??DFS

1
???????????

• ??????
• ???

2
????????
?????
??DFS
? ?
??????
?????
?????????????????????
3
CINV Compromises Quality of Daily Life
Mean changes in functional domain scores of
health-related quality of life after eight days
of chemotherapy
Group 1 (no nausea or vomiting) Group 2
(vomiting, no nausea) Group 3 (nausea, no
vomiting) Group 4 (nausea and vomiting)
10
Quality of Life Improved
5.3
5.3
4.9
5
1.9b
0.8
0.6f
0
0.5d
0.6
0.6
1.1c
1.1
2.6
Mean change in score
Quality of Life Diminished
5
3.8a
5.7
7.4g
8.4
8.8e
10
8.7
10
15
14.2
Physical
Emotional
Cognitive
Social
Global
20
Functional domain
Group 1 n166 Group 2 n30 Group 3 n157
Group 4 n332 aGroup 1 vs. Group 4, p0.007
bGroup 1 vs. Group 4, p0.0001 cGroup 3 vs.
Group 4, p0.0002 dGroup 3 vs. Group 4, p0.003
eGroup 1 vs. Group 4, p0.0001 fGroup 2 vs.
Group 4, p0.0005 gGroup 3 vs. Group 4,
p0.002 Adapted from Osoba D et al Support Care
Cancer 19975307313.
4
Need for Improved Control of CINV
Most distressing adverse effects of chemotherapy
before and during 5-HT3 receptor antagonist era

• 1983 1996 
• 1 Being sick (vomiting) Feeling sick (nausea)
• 2 Feeling sick (nausea) Loss of hair
• 3 Loss of hair Being sick (vomiting)
• 4 Thought of coming for treatment Constantly
  tired
• 5 Duration of treatment at the clinic Need for
  an injection
• 6 Need to get a needle Constipation
• 7 Shortness of breat
  Thought of coming for treatment
• 8 Constantly tired Affects family or partner
• 9 Difficulty sleeping Feeling low, miserable
  (depression)
• 10 Affects family or partner Feeling anxious or
  tense

Adapted from de Boer-Dennert M et al Br J Cancer
199776(8)10551061 Coates A et al Eur J
Cancer Clin Oncol 198319203208.
5
????????????????????????

• ?? ???
• ?? ??????????????
• ?????????
• ???????
• ????
• ??????

6
?????????

• ?? ????????????????
• CINV ?????????
• Chemotherapy induced nausea and vomiting
• RINV ?????????
• Radiation-Induced Nausea and Vomiting

7
CINV??

• ???? ???24h???
• ????? ???gt24h or ????
• ????? ??CINV??,?????????
• ????? ???????
• ????? CINV?????????

8
CINV??????
Gamma-aminobutyric acid. Diemunsch P, Grélot L
Drugs 200060533546. Grunberg SM, Hesketh PJ N
Engl J Med 199332917901796. Hornby PJ Am J
Physiol Gastrointest Liver Physiol
2001280G1055G1060.
9
??????????

• ???? ???????? ????????????
• ???????(Chemoreceptor triggerzone,CTZ)??????????,
  ??????
• ????
• ?????????
• ????(TC)????
• ???????,????
• ???????

10
????????????

• 5HT3??
• ?????????CTZ????
• ???? (neurokinin, NK) ??
• ????CTZ????
• (P?????????)
• ?????
• ????CTZ????

11
?????????

• 5HT ??CINV,RINV
• P?? ??????CINV
• ???? ???CINV
• ??? ??CINV

12
??????????
Sensory input Anxiety?fear memory
Vestibular System
Motion Labyrinth disorders
ACh H1
Intracerebral projections
?????
Vomiting Center
Chemoreceptor Trigger Zone
Chemotherapy
ACh H1 5HT3
D2 5HT3 NK1
????
Peripheral Pathways
5HT3 Chemo- receptors
Adapted from JAMA 2007298(10)1196-1207
13
CINV???????

• ???????????????
• ??
• ??????????
• ?????
• ?????
• ??
• ????
• ?? lt 50?
• ??????
• ?????
• ??

14
?????????
?50
70 40
15
??????

• 5-??????
• NK1 R???
• ??????
• ????(????????)
• ????(????)
• ?????

16
??????

• ????
• ?????(????)????
• ????(????,???)
• ????????????????????????
• ??????

17
???????????

• ??
• ??????????????????????????????????????
• ???????????????5-?????????5-HT3?????

18
5-HT3RA?????
????
??
19
5-HT3 RA???

• ???
• Ondansetron(???)-1984???,1991?????
• Tropisetron-??
• Granisetron-1988???,1991 ?1994??????????????
• Dolasetron-1997?????
• Ramosetron-???????
• ???
• Palonosetron-2003?

20
??5-HT3R??????
???????
?5HT??????
Rojas C, Anesth Analg,2008107469 478.
21
??5-HT3R??????
????? ?5-HT3R???pKi(-?Ki) ?? ??
???? 3-4h 8.39 8mg,3?/? ???
???? 7.3h 7.6 10mg/? ???
???? 8h / 5mg/? ???
???? 9h 8.91 3mg/? ???
???? 6h / 0.3mg/? ???
????? 40h 10.45 0.25mg ???
22
???5-HT3RA????????
?? ?? n ???? ?? ?? ??? ???
?? ?? n ???? ??() ??() ??() ??()
1995 Granisetron 137 ? 72.3 48.2 71.6 37.3
1996 dolasetron 403 ?? 42.2 / / /
1998 Ondansetron 184 ? 58 43 / /
1998 Granisetron 187 ? 51 35 / /
2003 dolasetron 191 ? 52.9 / 38.7 32
2004 ramosetron 134 ? 54 57 41 31.9
2006 Ondansetron 98 ?? / / 49.5 /
2006 Ondansetron 221 ? 57 / 38.9 /
N Engl J Med 19953321-5. J Clin Oncol
1996,142242-2249. Support Care
Cancer,2004,25863 Anti-Cancer Drugs 2006,
17217224 Annals of Oncology 2006,171441-1449,
Cancer 200398247382.
?????
23
???5-HT3RA ?????

• ???2?1?????(2.2.2)??3S???2,3,3aS,4,5,6????1
  H???de????1?????
• ????C19H24N2OHCL
• ???332.87
• ????????5-HT3?????

24
III????? ????? vs ?????? ?????????????

• Study Design
• Phase III randomized, multicenter, double-blind,
  active-controlled, stratified, parallel-arm trial
• Moderately emetogenic chemotherapy (single dose)
• Active comparator trial (n 563)
• Day 1
• Palonosetron 0.25 mg IV
• Palonosetron 0.75 mg IV
• Ondansetron 32 mg IV
• No corticosteroid administered prophylactically
• Patients were followed for 14 days for evaluation

Gralla R et al. Ann Oncol. 2003141570-1577.
25
????? vs ???? CINV Complete Response
Palonosetron 0.25 mg (n189) Palonosetron 0.75 mg
(n189) Ondansetron 32 mg (n185)
97.5 CIs and 2-sided Fishers exact test
(significance level 0.025) indicate a
difference between palonosetron and
ondansetron. Complete response (CR) no emesis,
no rescue medication.
Gralla R et al. Ann Oncol. 2003141570-1577.


26
?????/????vs????/??????III?????,?????0.75mg
Saito M,et al.Lancet Oncol. 2009,10(2)115-124.
27
?????????????????????????????????????????
?? ??
???111 ?????0.25mg
1??? 7???
???112 ???? 3mg
28
????
?????????? /????? 5ml
????
????? 3ml/ ?????????
20ml Iv 30???
?7?
??????
???? 12ml
??????????2?/? ??????????3mg
????5mg
29
??????
P0. 1420
P0.0282
P0.0140
???? CRR
?????CCR
0-7??? ????
2014?10?
29
30
??????

• ????????,????????0.5??????????????(??)??????168.00
  112.00(??)?168.00 140.00(??),????????(P0.0377)
  ,??????????????

??????(h) ????????(h)
??? 3.0 121.7864.87
??? 0.5 103.10 70.55
2014?10?
30
31
??????????????
??? ?? ?? ?? ?? ?? ?? ??? P
??? ?? 0 1 2 3 ?? ??? P
FAS ??? 49 35 20 7 111 0.860.93 0.0198
FAS ??? 35 33 37 7 112 1.140.94 0.0198
PPS ??? 46 34 20 7 107 0.890.93 0.0474
PPS ??? 32 31 33 6 102 1.130.93 0.0474
32
5-HT3RA???-?????????
??? ????? ???
????
?????
??? ?? ???
??????
????
33
palonosetron vs other 5-HT3RA Systematic review
and meta-analysis

• 4 ?????????, 1,298?
• ?????????????????????
• ??????????????????
• RR0.75 P 0.0004
• RR 0.73 P lt 0.00001
• ??????????????????
• RR 0.78 P 0.0008
• RR 0.75 P lt 0.00001
• ???????

J Clin Oncol 27, 2009 (suppl abstr e20620)
34
???????CINV?????????????
CDDP 20mg/m2 d1-4,VLB 1.6mg/m2 d1-4, dacarbazine
800mg/m2d1 IL-2 9 MIU/m2/d CIV d1-4,IFN alpha 5
MU/m2/d d1-5.
PALO d1,4 (n15) PALO d1,3,5 (n15)
??/??????? (7??) N 137 /V 70 N 85 / V 44
?????????(7??) 100 57
?????????(21?) 6.2 3.9
???????????(???) 41 31
???????????(???) 20 13
??????????(???) 31 20
????????????(???) 32 21
J Clin Oncol 27, 2009 (suppl abstr e20008)
35
5-HT3 RA???????
Saito M,et al.Lancet Oncol. 2009,10(2)115-124.
36
????????????????????????? CINV
D-1 D-2 D1 D2 D3 D4
??? ??? PAL 0.25 ?? 12mg APR 125mg ?? 4mg bid APR 80mg ?? 4mg bid APR 80mg ?? 4mg bid APR 80mg
??? 5mg ??? 5mg PAL 0.25 ?? 12mg ??? 10mg ?? 4mg bid ??? 10mg ?? 4mg bid ??? 10mg ?? 4mg bid ??? 10mg
?????CR? 75(OLN) vs. 44 ( APR) ?????CR?
62.5(OLN) vs. 55.6 (APR) ????????62.5(
OLN) vs. 44.2( APR) ????????62.5 (OLN )vs.
66.7 (APR)
J Clin Oncol,2715s, 2009 (suppl abstr 9633)
37
CINV???????
38
CINV???????
39
CINV???????
40
CINV???????
41
???????

• ???????????
• ?????????????????????4??????????????????
• ???????????????
• ??????
• ????????
• ????????????????????????????????

?????,????,???
42
CINV????

• ??
• ??????????
• ????????
• ????
• ??????
• ????

43
???????????????

• ?????????
• ??????
• ???
• ?????????,????,????
• ???
• ??????,????
• ????(?????)??????
• ????????,???

44
????????
???????????gt90
45
????????
???????????30 90
46
????????
???????????lt30
47
????????
???????????lt10
48
?????????????
?1? ?2? ?3?
?4?
125mg po 115mg iv
80mg po
80mg po
NK1?? ???
5-HT3 R ???
8-24/3/100/ 5/0.25mg
? ? ? ?
12mg
8mg
8mg
8mg
0.5-2mg q4-6h
0.5-2mg q4-6h
0.5-2mg q4-6h
? ? ? ?
0.5-2mg q4-6h
49
?????????????
?1? ?2? ?3?
125mg po 115mg iv
80mg po
80mg po
NK1?? ???
5-HT3 R ???
8-24/3/100/ 5/0.25mg
? ? ? ?
12mg
8mg
8mg
0.5-2mg q4-6h
0.5-2mg q4-6h
0.5-2mg q4-6h
? ? ? ?
50
?????????????

• ???? 12 mg /??
• ????10 mg q4-6 h?
• ?????20-40 mg PO q4-6h/1-2 mg/kg IV
  q3-4h????25-50 mg q4-6 h
• ????0.5-2 mg q4-6 h

51
????????
52
????????????

• ?????????????
• ?????
• ??????(??????)
• ????
• ????,?????????

53
????????????

• ????
• ?????????
• ????
• 5-HT3R
• ????
• ????/???
• ???
• ???

54
????