Supplement 1. eAppendix. List of collaborators

Supplementary Online Content
Foukakis T, von Minckwitz G, Bengtsson N-O, et al; Swedish Breast Cancer
Group (SweBCG); German Breast Group (GBG); Austrian Breast & Colorectal
Cancer Study Group (ABCSG). Effect of tailored dose-dense chemotherapy vs
standard 3-weekly adjuvant chemotherapy on recurrence-free survival among
women with high-risk early breast cancer: a randomized clinical trial. JAMA.
doi:10.1001/jama.2016.15865
eAppendix. List of collaborators
eTable 1. Treatment dose levels of tddEC (mg/m2)
eTable 2. Dose levels of tailored dose-dense docetaxel
eTable 3. Dose-modification schedule for tailored dose-dense treatment based
on the observed hematological toxicity
eTable 4. Cumulative doses of study treatments in mg/m2
eTable 5. Summary of all events reported in the trial
eTable 6. Secondary (non-breast) cancers diagnosed during follow-up
eTable 7. Health-related quality of life scores using the EORTC QLQ-C30 and
EORTC QLQ-BR23 instruments measured at baseline and at the end of
treatment
eFigure 1. Cumulative incidence of all events over time, including contralateral
breast cancer (CLCA), loco-regional recurrence (LRR), distant recurrence (DM),
secondary malignancy (SECA) or intercurrent death (ID)
eFigure 2. Health-related quality of life according to treatment group
This supplementary material has been provided by the authors to give readers
additional information about their work.
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eAppendix.Listofcollaborators
TheSwedishBreastCancerGroup(SweBCG)membersincludeNiklasLohman,
Skånesuniversitetssjukhus,Malmö;MartinSöderberg,Skånesuniversitetssjukhus,
Malmö;PerMalmström,Skånesuniversitetssjukhus,Lund;ZakariaEinbeigi,
SU/Sahlgrenska;PerKarlsson,SU/Sahlgrenska;BarbroLinderholm,
SU/Sahlgrenska;StigHolmberg,SU/Sahlgrenska;LottaDabrosin,
UniversitetssjukhusetLinköping;ElhamHedayati,UniversitetssjukhusetLinköping;
KennethVillman,UniversitetssjukhusetÖrebro;SamRotstein,Karolinska
universitetssjukhuset(DS);BirgittaWallberg,Karolinskauniversitetssjukhuset
(RH);TommyFornander,Karolinskauniversitetssjukhuset(SöS);HenrikLindman,
AkademiskasjukhusetUppsala;JohanAhlgren,SjukhusetiGävle;PerEdlund,
SjukhusetiGävle;LenaCarlsson,LänssjukhusetSundsvall;Nils‐OlofBengtsson,
Norrlandsuniversitetssjukhus;EvaKarlsson,CentralsjukhusetKarlstad.
TheGermanBreastGroup(GBG)membersincludeSabineSchmatloch,Elisabeth
Krankenhaus;MatthiasKögel,StadtkrankenhausWorms;AndreasKohls,Ev.
KrankenhausLudwigsfelde‐Teltow;Eva‐MariaGrischke,Universitätsfrauenklinik
Tübingen;GeroldBaake,OnkologischePraxisPinneberg;GeraldHoffmann,St.
Josefs‐Hospital;MariaDietrich,KlinikumFichtelgebirge;VolkerMöbus,Klinikum
FrankfurtHöchstGmbH;RalfAdrion,KlinikumamBruderwald,Bamberg;Volker
Heyl,AsklepiosPaulinenKlinik;BenjaminSchnappauf,KlinikumderJ.W.Goethe
Universität;ThomasGöhler,GemeinschaftspraxisDresden;GabrieleZiemendorff,
KlinikumLudwigsburg;IngoThalmann,KlinikumamSteinenberg;Claudia
Schumacher,St.Elisabeth‐KKH;Dr.ErichWeiss,KlinikumSindelfingen‐Böblingen/
KlinikenBöblingen;Dr.OliverTomé,St.VincentiusKlinikenKarlsruhe;Wolfgang
Bauer,KlinikumVillingen‐Schwenningen;AngelikaOber,St.VincenzKrankenhaus;
AndeasSchneeweiss,UniversitätHeidelberg;HGHöffkes,KlinikumFulda;Helmut
Forstbauer,GesellschaftfüronkologischeStudien,Troisdorf;Erich‐Franz
Solomayer,UniversitätsfrauenklinikHomburg;DorisAugustin,Klinikum
Deggendorf;HolgerSchultz,KlinikumBerlin‐Buch;BarmakAdhami,PraxisDr.
Adhami;MichaelNiedermeier,OnkologischePraxisMemmingen;HansUlrichUlmer,
StädtischesKlinikumKarlsruhe;AndreaHocke,UniversitätsfrauenklinikBonn;
ManfredKusche,MarienhospitalAachen;ReinhardHackenberg,Klinikum
Heilbronn;AndreasRossmann,KlinikumWeiden;TilmannLantzsch,Krankenhaus
St.ElisabethundSt.Barbara,Halle/Saale;JürgenSchulze‐Tollert,Kreiskrankenhaus
Freudenstadt;ChristophLerchenmüller,GemeinschaftspraxisMünster;Ekkehart
Ladda,PraxisamKlinikumNeumarkt;ElkeWierick,OnkologischeTagesklinik
Lohsa;HansWernerTessen,OnkologischeSchwerpunktpraxisGoslar;GerdRaudies,
KlinikumBietigheim;AlexandraSallmann,KlinikumRheinfelden;BerhardtMartin,
KlinikumTuttlingen;ChristophUleer,GemienschaftspraxisHildesheim;Kristina
MariaLübbe,HenriettenstiftungHannover;RicardoFelberbaum,Klinikum
Kempten;WolfgangWiest,St.VincenzundElisabeth‐HospitalMainz;MarcSütterlin,
UniversitätsfrauenklinikMannheim;ChristophThomssen,Universitätsfrauenklinik
Halle/Saale;Uwe‐JochenGöhring,JohanniterKrankenhausBonn;HansTesch,
OnkologischeGemeinschaftspraxisFrankfurt;AxelGatzweiler,KrankenhausSt.
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Joseph‐StiftDresden;WolfgangJanni,UniversitätsfrauenklinikUlm;Marcus
Schmidt,UniversitätsfrauenklinikMainz;AndeasWerner,DiakonissenKrankenhaus
Dresden;LeliaBauer,KlinikumWeinheim;AgustinusTulusan,KlinikumBayreuth;
Tjong‐WonPark,MedizinischeHochschuleHannover;MichaelBerghorn,
KrankernhausCelle;ThomasNoesselt,KlinikumHameln;StephanHenschen,
KlinikumSchwerin.
TheAustrianBreast&ColorectalCancerStudyGroup(ABCSG)membersinclude
HerbertStöger,MUG‐Med.Univ.‐KlinikGraz;ChristianMarth,MUI‐Univ.Klinikf.
FrauenheilkundeInnsbruck;AngelikaPichler,LKHLeoben;MichaelFridrik,AKH
Linz;VolkerÖmer,KHBHSLinz;AloisLang,LKHRankweil;RichardGreil,LKH
Salzburg/PMU;HaraldWeiß,KHBHBSt.Veit/Glan;JohannesAndel,LKHSteyr;
JosefThaler,KlinikumWels–GrieskirchenGmbH;ArikGalid,Brustzentrum
Hanusch‐KH;PaulSevelda,KHHietzingWien;ChristianSinger,MUW‐Med.Univ.‐
Klinikf.Frauenheilk.;GüntherSteger,MUW‐Med.Univ.‐Klinikf.Inn.Med.I;
ElisabethMelbinger‐Zeinitzer,LKHWolfsberg;JörgKeckstein,LKHVillach;Felix
Keil,LKHLeoben;ChristophTinchon,LKHLeoben;ErnstKubista,MUW‐Med.
Univ.‐Klinikf.Frauenheilk.;MichaelStierer,BrustzentrumHanusch‐KH;HansJörg
Neumann,KHBHBSt.Veit/Glan;ThomasBauernhofer,LKHLeoben;Gertraud
Tschurtschenthaler,KHBHSLinz;HellmutSamonigg,MUG‐Med.Univ.‐KlinikGraz.
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eTable 1. Treatment dose levels of tddEC (mg/m2)
Dose levela
Epirubicin
Cyclophosphamide
38
60
75
90
105
120
450
600
600
600
900
1200
Step-3
Step-2
Step-1
Step 1 (starting dose)
Step 2
Step 3
Mesna
240 x 3b
a
Starting dose step was the protocol recommended level for the first course of
chemotherapy. If a dose reduction was indicated according to the dose modification
schedule (eTable 3) or other reasons, doses below the starting level were used (designated
as negative to indicate the lower dose level).
b
Hours 0, 4, 8 after cyclophosphamide if administered intravenously, hours 0, 2, 6 if
administered orally. Abbreviations: tddEC, tailored dose-dense epirubicin and
cyclophosphamide.
eTable 2. Dose levels of tailored dose-dense docetaxel
Dose levela
Dose (mg/m2)
-1
0 (starting dose)
1
2
60
75
85
100
a
Starting dose step was the protocol recommended level for the first course of
chemotherapy. If a dose reduction was indicated according to the dose modification
schedule (eTable 3) or other reasons, doses below the starting level were used (designated
as negative to indicate the lower dose level).
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eTable 3. Dose-modification schedule for tailored dose-dense treatment based on the observed hematological toxicitya
Nadir day: 8 or 11/12 Day 8 or 11/12
(except nadir
value)
WBC
Platelets
Day 14/15
Action
Platelets WBC
Platelets
WBC
>1.0
>50
and
≥1.5
≥75
and
≥3.0
and
≥100
Dose escalation. Continue to next step
≤1.0
≤50
and/or
<1.5
<75
and
≥ 3.0
and
≥100
Repeat same step for next cycle
Any
≤15
and/or
Any
Any
and
≥3.0
and
≥100
Reduce 1 step
>1.0
>50
and
≥1.5
≥75
and 2.5-2.9
and
≥100
Repeat same step for next cycle
Any
Any
and
Any
Any
and 2.0-2.9
and/or
75-99
Reduce 2 steps; if tolerated then escalate according to
schedule
Any
Any
and
Any
Any
and
and/or
<75
Delay cycle by 1 week; reduce dose by 2 steps when
normal values return
<2.0
a
Epirubicin and cyclophosphamide (cycle 1-4) or docetaxel (cycle 5-8). All values are in 109 cells/ L. Abbreviations: WBC, white
blood cells count. In addition to hematological toxicity, dose reduction with one step was recommended after occurrence of diarrhea
grade ≥3 or stomatitis grade ≥3. Dose reduction by one or two steps was recommended, after uncomplicated or life-threatening
neutropenic fever respectively. For patients with fatigue grade 2 or more during treatment with docetaxel, it was considered not to
escalate further, with re-evaluation at each course.
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eTable 4. Cumulative doses of study treatments in mg/m2
Tailored dose-dense group
Control group
Epirubicin Cyclophosphamide Docetaxel
Fluorouracil Epirubicin Cyclophosphamide Docetaxel
Mean
396.5
Q1
388.4
Median
405.8
Q3
433.5
3296
318.6
3000
3306
3892
299.4
334.7
359.5
1487.1
1497.1
1500
1510.3
Abbreviations: Q1, first quartile; Q3, third quartile.
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296.3
1484.3
298.9
300
300
285.5
1497
1500
1500
291.8
300
300
eTable 5. Summary of all events reported in the trial
No. of patients with events
Treatment group
Type of event
tddEC-D
FEC-D
All events
Contralateral cancera
Loco-regional recurrence
Distant recurrence
New cancer, nonbreast
BC death
Non-BC death
First events
Contralateral cancera
Loco-regional recurrence
Distant recurrence
New cancer, nonbreast
Death
Study end points
Primary, BCRFS
Secondary 1, DDFS
Secondary 2, EFS
Secondary 3, OS
7
27
101
18
68
14
9
47
126
19
88
16
4
22
91
16
6
16
74
227
37
156
30
7
34
111
19
11
118
110
139
82
Total
11
56
202
35
17
151
134
182
104
269
244
321
186
Abbreviations: tddEC-D, tailored dose-dense epirubicin and cyclophosphamide followed
by docetaxel; FEC-D,standard fluorouracil, epirubicin and cyclophosphamide followed
by standard docetaxel; BC,breast cancer; BCRFS, breast cancer relapse free survival;
DDFS, distant disease free survival; EFS, event-free survival; OS, overall survival.
a
Including 4 events of ductal cancer in situ, 3 in the tddEC-D group and 1 in the FEC-D
group.
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eTable 6. Secondary (non-breast) cancers diagnosed during follow-up
No. of patients with events per treatment group
Diagnosis
AML/MDS
Gastric adenocarcinoma
Pancreatic adenocarcinoma
Rectal adenocarcinoma
Gynaecological cancer
Glioma
Lung cancer
Lymphoma
Malignant phyllodes tumour
Salivary gland cancer
Skin cancer incl. Melanoma
Thyroid cancer
Total
tddEC-D
FEC-D
3
3
1
0
3
2
2
0
1
1
2
0
18
2
1
3
2
2
0
2
1
0
0
4
2
19
Abbreviations: tddEC-D, tailored dose-dense epirubicin and cyclophosphamide followed
by docetaxel; FEC-D, standard fluorouracil, epirubicin and cyclophosphamide followed
by standard docetaxel; AML/MDS, acute myeloid leukemia / myelodysplastic syndrome.
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eTable 7. Health-related quality of life scores using the EORTC QLQ-C30 and EORTC QLQ-BR23
instruments measured at baseline and at the end of treatment
Instrument and scales
EORTC QLQ-C30
Global health status*
Physical functioning*
Role functioning*
Emotional functioning*
Cognitive functioning*
Social functioning*
Fatigue
Nausea and vomiting
Pain
Dyspnea
Insomnia
Appetite loss
Constipation
Diarrhea
Financial difficulties
EORTC QLQ-BR23
Body image*
Sexual functioning*
Sexual enjoyment*
Future perspective*
Systemic therapy side
effects
Breast symptoms
Arm symptoms
Upset by hair loss
Baseline scorea
Mean (95% CI)
tddEC-D
FEC-D
(N=800)
(N=829)
End of treatment scorea
Mean (95% CI)
tddEC-D
FEC-D
(N=686)
(N=733)
Mean
Differenceb
(95% CI)
Pc
68 (67-70)
88 (87-89)
64 (62-66)
66 (65-68)
85 (83-86)
75 (73-77)
27 (26-29)
3 (3-4)
25 (23-27)
12 (11-14)
31 (29-33)
9 (8-11)
6 (5-7)
6 (5-7)
20 (18-22)
68 (66-69)
89 (88-90)
65 (63-67)
66 (65-68)
86 (85-87)
73 (71-75)
26 (25-28)
3 (3-4)
25 (24-27)
12 (10-13)
30 (28-32)
10 (9-12)
7 (6-8)
5 (4-5)
20 (18-22)
44 (42-46)
63 (62-65)
38 (35-40)
63 (61-65)
69 (67-71)
52 (50-54)
61 (59-63)
8 (7-10)
42 (40-45)
49 (46-51)
46 (44-49)
32 (30-35)
17 (15-19)
21 (19-23)
26 (24-29)
56 (55-58)
73 (72-74)
52 (50-54)
67 (65-68)
74 (73-76)
62 (60-64)
49 (47-51)
6 (5-7)
29 (27-31)
39 (37-41)
39 (37-42)
21 (19-23)
16 (14-18)
15 (13-17)
26 (24-28)
-13 (-15 to -10)
-9 (-11 to -7)
-14 (-17 to -11)
-4 (-6 to -2)
-5 (-7 to -2)
-12 (-14 to -9)
12 (9 to 5)
2 (1 to 4)
14 (11 to 17)
10 (7 to 13)
6 (3 to 9)
12 (9 to 15)
1 (-2 to 4)
6 (3 to 9)
1 (-2 to 3)
<0.001
<0.001
<0.001
0.001
0.001
<0.001
<0.001
0.004
<0.001
<0.001
<0.001
<0.001
0.500
<0.001
0.623
78 (77-80)
29 (27-31)
68 (65-71)
42 (40-45)
11 (10-12)
79 (77-80)
30 (28-32)
67 (64-69)
42 (40-44)
11 (10-12)
59 (57-61)
15 (13-16)
53 (49-56)
49 (47-52)
55 (53-56)
62 (60-64)
19 (17-21)
57 (53-60)
48 (46-51)
44 (43-46)
-2 (-5 to 1)
-5 (-7 to -3)
-4 (-9 to 1)
0 (-3 to 3)
11 (9 to 13)
0.122
<0.001
0.098
0.765
<0.001
25 (24-27)
28 (27-30)
3 (2-4)
26 (25-28)
28 (27-30)
3 (2-4)
14 (13-15)
19 (17-20)
37 (34-40)
16 (14-17)
20 (19-22)
33 (30-36)
-1 (-3 to 1)
-1 (-3 to 1)
4 (-1 to 8)
0.191
0.329
0.091
a
The range of possible scores is between 0 and 100 for all measures. A high score on functional
scales (marked with an asterisk) indicates a high level of functioning, and a high score on
symptom scales indicates a high level of symptoms.
b
Mean difference between groups at end of treatment controlling for country, hormone receptor
status and baseline values. Differences in scores between 5-9 points are considered as small and
between 10-19 as moderate.
c
by Wald tests. Abbreviations: tddEC-D, tailored dose-dense epirubicin and cyclophosphamide
followed by docetaxel; FEC-D, standard fluorouracil, epirubicin and cyclophosphamide followed
by standard docetaxel.
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eFigure 1. Cumulative incidence of all events over time, including contralateral breast cancer
(CLCA), loco-regional recurrence (LRR), distant recurrence (DM), secondary malignancy (SECA)
or intercurrent death (ID)
tddEC-D
20%
15%
10%
5%
0
0
1
No. at risk
1002 960
2
3
91 0
850
4
5
6
7
759
486
218
87
Year
ID
SECA
25%
Cumulative incidence
25%
20%
15%
10%
5%
0
0
1
No. at risk
1001
957
DM
2
9 12
3
4
Year
5
6
7
870
781
514
219
82
LRR
Cumulative incidence
FEC-D
CLCA
Abbreviations: tddEC-D, tailored dose-dense epirubicin and cyclophosphamide followed
by docetaxel; FEC-D, standard fluorouracil, epirubicin and cyclophosphamide followed
by standard docetaxel.
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eFigure 2. Health-related quality of life according to treatment group
A. Mean difference (tddEC-D vs FEC-D) at baseline
B. Mean difference (tddEC-D vs FEC-D) at end of treatment
Scale
Difference
(95%CI)
P-value
Scale
(95%CI)
Global health status*
Physical functioning*
Role functioning*
Emotional functioning*
Cognitive functioning*
Social functioning*
Fatigue
Nausea vomiting
Pain
Dyspnoea
Insomnia
Appetite loss
Constipation
Diarrhoea
Finacial difficulties
Body image*
Sexual functioning*
Sexua enjoyment*
Future perspectice*
Systemic therapy side ef fects
Breast symptoms
Arm symptoms
Upset by hair loss
1 (-1 to 3)
-1 (-2 to 0)
-1 (-4 to 2)
0 (-2 to 2)
-2 (-3 to 0)
2 (-1 to 4)
1 (-1 to 3)
0 (-1 to 1)
-1 (-3 to 2)
1 (-1 to 3)
1 (-2 to 4)
-1 (-3 to 1)
-1 (-2 to 1)
1 (0 to 3)
0 (-3 to 3)
0 (-3 to 2)
-1 (-3 to 2)
1 (-3 to 5)
0 (-3 to 3)
0 (-1 to 2)
-1 (-3 to 1)
0 (-2 to 2)
0 (-1 to 1)
0.484
0.152
0.577
0.970
0.116
0.229
0.357
0.981
0.681
0.453
0.701
0.298
0.412
0.049
0.924
0.914
0.599
0.533
0.880
0.643
0.377
0.846
0.923
Global health status*
Physical functioning*
-13 (-15 to -10) 0.000
-9 (-11 to -7)
0.000
-14 (-17 to -11) 0.000
-20
-15
-10
-5
0
FEC-D higher score
5
10
15
20
tddEC-D higher score
Difference
Role functioning*
Emotional functioning*
Cognitive functioning*
Social functioning*
Fatigue
Nausea vomiting
Pain
Dyspnoea
Insomnia
Appetite loss
Constipation
Diarrhoea
-4 (-6 to -2)
-5 (-7 to -2)
-12 (-14 to -9)
12 (9 to 15)
0.001
0.001
0.000
0.000
2 (1 to 4)
14 (11 to 17)
10 (7 to 13)
0.004
0.000
0.000
6 (3 to 9)
12 (9 to 15)
1 (-2 to 4)
0.000
0.000
0.502
0.000
6 (3 to 9)
1 (-2 to 3)
Financial difficulties
Body image*
Sexual functioning*
-2 (-5 to 1)
-5 (-7 to -3)
-4 (-9 to 1)
Sexual enjoyment*
Arm symptoms
0 (-3 to 3)
11 (9 to 13)
-1 (-3 to 1)
-1 (-3 to 1)
Upset by hair loss
4 (-1 to 8)
Future perspective*
Systemic therapy side effects
Breast symptoms
-20
-15
-10
-5
FEC-D higher score
0
5
10
15
20
tddEC-D higher score
A total of 1629 patients participated in the health-related quality of life study (800 in the
experimental group and 829 in the control group). A. At baseline (800 in the
experimental group and 829 in the control group). B. At the end of treatment (686 in the
experimental group and 733 in the control group). Scales for EORTC QLQ-C30 are
above and for EORTC QLQ-BR23 below the horizontal gray line. A high score on
functional scales (marked with an asterisk) indicates a high level of functioning, and a
high score on symptom scales indicates a high level of symptoms. Differences in scores
between 5-9 points are considered as small and between 10-19 as moderate. The scores
for each scale are detailed in eTable 7. Abbreviations: tddEC-D, tailored dose-dense
epirubicin and cyclophosphamide followed by docetaxel; FEC-D, standard fluorouracil,
epirubicin and cyclophosphamide followed by standard docetaxel.
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P-value
0.644
0.122
0.000
0.098
0.765
0.000
0.191
0.329
0.091

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