!6"CSP-HOR#$!6"CSP
HOR#$!1% &'()*+,-./012

34567QOL

N-SAS BC 02 (2001-)<89:;<89:;defgQhijklmUQnopQCSPOR, CSP-HOR, CSPOR(qrs)rq(rs)r , tuvw+gx17yzQ{|j}~jQttuvw+gx17yz {|j}~j tuj72 y0
2Q1z+y.

=> ?@A
Kojiro Shimozuma, MD, PhD
k-shimoz@sk.ritsumei.ac.jp@jBCSADEFGH+IJ

CSP-HOR KLMN$ OMNPQR STUMN$ MNPVWXBY ZW[Y% ZW\[Y[ ]\^_`ab,YcKuroi K, et al: Jap J Clin Oncol, 2008
Shimozuma K, et al: Support Care Cancer, 2009
Shiroiwa T, Shimozuma K, et al: Value in Health, 2011
Watanabe T, et al: 2011 SABCSgy, 2012
Ohsumi S,, et al: Oncology,
Shimozuma K, et al: Support Care Cancer, 2012

July 7, 2012@Tokyo Univ.
1Study Design&))

ACP

randommization

Doxorubicin 60 mg/m2
Cyclophosphamide 600 mg/m2

eligiblepatients
ti t

ACD

2

" Primary endpoint# Disease free survival (DFS)

Paclitaxel 175 mg/m2" Secondary endpoints
PTXDTX0369Docetaxel 75mg/m2# Recurrent free survival (RFS), Overall! Pts with breast-conserving
surgery received radiotherapy.
! Pts with hormone-receptorpositive BC received 20 mg
TAM or an AI for 5 years.

# CIPN (Chemotherapy-Induced Peripheral

12 15 18 21weeks
Watanabe T, et al

survival (OS)(OS),
Neuropathy),Nth ) HRQOL (Health-Related(H lth R l t d
Quality Of Life), Incidence and severity ofadverse
devents,t cost-effectivenesst ff ti4

2011 SABCSCIPN]^2o/89:;cj

CIPN7HRQOLj56¾¿
7 Q j56¾¿" # 22QQ¡¢Qyp¡¢ yp Q2£¤zg\^l2£¤zg\^l¥¦j!§l2o/567klj562¨©Tª/«7T¬E z¤/z¤/

Patient based
Patient-based

Physician based
Physician-based

PNQ*(Patient Neurotoxicity
Questionnaire)

NCI-CTC (Version 2.0)
(Neuro-sensory & Neuro-motor)

FACT/GOG Ntx**
FACT/GOG-Ntx**(Functional Assessment of Cancer
Therapy-Neurotoxicity)

PNEF***(Physician Neurotoxicity
Examination Form)" ­®
# r¯°)±²TU³j89:;j´µj¶·7Qr¯°)±²TU³j89:;j´µj¶·7klj¸¹®56jº»;+¼½./

* Hausheer, et al., Semin Oncol 2006, Shimozuma, et al., 2004 SABCSyCancer 2003**Calhoun,, et al.,, Int J Gynecol***Developed by Hausheer, et al
5Patient Neurotoxicity Questionnaire (PNQ)
Item
11.

Item
2.

$A

B

C

D*E*

I have nonumbness,pain, ortingling in
my hands orfeet.

I have mild
tingling, pain or
numbness in myhands or feet.
This does notinterfere with myactivities
activities.

I have moderate
tingling, pain or
numbness in myhands or feet.
This does notinterfere with myactivities of dailyliving.

I have moderate
to severe tingling,
pain or numbness
in my hands orfeet. This
interferes with myactivities of dailyliving.

I have severe
tingling, pain or
numbness in myhands or feet. It
completely
prevents me fromdoing mostactivities.

$

$

$

$

A

BCD*

I havehmild
ildweakness in myarms or legs.
This does not
i t finterferewith
ith myactivities.

$

HRQOL¾¿$

I have noweakness in
my arms orllegs$

I havehmoderatedI have
hmoderate
dtoweakness in mysevere weaknessarms or legs. This in my arms or legs.
does not interfere
This interferes
off my activities
ti iti off withith my activities
ti itidaily living.
of daily living.

6$$
E*I have severe
weakness in myarms or legs. It
completelyprevents me fromdoing mostactivities.

*Patients answering D or E provided additional information on specific Activities ofDaily Living (ADL’s) that were affected.
7" General HRQOL# FACT-G (Functional Assessment ofCancer Therapy)" Disease-specific HRQOL# FACT-Taxane (FACT/GOG-Ntx)" Utility index# EQ-5D8ÂÃÄj

FACT-GjÀÁ\^9Å56 ÆÇ ÈÉÃÂÃÊËÌ2Ã¤/01\^9Å56QÆÇQÈÉÃÂÃÊËÌ2Ã¤/01
ScaleItem1ÍÎjÈÂÃ ª0ÏjÈÉÃ +ÐÑ ÒÓ./1ÍÎjÈÂÃÌª0ÏjÈÉÃÌ+ÐÑQÒÓ./Physical Well-Being

PWB

1 to 7

Social/Family Well-Being

SWB

8 to 14

Emotional Well-Being

EWB

15 to 20

Functional Well-Being

FWB

21 to 27

– !"#$%&'QOL("#)*+,-./012– 34+56789:"#;<=– >,-012 Quality-Adjusted Life Years: QALY910

QALYjÐÑ

! # QH " L H

QALYs

H
H ?@ABC
QH?@ABCH+;Quality Weight(Full health=1,Dead=0*
LH?@ABCH+;012D@ABCH+;012D
1QALY?EFG@ABC+01H:1211ÔB ÕÖ×ØZoÏÙÃ34+56,78,9:;34+56,78,9;

CIPN+HRQOL,-./012

Taxanearms

Paclitaxel x 8
Docetaxel x 8

34
NCI-CTC-motor

01234A(0)

489

38000

B(1)

432

252

400C(2)

113

171

500

D(3)

44

66

1131E(4)9100056

Paclitaxel x 4
Docetaxel x 4

34
NCI-CTC-sensory

PNQ
Q-motorAC x 4
AC x 4

12 months

PNQ--sensory

AC ->Taxanearms

7 months

56

Baseline Cycle 3 Cycle 5 Cycle 712! "#$%&'()*

0123A(0)4925100B(1)70137200C(2)231

17300D(3)6210510E(4)90000

Kappa=0.16
pp

CIPN andd HRQOL assessmentst were obtained
bt i d att bbaseline,li
3rdd, 5th &7th cycle, and 7 and 12 months after starting adjuvant treatment.

4

Kappa=0.02
pp• PNQ scores distributed between A and E (full range), while NCI-CTC scores
mainlyi l di
distributedt ib t d betweenb t
0 andd1
1.
Shimozuma K, et al
Support Care Cancer, 200913

Shimozuma K, et al, Support Care Cancer 200914

Disease-free Survival (DFS)Overall Survival (OS)Summary of events (DFS)

90ACP

ACD

PTX

DTX

260

258

261

260

No. of pts

80

Hazard ratio (AC + a taxane as standard)

1.19

90.3% CI

1.00 - 1.41

p value

0.31

60
ACP
ACD
PTX
DTX

50
40

Hypothesis 2: Whether PTX or DTX is more effective
Hazard ratio (PTX as standard)

0.74

95.2% CI

0.60 - 0.91

p value0.0037

00

12

3

4

5

6

7

Time from randomization (year)
260
258
261
260

239
246
239
237

220
225
203
218

197
205
178
201

184
186
162
187

150
156
134
165

10511794114

Comparison of four arms (DFS<64674570

patients at risk
1009080706050AC Taxane
TaxaneHR1.19 (90.3%CI:1.00-1.41)

40

Hazard ratio
95= CI

Percennt Probability

Percennt Probability

ACP
ACD
PTX
DTX

100

Summary of events (OS)Hypothesis 1: A taxane alone is not inferior to AC + a taxane

70

ACP

ACD

PTX

DTX

reference

0.89
0.66-1.20

1.40
1.06-1.84

0.86
0.64-1.17

AC Taxane 518
Taxane 521

12485
476

445
421

70
6050

ACP
ACD
PTX
DTX

400ACP
ACD
PTX
DTX

50

ACD+DTX
ACP+PTX
HR0.74 (95.2%CI:0.60-0.91)

56

70402
379

370
349

306
297

222
208

131
115

DTX 518
PTX 521

12483
478

443
423

34

56

406
375

373
346

319
284

231
199

Time from randomization (year)

7PTX

DTX

263

263

261

12

262
263
263
261

256
258
259
258

248
250
248
248

Hazard ratio(AC + a taxaneas standard)

1.06

90.3% CI

0.83 - 1.36

p value

0.14

3

4

5

6

7

235
241
229
239

222
226
214
230

187
195
183
202

139
151
130
144

84
88
7091

Hazard ratio(PTX asstandard))

0.73

95.2% CI

0.54 - 0.98

p value

0.035

patients
ti t att risk
i k137109

patients at risk

Watanabe T, et al

ACD

262

Hypothesis 2:
Whether PTX or DTX is more effective

Time from randomization (year)

70
60

ACP

Hypothesis 1:
A taxane alone is not inferior to AC + a taxane

80

4patients at risk

80

90

3

Time from randomization (year)

No. of pts

00090

100

400Perrcent Probability

Percent Probability
P100

2011 SABCSWatanabe T, et al2011 SABCSShimozuma K, et al
Support Care Cancer, 2012

FACT-G scores

Baseline

Cycle 3

Cycle 5

Cycle 77 Months

1 Year67(0.9)64(0.8)65(0.8)67(1.0)60(0.7)64(0.7)63(0.8)66(1.0)58(0.9)53(0.6)57(0.8)56(0.9)FACT-G Scoore

Q Motor ScoreePNQ

PNQ Sensory Scoore

PNQ scores

Baseline

No. of patients(Standard Deviation)

72(0.9)69
ACD (0.7)
70
PTX (0.9)69
DTX (0.7)
ACP

69(0.6)70(0.8)70(0.9)70(0.9)Cycle 3

Cycle 5

Cycle 77 Months

1 Year66(0.9)61(0.8)61(0.9)63(1.0)56(0.8)60(0.8)59(0.8)62(0.9)56(0.8)52(0.6)52(0.6)54(0.9)No. of patients(Standard Deviation)

68(1.1)66(0.8)67(0.8)72(1.0)

ACP
ACD
PTX
DTX

69(0.8)69(0.6)69(0.9)68(0.8)68(0.6)68(0.6)70(1.0)
69(0.8)66(1.0)
63(0.8)62(0.9)70(1.0)

Shimozuma K, et al
Support Care Cancer, 2012

Baseline
No. of patients(Standard Deviation)
72(15.1)

Cycle
y3

Cycle
y5Cycley77 Months

70(14.2)

68(16.7)

67(16.4)

60(14.5)

58(15.8)

ACD

71(13.9)(139)

71(16.1)(161)

66(15.5)(155)

64(15.4)(154)

65(13.8)(138)

55(13.4)
(134)

PTX

72
(15.5)
69(14.2)

71(14.3)
71(13.3)

68(15.2)
73(15.2)

66(14.6)
67(15.3)

63(14.8)
68(13.0)

56(14.3)
58(14.2)18

ACP

17DTX

1 Year

EQ-5D scores

Ntx Subsca
ale Score

FACT/GOG-Ntx subscale scores

Shimozuma K, et al
Support Care Cancer,Cancer 2012
Shiroiwa T, et all Value in Health, 2011
Baseline
No. of patients(Standard Deviation)
74(1.7)

Cycle
y3

Cycle
y5

Cycle
y7

7 Months

1 Year70(2.1)69(6.2)67(6.6)60(6.5)58(4.3)ACD

72(2.3)(23)

72(3.6)(36)

67(4.1)(41)

65(5.5)(55)

65(5.9)(59)

56(4.4)(44)

PTX

75(4.1)72(2.2)70(5.8)71(4.7)66(6.2)73(6.7)66(5.9)67(6.3)64(6.1)68(6.9)56(4.8)58(5.2) 19ACP

DTX

20?+@AB<?+@A<CDEFGH,'IJ3K6LMNOPQRST,UVPWRXYZ56,[\]J^_`APatientreported outcome: PRO<,78aZ3Kbcd,7
8++aPefgWh*ijkl+LmngPJopq

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rstuvwKxPyz{K+OX|*}~k180,{KxY  ,AC40!
180,{KxYZ140+OXZCDEFSGHY
Ra,, 1uPYO gW {KYRa,,Z1uPYOZgWZ{KY
QOLhP}JRZS,R{Kxijkl+LmngPJopq
jkl+LmngPJop21

22