15/02/26 Division of Medical Oncology, Nippon Medical School Musashikosugi Hospital

15/02/26 Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

o

http://law.e-gov.go.jp/announce/H18HO098.html

2006

0 100 200 300 400 500 600 700 800 900

1000

47 126 205

306 451

586 716

867 954

- -

14,158 13

954 (1411)

1.27 1311

3.16 13

http://www.asco.org/sites/www.asco.org/files/workforce_information_system_01172014.pdf http://www.japan-senmon-i.jp/data/

http://quickfacts.census.gov/qfd/states/00000.html http://www.stat.go.jp/data/jinsui/new.htm

1/2.6

/14

?

()

120

15/02/26

20001012VAC7

648370

15/02/26

20050930

A

B

CQOL

D

62013

A

B

D

62013

CQOL

15/02/26 Division of Medical Oncology, Nippon Medical School Musashikosugi Hospital

1970

1980

1990

2000

1960

5-FU

15/02/26 Division of Medical Oncology, Nippon Medical School Musashikosugi Hospital

15/02/26 Department of Medical Oncology, Nippon Medical School Musashikosugi Hospital

Dose intensity (

QOL

0 5 10 15 20

20

40

60

80

100

0

CMF

Control 65% 6584% 85%

0 5 10 15 20

20

40

60

80

100

0

(n=179) (n=71) (n=94) (n=42)

Bonadonna G et al. N Engl J Med, 332 : 901-906, 1995

Division of Medical Oncology, Nippon Medical School Musashikosugi Hospital

Average dose intensity (DI) v MST

for ovarian chemotherapy regimens.

JCO 5:756-767, 1987

10

20

30

40

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

P P P

C C C C C

C C

C C

C C C

C C

C C

C

average DI

M S T

( m o

s . )

CHAP CAP CHA CH CA CP AP

r=0.44 (p 0.01)

1

22DPC

TC(+ 795 89 9.7 795 56 8.4 FEC 1214 41 7 1214 50 5 1214 39 7 1264 91 26 FOLFOX 1394 77 8.1 CDDP+S1 1399 75 5.6 TC 818 65 23.6

(CPA) (IFM) (L-PAM) (BU) (DTIC) (TMZ) (CDDP) (CBDCA) (L-OHP)

(MTX) (Alimta) (5-FU) (TS-1)

(Ara-C) (GEM) TAS102)

(ADM) (EPI) (IDR) (ACT-D) (BLM)

(VCR) (VDS) (VLB) (VNB) (PTX) (DTX)

(CPT-11) (VP-16)

Goldie-Coldman

Coldman AJ, Goldie JH.. Drug and hormone resistance in neoplasia. Boca raton, CRC. 1982:55.

Gompertzian KineticsNorton-Simon

11012

81011

61011

41011

21011

0

A

1012

1010

108

106

104

102

1

0 2 4 6 8 10 12 14 16 18 20

C

1012

1010

108

106

104

102

1

B

Norton L. Cytokinetics and breast cancer chemotherapy, Disease of the breast, Lippincott, 751, 1996

()

Clinical Disease

Clinical Disease

Clinical Disease

Goldie-Coldman (Combination therapy)

CODE (SCLC) MACOP-B (NHL) VAB-6 (Germ cell tumor)

Dose-intensive therapy Intensive chemotherapy with G-CSF High-dose chemotherapy

(Alternating therapy) CAV/PE (SCLC) ProMACE/CytaBOM (NHL) MOPP/ABVD (Hodgkins disease) EMA/CO (trophoblastic tumor)

10 2 10 4 10 6 10 8 10 10 10 12

0 2 4 6 8 10 12 14 16 18 20

Conventional chemotherapy

10 12 10 10 10 8 10 6 10 4 10 2

Dose-dense chemotherapy

0 2 4 6 8 10 12 14 16 18 20

Concept of Dose-density based on Norton-Simon model Larry Norton, The Oncologist 2001;6(suppl 3):30

Division of Medical Oncology, Nippon Medical School Musashikosugi Hospital

Norton-Simon

Colsolidation therapy High dose Ara-C (acute leukemia) BMT (hematologic malignancy)

Sequential therapy ADMCMF (Breast cancer) ACTaxol (Breast cancer)

Dose-dense therapy Weekly Taxol (Solid tumor)

Types of dose-dense chemotherapy

Conventional treatment

Dose-dense treatment nSame doses, same agents

nSimilar doses, different agents

nReduced doses, same agents

J Natl Cancer Inst 2010;102:1845

Dose-Dense Chemotherapy in Nonmetastatic Breast Cancer: A Meta-analysis of Randomized Controlled Trials

J Natl Cancer Inst 2010;102:1845

Linden 2007 0.90 (0.76 to 1.07) Untch 2009 0.66 (0.38 to 1.15) Moebus2003 0.65 (0.44 to 0.96) Therasse 2003 0.99 (0.76 to 1.29) Von Minckwitz 2003 0.79 (0.54 to 1.17) Kummel 2006 0.57 (0.30 to 1.10) Subtotal 0.85 (0.75 to 0.96)

All trials combined (95% CI) 0.85 (0.77 to 0.93)

Baldini 2003 0.87 (0.49 to 1.55) Citron2003 0.81 (0.66 to 1.00) Venturini 2005 0.88 (0.68 to 1.15) Subtotal 0.84 (0.72 to 0.98)

Trials with same doses, same agents

Favors dose-dense

chemotherapy

Favors conventional

chemotherapy

0.2 0.5 1.0 2.0 5.0

Trials with similar doses, different agents

Goldie-Coldmanvs. Norton-Simon Breast Cancer : 10 yr Disease-Free Survival

28%

42%

n=403 p=0.002

Dox : 75 mg/m CMF : 600/40/600 mg/m

Bonadonna et al: JAMA 1995;273:542-547

Goldie-Coldmanvs. Norton-Simon

(PSL) (TAM) (MPA)

DNA

RNA(Transfer Messenger Ribosomal)

DNADNA

RNA

L-Asp

MMC CDDP

CBDCA 254S PCZ

DNA Ara-C, GEM DNA

cTMP5-FU

cTMP

MTX

6-MP

HU

BLM VP-16

CPT-11

DTIC DNR ADM EPI MIT

TAM

EGF

Gefitinib

Tyrosinekinase

Rituximab Trastuzmab

CD20HER2

BCR-ABLc-kit

Tyrosinekinase

Imatinib

4

HER HER HER HER EGFR EGFR EGFR EGFR VEGF Multi target Multi target Multi target Multi target Multi target m-TOR m-TOR ALK ALK PDL1

TDM-1

GIST GIST

immune-checkpoint inhibitor PD-1programmed cell death-1

15/02/26 Division of Medical Oncology, Nippon Medical School Musashikosugi Hospital

Arch Dermatol Res (2014) 306:511519

Nivolumab2014

QOL

PS PS 2 PS 3

CD HER2, EGFR, ALK

AB

PS

PS (PS : performance status)ECOG (Eastern Cooperative Oncology Group)

0

1

2 50%

3 50%

4

PSPSPS0-2