marrow
`PBPC infused*
`Infused*
`Bone
`Marrow
`PBPC
`No.of
`(nucleated
`{nucleated
`
`Administered
`Administered
`CSF
`Patients
`cells/10°/kg}
`cells/10°kg)
`Yes
`No
`G-CSF
`15
`0.68 + 0.17
`_
`Yes
`Yes
`G-CSF
`22
`0.81 + 0.36
`10.72 + 3.86
`Yes
`No
`GM-CSF
`5
`0.61 + 0.11
`_
`Yes
`Yes
`GM-CSF
`43
`0.69 + 0.24
`6.44 + 5.54
`
`0.76 + 0.39Total 7.65 + 5.47
`
`
`*Values are expressed os mean + SD.
`
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:68)(cid:86)(cid:70)(cid:82)(cid:83)(cid:88)(cid:69)(cid:86)(cid:17)(cid:82)(cid:85)(cid:74)(cid:3)(cid:69)(cid:92)(cid:3)(cid:53)(cid:72)(cid:83)(cid:85)(cid:76)(cid:81)(cid:87)(cid:86)(cid:3)(cid:39)(cid:72)(cid:86)(cid:78)(cid:3)(cid:82)(cid:81)(cid:3)(cid:49)(cid:82)(cid:89)(cid:72)(cid:80)(cid:69)(cid:72)(cid:85)(cid:3)(cid:21)(cid:20)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:26)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)(cid:21)(cid:20)(cid:25)(cid:17)(cid:20)(cid:27)(cid:24)(cid:17)(cid:20)(cid:24)(cid:25)(cid:17)(cid:19)(cid:21)(cid:27)
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`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`

`

`CHEMOTHERAPY WITH ABMS FOR BREAST CANCER
`
`1135
`
`and 739 days after the first infusion; each had less than 0.65 x 10°
`nucleated cells per kilogram patient weight infused during their first
`bone marrow infusion. Three of these four patients subsequently be-
`cameplatelet transfusion-independent.
`CSF-primed PBPC.
`In addition to bone marrow, 65 patients re-
`ceived CSF-primed PBPC. CSF-priming was begunafter the leukocyte
`count recovered to greater than 3,000/zL following the fourth cycle
`ofCAF and before high-dose chemotherapy." In the afternoon,patients
`received either granulocyte CSF ([G-CSF] filgrastim; Amgen, Inc,
`Thousand Oaks, CA) at 6 yg/kg/d subcutaneously for 8 days (22 pa-
`tients), G-macrophage CSF ([CHO-glycosylated GM-CSF] regramo-
`stim; Sandoz Pharmaceuticals, Nutley, NJ) at 8 ug/kg/d as a daily 4-
`hour intravenousinfusion for 8 days (eight patients) or 16 ug/kg/d as
`a daily 4-hourintravenous infusion for 8 days (four patients) or 14
`days (five patients), or GM-CSF ([Escherichia coli GM-CSF] mol-
`gramostim; Schering-Sandoz Pharmaceuticals, Nutley, NJ) at 10 yug/
`kg/d subcutaneously for 8 days (19 patients) or 10 yg/ke/d as a daily
`4-hour intravenous infusion for 8 days (seven patients). Significant
`differences between the type, dose, and schedule of GM-CSFused for
`primingin this study were not seen and they are analyzed togetherfor
`the purposes of this report. No other growth factors were used.
`All 65 CSF-primed patients were leukapheresed three times. Patients
`whoreceived 8 days of CSF-priming were leukapheresed the morning
`after the fifth, seventh, and eighth doses ofCSF; patients who received
`14 days of CSF-priming were leukapheresed the morning after the
`eleventh, thirteenth, and fourteenth doses. Each leukapheresis was per-
`formed via a central catheter using a Cobe Spectra (Cobe Industries)
`with an approximate processed volume of 9 L over 3 hours. A mono-
`nuclear-cell fraction ofapproximately 200 mL was collected with each
`pheresis. The total nucleated-cell collections for the three collections
`are shown in Table 2. The PBPC were mixed with 10% dimethyl sulf-
`oxide, controlled-rate cryopreserved at —1°C/min until —90°C, and
`then stored in the liquid phase of nitrogen until used.
`CSF-primed PBPC were intravenously administered via a central
`catheter. One third of the available CSF-primed PBPC were admin-
`istered on the day of bone marrow infusion (day +1) and for 2 sub-
`sequent days (days +2 and +3; eight patients) or, in the remaining
`57 patients,daily for 3 days beginning 2 days before marrow infusion
`(days —1, 0, and +1).
`CSF Administration. After high-dose chemotherapy, CSF ad-
`ministration was begun on the day of bone marrow infusion or on
`the first day ofprogenitor-cell infusion. All CSF-primed PBPC patients
`received either G-CSF 16 ng/ke/d as a daily 4-hour infusion for up
`to 21 days from marrow infusion (22 patients), or GM-CSF 10 xg
`protein by amino acid analysis per kilogram per day as a daily 4-
`hour infusion for 7 days, then reduced to 5 we/kg/d again for up to
`21 days following marrow infusion (43 patients). The same cytokine
`that was used to prime for progenitor-cell collection was used after
`cell infusion. Patients who received only bone marrow were given
`G-CSFat doses ranging from 5 to 80 zg/kg/d as a 14-day continuous
`intravenous infusion (seven patients), G-CSF at doses ranging from
`10 to 80 wg/ke/d as a daily 4-hour infusion for up to 21 days (eight
`patients), or GM-CSFat doses ranging from 5 to 20 yg/ke/d asa 14-
`or 21-day continuousintravenousinfusion (three patients) or a daily
`4-hourintravenousinfusion for up to 21 days (two patients).
`
`Radiation Therapy
`The protocol did not initially prescribe locoregional radiation
`therapy. However, after three of the first nine patients recurred in
`the surgical area, the protocol was amended to include locoregional
`radiation therapy following recovery from the high-dose chemother-
`
`apy and bone marrowtransplantation. Patients received 45 to 50 Gy
`to the chest wall and regional lymph nodes (internal mammary, su-
`praclavicular, + axillary) with a 10- to 15-Gyscar boost at 1.8 to 2.0
`Gyperfraction, in approximately 6 to 7 weeks, using standard ra-
`diation techniques.
`
`Tamoxifen
`Patients with hormonereceptor-positive tumors (measured estro-
`gen or progesterone receptor level > 7 fmol/mg protein) were pre-
`scribed tamoxifen 10 mg by mouth twice daily for 5 years.
`
`Evaluations Performed After Transplant
`Six weeks after high-dose chemotherapy, patients were fully eval-
`uated using the sametests as pretreatment except for bone marrow
`aspiration, biopsy, and bone scan. Patients were then monitored at
`6-weekintervals with physical examination, and at !2-weekintervals
`with computed tomography of the chest, abdomen, and pelvis for
`the first 2 years. Evaluationsafter 2 years were performed at 6-month
`intervals or more often as clinically indicated.
`
`Quality-of-Life Evaluation
`Between May 1991 and April 1992, 52 patients who were more
`than I year after high-dose chemotherapy were asked to complete a
`quality-of-life evaluation; 43 (83%) provided assessable information.
`Patients received mailed questionnaires, and data collection was
`completed with follow-up telephone interviews. The questionnaire
`consisted of the Functional Living Index-Cancer (FLIC)'® and the
`Symptom Distress Scale (SDS).”°
`
`Hospital Charges
`Actual hospital charges for all patients transplanted under this
`protocol were retrieved and analyzed. In this presentation, no dis-
`counting or other manipulation of the data was performed. There
`was no significant changein the cost structure ofcharges that occurred
`duringthe timeofthe study except for annual adjustments forinfla-
`tion. Charges presented do not include those related to harvesting of
`bone marrow (median, $6,276), harvesting of PBPC ($5,100), or
`physician costs (~ $8,500). Except for 11 of22 patients who received
`G-CSF-primed PBPC who werecharged for the CSF, the CSFs were
`provided free of cost.
`
`Comparison Populations
`
`Patient populations obtained for comparison were derived from
`the clinical trials of adjuvant chemotherapyin stage II breast cancer
`conducted by the CALGB during the past 17 years. Three trials had
`been performed and used for comparison:(1) CALGB 7581 compared
`schedules of cyclophosphamide, methotrexate, fluorouracil, vincris-
`tine, and prednisone (CMFVP) with or without immunotherapy.”!
`Postoperative radiation therapy was discouraged, but not prohibited.
`The available radiation treatment data indicate that 10 of the 104
`patients selected received radiation therapy, but this analysis is com-
`promised in that information is available on only 19% ofthe patients.
`(2) CALGB 8082 compared schedules of CMFVP with CMFVPfol-
`lowed byintensification with vinblastine, doxorubicin, thiotepa, and
`fluoxymesterone (VATH).” Noneofthese patients received radiation
`therapy. (3) CALGB 8541 compared three doses and schedules of
`CAF’; noneofthese patients received radiation therapy. To provide
`groups of patients comparable to eligible and assessable transplant
`patients, we selected patients who, at surgery, had 10 or more involved
`
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`Downloaded from ascopubs.org by Reprints Desk on November21, 2017 from 216.185.156.028
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`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`

`

`1136
`
`PETERS ET AL
`
`axillary lymph nodes, were age 56 years or younger, and did not
`relapse during the first 4 months of therapy. For protocol CALGB
`8541, only patients who received the exact same dose and schedule
`of CAF (“high-dose” CAF)as in the currenttrial were selected.
`
`Statistical Methods
`
`Kaplan-Meierestimates were determined from the dateofinitiation
`of study chemotherapy using statistical software developed at our
`institution. Nonparametric confidence limit intervals were calculated
`using previously described methods.” For the patients reported in
`this study, the calculation of time intervals is from the first day of
`chemotherapy with CAF. This date may be later by several days to
`1 week or more from theregistration date used in the CALGBstudies,
`since patients may be registered on study andreceivetheir first dose
`of chemotherapyslightly later. The last date of follow-up for patients
`in CALGBwasthe last confirmed clinic visit date or status confir-
`mation; for the current study, inquiry about the patient status eval-
`uation was performed May 1, 1992 andthisis usedasthelast follow-
`up date. Median follow-up time was calculated using the method
`reported by Korn.”4 Numerical data are reported as the mean + SD
`or median with range.
`
`have died; the Kaplan-Meier estimate of survival at 2.5
`years is 79% (95% confidence interval, 0.64 to 0.88). The
`Kaplan-Meier estimate of event-free survival (which in-
`cludesall local and systemic relapses andall therapy-re-
`lated mortality) at a median follow-up of 2.5 years is 72%
`(95% confidence interval, 0.56 to 0.82); no events have
`occurred after 28 months.
`Ten patients died of therapy-related complications.
`Refractory thrombocytopenia with complicating hem-
`orrhage andliver toxicity were the cause of death in one
`patient each, lung toxicity in two patients, and hemolytic-
`uremic syndromein three. Twopatients died of infection
`with Candida species complicating multiple organ failure
`despite amphotericin B therapy after full hematopoietic
`recovery, and onepatient died of cytomegalovirusinfec-
`tion.
`
`Treatment Conduct and Nonfatal, Treatment-Associated
`Toxicity
`
`RESULTS
`
`Eighty-five patients registered on this protocol were eli-
`gible and treated. The minimum follow-up duration for
`these patients is 16 months from theinitiation of che-
`motherapy, the maximum 5.2 years, and the median 2.5
`years. The median age is 38 years, with a range of 25 to
`56 y. Only three patients were older than 5O years (51,
`52, and 56 years). Table |
`lists the distribution of the
`patients by stage, number of lymph nodes involved with
`malignancy, and hormone-receptorcharacteristics. Sixty-
`four patients (75%) were stage IIA or IIB, and the median
`number of involved lymph nodes was 14 (range, 10 to
`39). Fifty-one patients (60%) were hormone receptor—
`positive.
`
`Treatment Results
`
`CAF-associated toxicity. CAF was generally welltol-
`erated. No patient required dose red