胃癌gastric cancer 鑑古知今from past to future

胃癌Gastric Cancer

鑑古知今From Past to Future

周政緯醫師血液腫瘤科

台中榮民總醫院

1

Outlines

• Introduction :Epidemiology, mortality rate, risk factor

• Diagnosis• Treatment: EMR, Surgery, Chemotherapy,target therapy..

• Chemotherapy and side effect

2

Gastric Cancer: A Global Disease Fourth most common malignant disease: ~ 930,000 cases/yr Second most common cause of cancer‐related death worldwide: ~ 700,000 deaths/yr Decreasing incidence of distal gastric cancer Increasing incidence of proximal gastric cancer Wide geographic variation

20/100,000

< 10/100,000 10 to 20/100,000

Incidence (Males)

Kamangar F, et al. J Clin Oncol. 2006;24:2137-2150. National Cancer Institute. 2010.4

The Incidence of Gastric Cancer is Highest in Asia and Eastern Europe

Parkin et al. CA Cancer J Clin 2005;55(2):74-108.

Age-standardized incidence (per 100,000)

60 40 20 0 20 40 60

Western AfricaNorthern Africa

MelanesiaSouth Central AsiaNorthern America

Eastern AfricaSoutern Africa

South-Eastern AsiaAustralia/New Zealand

Western AsiaNorthern EuropeWestern Europe

Middle AfricaCaribbean

Central AmericaMicro/Polynesia

Southern EuropeSouth America Eastern Europe

China Japan

Males Females

62.141.4

29.624.2

18.015.715.213.613.412.812.411.69.9

8.58.27.47.46.96.34.43.4

26.119.2

12.812.2

8.78.3

10.86.7

12.66.65.96.4

4.24.5

3.75.5

3.43.64.6

2.53.6

5

Standardized Death Rate of Top 10 Cancer in Taiwan 2013

Lung Ca, 25.3%

Hepatic Ca, 24.2%

Colorectal Ca, 14.9%

Breast Ca, 11.6%

Oral Cavity Ca, 8.2%

Prostate Ca, 6.6%

Gastric Ca, 6.2%

Pancreatic Ca, 5.2%

Esophageal Ca, 5.0%

Cervical Ca, 4.0%

Annual Report on the Cause of Death Statistics 2013

7th

6

Gastric Cancer Mortality Rate in Taiwan

18791942

2044

2519

2360 23742446 2443

23492500 2490

23982474

2292 2282 2261 22882386

224110.5

10 10

11.7

10.7 10.7 10.9 10.810.4

11 1110.5

10.8

10 9.9 9.8 9.910.3

9.6

0

1

2

3

4

5

6

7

8

9

10

11

12

13

0

500

1000

1500

2000

2500

3000

1981 1986 1991 1996 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

台灣歷年胃癌死亡人數、死亡率

死亡人數(人) 死亡率(每十萬人口)

Ref: Annual Report on the Cause of Death Statistics 2013

The number of deathMortality rate

7

病理臨床

分期申報數 % 申報數 %

I 643 20.9 745 24.3

II 456 14.8 622 20.3

III 718 23.4 562 18.34

IV 410 13.4 798 26.0

unknown 810 26.4 319 10.4

Cancer Registry 2012

胃癌病患期別胃癌病患分期-臺灣

8

Overall Survival

Data from Mount Sinai Hospital 9

Risk factor of Gastric Cancer

10

Symptoms of Gastric Cancer

11

Diagnostic and staging steps

From http://www.doctortipster.com

12

Treatment for Gastric Cancer

Endoscopic mucosal resection(EMR) Surgery :

• Primary tumor • LN dissection

Chemotherapy Radiotherapy Target Therapy

13

EUS ( Endoscopic ultrasound)Tis /T1 : Endoscopic mucosal resection

14

From John Hopkis’s Medicine web site

Endoscopic mucosal resection

15

taken from Cancer Research UK's

Partial Gastrectomy (Bilroth 2)

16

oesophagogastrectomy.

17

Total Gastrectomy Roux‐en‐y surgery

18

D1

20

D2

22

Figure 1. The type of gastrectomy and the extent of the D2 dissection were determined by the tumour location.

Chen S, Zhao BW, Li YF, Feng XY, Sun XW, et al. (2012) The Prognostic Value of Harvested Lymph Nodes and the Metastatic Lymph Node Ratio for Gastric Cancer Patients: Results of a Study of 1,101 Patients. PLoS ONE 7(11): e49424. doi:10.1371/journal.pone.0049424http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0049424

D2

23

NCCN 2016:D2A pancreas‐ and spleen‐preserving D2

1. Degiuli M et.al.. Br J Surg. 2010 May. 97(5):643‐9

D1 D2Complication rate 12% 17.9%Post‐op mortality rate 3% 2.2%

D2 Vs. D1 LN dissection

P without statistical significance 1

24

Surgical treatment of gastric cancer: 15‐year follow‐up results of the randomized nationwide Dutch D1D2 trial

Death due to Gastric cancer

D1

D2

N = 1078

Lancet Oncol 201025

Chew‐Wun Wu , Lancet Oncol 2006; 7: 309–15

In Taiwan , single institute . D1 vs. D3

26

JAMA. 2010;303(17):1729‐1737

The GASTRIC Group

27

About ChemotherapyRadiotherapy

28

Gastric Cancer – Adjuvant Chemotherapy

JAMA. 2010;303:1729‐1737

17 randomized clinical trials 6% improvement in 5‐year overall survival (55.3% vs 49.6%) maintained at 10 years.

5FU‐based

30

Rafael Diaz‐Nieto . 2013 The Cochrane Collaboration

The Benefit of Adjuvant Chemotherapy

31

Treatment in Early‐stage Gastric Cancer

ACTS‐GCJCO 2011

INT016 NEJM 2001CALGB80101 JCO 2011

ARTIS JCO 2015

32

Gastric cancer – adjuvant • phase III CLASSIC study• randomized 1035 patients

• stage II‐IIIB gastric cancer (D2 )

• South Korea, Taiwan, and China

• capecitabine plus oxaliplatin (n = 520) or no chemotherapy (n = 515).

• ACTS‐GC• 1059 patients

• stage II or III (D2 )

• Japan

• S‐1 for 1 year

• Subgroup: stage II > more benefit

3‐yr DFS: 74% vs. 59%3‐yr OS: 83% vs.78%

Lancet. 2012;379:315‐321 N Engl J Med. 2007;357:1810‐1820.

3‐yr DFS: 72.2% vs.59.6%3‐yr OS: 80.1% vs.70.1%

33

The Adjuvant Chemotherapy Trial of S‐1 for Gastric Cancer (ACTS‐GC)

Courtesy from 陳仁熙醫師 34

ACTS‐GC : 5 yrs F/U

5‐years OS : S‐1 71.7% vs. Surgery only 61.1%

Mitsuru Sasako. JCO 201136

5‐ years Results of S‐1 Adjuvant Therapy in Gastric Caner

37

Courtesy from 陳仁熙醫師 38

CLASSIC Study Design Korea, China, Taiwan

41

42

CLASSIC study : 5‐years DFS

Chemotherapy: 68%Surgery only: 53%

Phase III ARTIST trial (Korea) : (D2)

Jeeyun Lee JCO 2012 44

But , metastatic gastric cancer is another story…

45

XPFP

10.5Mo9.3Mo

Kang YK. Ann Oncol.2009

ECFEOX

9.9 Mo

11.2 MoCunningham D N Engl J Med. 2008

9.2 Mo8.6Mo

DCFCF

Van Cutsem E. J Clin Oncol. 2006

OS in 1st‐line chemotherapy

5.6Mo5.0Mo

6.7Mo7.0Mo

5.6Mo3.7Mo

ECXFOLFIRI

9.5 Mo9.7 Mo

Guimbaud R. J Clin Oncol 20145.3Mo5.8Mo

BSC Murad. Cancer 1993;72(1):37‐41

3 Mo

46

2nd –line Therapy for Metastatic Gastric Cancer: Single Agent Chemotherapy

Clinical trials showing benefit

Docetaxel 60mg/m2, N= 202aIrinotecan 250‐350mg/m2, N= 40bDocetaxel 75mg/m2, N= 168: COUGAR‐02c,d

• OS: 5.2mo vs. 3.6mo, HR=0.67; P=.01

47

Combination Chemotherapy for Metastatic Gastric cancer in the Second Line

Head‐to‐head OS comparisionsPaclitaxl was similar to irinotecan(although list in NCCN guideliness) aAddition for cisplatin to irinotecan: not superior bFOLFIRI not superior to irinotecan c

48

1st line therapy with fluropyrimidine plus platium given for 6‐8 cycles has been the standard of care for 20 years and has reached a plateau.

49

Target Therapy in mGC

50

Metastatic Gastric cancer: inhibitor and Pathway

51


52

Events

167182

ToGA Primary Endpoint: OS

Mos

294290

277266

246223

209185

173143

147117

11390

9064

7147

5632

4324

3016

2114

137

126

65

40

10

00

Pts at Risk, n

11.1 13.80

0.10.20.30.40.50.60.70.80.91.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Surv

ival

Pro

babi

lity

FC + T

FC

HR

0.74

95% CI

0.60‐0.91

PValue

.0046

MedianOS

13.811.1

Reprinted from The Lancet, 376(9742), Bang YJ, et al., Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. 687-697, Copyright 2010, with permission from Elsevier.

53

ToGA: Efficacy Outcome

Preplanned subgroup analysis indicated improved OS benefit with increasing HER2 expression by IHC

Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort demonstrated a 4‐mo increase in OS with trastuzumab HR: 0.65 (95% CI: 0.51‐0.83)

Outcome Chemotherapy + Trastuzumab

(n = 294)

Chemotherapy Alone

(n = 290)

HR (95% CI) P Value

Median OS, mos 13.8 11.1 0.74 (0.60-0.91) .0046Median PFS, mos 6.7 5.5 0.71 (0.59-0.85) .0002ORR, % 47 35 - .0017 CR 5 2 - .0599 PR 42 32 - .0145

Bang YJ, et al. Lancet. 2010;376:687‐697.54

Events

120136

Mos

228218

218198

196170

170141

142112

12296

10075

8453

6539

5128

3920

2813

2011

124

113

53

40

10

00

Pts at Risk, n

11.8 16.00

0.10.20.30.40.50.60.70.80.91.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Surv

ival

Pro

babi

lity FC + T

FC

HR

0.65

95% CI

0.51‐0.83

MedianOS

16.011.8

ToGA: OS in IHC 2+/FISH+ or IHC 3+ (Exploratory Analysis)

Reprinted from The Lancet, 376(9742), Bang YJ, et al., Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. 687-697, Copyright 2010, with permission from Elsevier.

55


Lapatinib

1ST line: Logic (x)2ND line:TYTANIHC 3+, OS: 14 movs 7.6 mo, HR of 0.59, P : .01

56


57

AVAGAST： 1st line in mGC

58

First‐line Targeting Therapy

• Only Herceptin

59

Physiologic and Tumor Angiogenesis

60

Tumor metastasis

61

Formation of Tumor Vasculature

• Endothelial sprouting leads to formation of tumor vasculature

• Mobilization of endothelial progenitor cells occurs from the bone marrowReviewed in Hicklin and Ellis. J Clin Oncol 2005;23(5):1011-27.

VEGF

62

Angiogenesis: An Overview

Reviewed in Adams and Alitalo. Nat Rev Mol Cell Biol 2007;8(6):464-78.

Secretion of Angiogenic Factors New Capillary Sprouting

Sprout Fusion and Lumen Formation

63

Angiogenesis: Secretion of Angiogenic Factors Leads to Initiation of Vascular Sprouting

1. Production of pro-angiogenic growth factors such VEGF-A and secretion into tissues

2. Activation of receptors on endothelial cells and pericytes

3. Activation of signaling cascades in endothelial cells and pericytes

4. Pericyte detachment and endothelial sprout formation

Reviewed in Adams and Alitalo. Nat Rev Mol Cell Biol 2007;8(6):464-78.

64

Rationale for Anti-angiogenic Therapy• Associations between microvessel density (and VEGF expression) and outcomes in breast cancer,2ovarian cancer,2 hepatocellular carcinoma,3,4NSCLC,5 and gastric cancer6

• Correlation between the number and density of blood vessels in resected gastric cancers and the incidence of subsequent metastasis6,7

1. Giatromanolaki et al. Am J Clin Oncol 2006;29(4):408-17.2. Delli Carpini et al. Angiogenesis 2010;13(1):43-58. 3. Zhu et al. Nat Rev Clin Oncol 2011;8(5):292-301.4. Yang et al. Gut 2010;59(7):953-62.

5. Salgia. Cancer 2011;117(17):3889-99.6. Maeda et al. Cancer 1996;77(5):858-63.7. Tanigawa et al. J Clin Oncol 1997;15(2):826-32. 65

The VEGF Family of Ligands and Receptors in Tumor Angiogenesis and Lymphangiogenesis

1. Reviewed in Adams and Alitalo. Nat Rev Mol Cell Biol 2007;8(6):464-78.2. Reviewed in Hicklin and Ellis. J Clin Oncol 2005;23(5):1011-27.

VEGF‐A

66

Strategies for Blocking the VEGF Receptor Pathways

Antibody to VEGFR-2• Blocks ligand binding• Blocks receptor activation

and signalingRamucirumab

Tyrosine kinase inhibitor to VEGFR-2• Blocks receptor kinase

activity and signalingSorafenibSunitinibPazopanibVandetanibAxitinib

Inhibition of VEGF ligand• Blocks VEGF binding• Inhibits signaling due to

VEGF(s)BevacizumabAfliberceptZiv-afliberceptNeovastat

Reviewed in Tugues et al. Mol Aspects Med 2011;32(2):88-111.

CediranibBrivanib alaninateMotesanibLinifanibTivozanib

67

VEGF family

68

Targeting VEGFR2

69

REGARD : 2nd line, single agent, phase 3

70

Time Since Randomization (Months)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28

Ove

rall S

urviv

al, %

0

20

40

60

80

100

RamucirumabCensoredPlaceboCensored

REGARD: Overall Survival1Placebo Ramucirumab

Patients/events 117/99 238/179

Median OS, mos (95% CI)2 3.8 (2.8, 4.7) 5.2 (4.4, 5.7)

6-month OS, % 32 42

12-month OS, % 12 18

HR (95% CI) = 0.776 (0.603, 0.998)

Stratified log-rank p-value (log-rank) = .047

RamucirumabPlacebo

Number at Risk

238 154 92 49 17 7 3 0 0117 66 34 20 7 4 2 1 0

1. Fuchs et al. Lancet 2014;383(9911):31-9.2. Fuchs et al. J Clin Oncol 2013;31(Suppl 4):Abstract LBA5. 72


0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Prog

ress

ion-

free

Surv

ival,

%

0

20

40

60

80

100

RamucirumabCensoredPlacebo Censored

REGARD: Progression‐Free Survival1

Ramucirumab

PlaceboNumber at Risk

238 213 113 65 61 45 30 18 18 11 5 4 2 1 1 1 1

117 92 27 11 7 4 2 2 2 2 2 1 1 0 0 0 0

0

0

Placebo Ramucirumab

Patients/events2 117/108 238/199

Median PFS, mos (95% CI)2 1.3 (1.3, 1.4) 2.1 (1.5, 2.7)

12-week PFS, % 16 40

HR (95% CI) = 0.483 (0.376, 0.620)

Stratified log-rank p-value <.0001

1. Fuchs et al. Lancet 2014;383(9911):31-9.2. Fuchs et al. J Clin Oncol 2013;31(Suppl 4):Abstract LBA5. 73

CT + BSC(n = 133)

BSC(n = 69)Phase III

1 or 2 CT lines(5-FU/platinum)

PS 0-1(N = 202)

2:1Docetaxel 60 mg/m2/3 wksOr Irinotecan 150 mg/m2/2 wks

R

➔ Primary endpoint: OS

Second‐line CT: First Phase III Trial

Kang JH, et al. J Clin Oncol. 2012;30:1513‐1518. 74

Second‐line CT: First Phase III Trial

• Median age: 56 yrs• 1 line: 73%; 2 lines: 27% • PS 0: 54% • > 1 M+ site: 65%• < 3‐mo treatment‐free interval: 74%

• Further CT, ≥ 3rd line: 40% vs 22%; P = .011• No QoL data

CT + BSC(n = 133)

BSC(n = 69)

OS, mos 5.3 3.8HR: 0.66

(95% CI: 0.48-0.89;P = .007)

Kang JH, et al. J Clin Oncol. 2012;30:1513‐1518. 75

REGARD: Most Frequent Adverse Events Regardless of Relationship to Study Drug

a2 patients in each group did not receive treatment; bConsolidated term

Preferred Term, n (%)Placebo

(N = 115)aRamucirumab

(N = 236)a

Any Event Grade 3 Any Event Grade 3

Fatigueb 46 (40) 11 (10) 84 (36) 15 (6)

Abdominal painb 32 (28) 3 (3) 68 (29) 14 (6)

Decreased appetite 26 (23) 4 (3) 57 (24) 8 (3)

Vomiting 29 (25) 5 (4) 47 (20) 6 (3)

Constipation 26 (23) 3 (3) 36 (15) 1 (<1)

Anemiab 17 (15) 9 (8) 35 (15) 15 (6)

Dysphagia 12 (10) 5 (4) 25 (11) 5 (2)

Dyspnea 15 (13) 7 (6) 22 (9) 4 (2)

76

REGARD: Adverse Events of Special Interest

a2 patients in each group did not receive treatment; bConsolidated term; cNo Grade 4 hypertension was observed

AE of Special Interest, n (%)Placebo

(n = 115)aRamucirumab

(n = 236)a

Any Event Grade ≥3 Any Event Grade ≥3

Hypertensionb,c 9 (8) 3 (3) 38 (16) 18 (8)Bleeding/hemorrhageb 13 (11) 3 (3) 30 (13) 8 (3)Arterial thromboembolismb 0 (0) 0 (0) 4 (2) 3 (1)Venous thromboembolism 8 (7) 5 (4) 9 (4) 3 (1)Proteinuria 3 (3) 0 (0) 7 (3) 1 (<1)Gastrointestinal perforation 1 (<1) 1 (<1) 2 (<1) 2 (<1)Fistula formation 1 (<1) 1 (<1) 1 (<1) 1 (<1)Infusion-related reaction 2 (2) 0 (0) 1 (<1) 0 (0)Cardiac failure 0 (0) 0 (0) 1 (<1) 0 (0)

77

REGARD: Another Choice After Progression?

78

RAINBOW: Study Design

Study Design Phase 3, double-blind, randomized study of ramucirumab plus paclitaxel versus placebo and paclitaxel for previously treated advanced gastric or gastro-esophageal junction adenocarcinoma

Primary endpoint Overall survival

Secondary endpoints Progression-free survival, time to progression, objective response rate, safety assessment, quality of life

Until Progression

or Unacceptable

Toxicity

Until Progression

or Unacceptable

ToxicityStratify by:•Time to progression on 1st-line therapy (<6 vs. ≥6 months) •Geographic region•Disease measurablility (measurable vs. nonmeasurable)

Stratify by:•Time to progression on 1st-line therapy (<6 vs. ≥6 months) •Geographic region•Disease measurablility (measurable vs. nonmeasurable)

Ramucirumab 8 mg/kg on Days 1 and 15

+ Paclitaxel 80 mg/m2 on Days 1, 8, and 15 of a 28-

day cycle

Placebo on Days 1 and 15+ Paclitaxel 80 mg/m2 on

Days 1, 8, and 15 of a 28-day cycle

N = 665N = 665

SCREEN

RANDOMIZE

RANDOMIZE

• CT scans every 6 weeks

• Survival follow-up• Safety follow-up

Inclusion Criteria•Metastatic/nonresectable, locally advanced gastric/GEJ adenocarcinoma •Disease progression ≤4 months after the last dose of first-line therapy •First-line therapy with any platinum/ fluoropyrimidine doublet with/without an anthracycline•ECOG PS 0/1

Inclusion Criteria•Metastatic/nonresectable, locally advanced gastric/GEJ adenocarcinoma •Disease progression ≤4 months after the last dose of first-line therapy •First-line therapy with any platinum/ fluoropyrimidine doublet with/without an anthracycline•ECOG PS 0/1

Wilke et al. Lancet Oncol 2014;15(11):1224-35. 79

RAINBOW: Geographic Regions

Region 3: Asia (N = 223)Hong Kong (3) Japan (140) Korea (45) Singapore (5) Taiwan (30)

Region 3: Asia (N = 223)Hong Kong (3) Japan (140) Korea (45) Singapore (5) Taiwan (30)

Region 2: Rest of World (N = 44) Argentina (1) Brazil (35) Chile (4) Mexico (4)Region 2: Rest of World (N = 44) Argentina (1) Brazil (35) Chile (4) Mexico (4)

Region 1: Europe/US/Australia (N = 398)Australia (41) Austria (6) Belgium (26) Bulgaria (12) Germany (40) Spain (21) Estonia (10) France (34) Great Britain (15) Hungary (29) Israel (30) Italy (28) Lithuania (12) Poland (33) Portugal (2) Romania (14) Russia (21) United States (24)

Region 1: Europe/US/Australia (N = 398)Australia (41) Austria (6) Belgium (26) Bulgaria (12) Germany (40) Spain (21) Estonia (10) France (34) Great Britain (15) Hungary (29) Israel (30) Italy (28) Lithuania (12) Poland (33) Portugal (2) Romania (14) Russia (21) United States (24)

Wilke et al. J Clin Oncol 2014;32(Suppl 3): Abstract LBA7. 80


0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Ove

rall

Surv

ival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

RAM+PacCensoredPBO+PacCensored

RAM + Pac 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0PBO + Pac 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0

Number at Risk

RAM + Pac(N = 330)

PBO + Pac(N = 335)

Events 256 260

Median (months) (95% CI) 9.6 (8.5, 10.8) 7.4 (6.3, 8.4)

6-month OS 72% 57%

12-month OS 40% 30%

HR (95% CI) = 0.807 (0.678, 0.962)

Stratified log-rank p-value = .0169

RAINBOW: Overall Survival


RAM + Pac 330 259 188 104 70 43 28 15 11 7 3 1PBO + Pac 335 214 124 50 34 21 12 8 5 3 3 3

Number at Risk

RAM + Pac(N = 330)

PBO + Pac(N = 335)

Patients/Events 279 296

Median (months) (95% CI) 4.4 (4.2, 5.3) 2.9 (2.8, 3.0)

6-month PFS 36% 17%9-month PFS 22% 10%

HR (95% CI) = 0.635 (0.536, 0.752)Stratified log-rank p-value <.0001

RAINBOW: Progression‐Free Survival

Wilke et al. Lancet Oncol 2014;15(11):1224-35.


0 2 4 6 8 10 12 14 16 18 20 22 24

Pro

gres

sion

-free

Sur

viva

l

0.0

0.2

0.4

0.6

0.8

1.0

RAM+PacCensoredPBO+PacCensored

82

RAINBOW: Objective Tumor Response

Response, n (%)RAM + Pac

N = 330 PBO + Pac

N = 335 p-valueBest Overall Response

Complete response (CR) 2 (<1) 1 (<1)

Partial response (PR) 90 (27) 53 (16)

Stable disease (SD) 172 (52) 159 (47)

Progressive disease (PD) 43 (13) 83 (25)

Not evaluable/not assessed 23 (7) 39 (12)

ORR (CR + PR), % (95% CI) 28 (23, 33) 16 (13, 20) .0001

DCR (CR + PR + SD), % (95% CI) 80 (75, 84) 64 (58, 69) <.0001

Median duration of response, months 4.4 2.8


aConsolidated adverse event category comprising synonymous MedDRA® preferred terms

RAINBOW: TEAEs Occurring in ≥10% of Patients in the RAM + Pac Arm (1 of 2)

Preferred TermRAM + Pac

(n = 327)PBO + Pac(n = 329)

Any Grade% of Patients

Grade ≥3% of Patients



Any 99 82 98 63Fatiguea 57 12 44 5Decreased appetite 40 3 32 4Abdominal paina 36 6 30 3Neuropathya 46 8 36 5Nausea 35 2 33 2Alopecia 33 0 39 <1Diarrhea 32 4 23 2Epistaxis 31 0 7 0Vomiting 27 3 21 4Peripheral edema 25 2 14 <1Constipation 21 0 22 <1Stomatitis 20 <1 7 <1Pyrexia 18 <1 11 <1


Preferred Term RAM + Pac (n = 327) PBO + Pac (n = 329)





Malignant neoplasm progression 16 14 18 18

Weight decreased 14 2 15 1Dyspnea 13 2 9 <1Back pain 12 1 12 2Rasha 13 0 9 0Cough 12 0 8 0Myalgia 10 0 10 <1Ascites 10 4 8 4Headache 10 0 7 <1Hypoalbuminemia 11 1 5 <1Hypertension 24 14 5 2Proteinuria 17 1 6 0Hematologic AEsa

Neutropenia 54 41 31 19Anemia 35 9 36 10Leukopenia 34 17 21 7Thrombocytopenia 13 2 6 2

RAINBOW: TEAEs Occurring in ≥10% of Patients in the RAM + Pac Arm (2 of 2)

aConsolidated adverse event category comprising synonymous MedDRA preferred termsWilke et al. Lancet Oncol 2014;15(11):1224-35. 86

Category of EventbRAM + Pac(N = 327)

PBO + Pac(N = 329)





Bleeding/hemorrhage 42 4 18 2

Hypertension 25 15 6 3

Proteinuria 17 1 6 0

Liver injury or failure 17 5 13 4

GI hemorrhage 10 4 6 2

Renal failure 7 2 4 <1

Infusion-related reaction 6 <1 4 0

Venous thromboembolism 4 2 6 3

Cardiac failure 2 <1 1 <1

Arteriothromboembolism 2 <1 2 <1

GI perforation 1 1 <1 0

RAINBOW: Adverse Events of Special Interesta


RAINBOW QoL: Percent of Patients with Stable or Improved Scores on EORTC QLQ‐C30 Scales

Al-Batran et al. Ann Oncol 2014; 25(2):i105-i117.

% of Patients with Stable or Improved Pain% of Patients with Stable or Improved Fatigue

% of Patients with Stable or Improved Physical Functioning% of Patients with Stable or Improved Global Health Status

RAM+Pac (N=330) PBO+Pac (N=335)




88

Summary‐ Ramucirumab for 2nd‐line treatment of gastric cancer and gastroesophageal junction adenocarcinoma

1. In REGARD: ramucirumab significantly prolonged OS (HR = 0.776, p = .047) and PFS (HR = 0.483, p<.0001) in patients with metastatic gastric or GEJ adenocarcinoma in 2nd line therapy.

2. In RAINBOW: RAM + Pac conferred a statistically significant and clinically meaningful OS benefit of >2 months (median); risk reduction of disease progression or death by 37%. Addition of RAM to Pac did not impair QoL

89

The Common Chemotherapy&

How to Manage Side effect

90

5FU mechanism

91

Tegafur

S‐1

92

Xeloda (capecitabine)

• 服用Xeloda的病患經常會出現下列不良反應

手足症候群

手足症候群腹瀉口炎

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不良反應分級

• Xeloda治療的相關不良反應，通常是依加拿大臨床試驗小組國家癌症研究中心（National Cancer Institute of Canada Clinical Trial Group，NCIC CTG）的一般毒性標準（Common Toxicity Criteria ）進行分級

– 第1–2級為輕至中度不良反應

– 第3–4級為重度不良反應

級數

重度輕至中度

4321

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手足症候群分級

Moore SH. The Oncology Report. 2005; Fall (suppl):18–23

級數* 臨床層面功能性層面

2 疼痛性血腫及腫脹不適感會干擾日常活動

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手足症候群分級

Moore SH. The Oncology Report. 2005; Fall (suppl):18–23Lacouture ME. The Oncologist 2008;13:1001–1011

級數* 臨床層面功能性層面

3 濕性脫屑、潰瘍、水泡、嚴重疼痛或不適感

無法工作或進行日常活動

11–17%

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腹瀉

• 有12–15%服用Xeloda的病患會出現中至重度腹瀉1

• 服用Xeloda的病患

– 發生首次第2–4級腹瀉之中位數時間為34 天（範圍介於11–360天）1

– 第3/4級腹瀉的中位數罹病時間為5天1

1Xeloda® (capecitabine) [package insert]. Nutley, NJ: Roche Laboratories; 200997

腹瀉分級

級數臨床表現

未接受結腸切除術之病患接受結腸切除術之病患

1 排便次數較基線增加<4次／日鬆軟、水狀結腸造口排泄物較基線略為增加

2排便增加至4–6次／天以及有任何夜間排便，需要靜脈輸注或口服液體之時間為<24小時

鬆軟、水狀結腸造口排泄物較基線中度增加，但不會干擾日常活動

3 排便增加 ≥7次／天、失禁、脫水、靜脈輸液≥24小時、住院

鬆軟、水狀結腸造口排泄物較基線重度增加，會干擾日常活動

4 危及生命之續發症狀，例如血液動力學崩潰（hemodynamic collapse）

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口炎

• 有2–7%服用Xeloda的病患會罹患中至重度口炎（口腔黏膜炎）1

1Xeloda® (capecitabine) [package insert]. Nutley, NJ: Roche Laboratories; 2009

級數臨床表現

1 無痛性潰瘍、血腫或無病灶之酸痛

2 疼痛性血腫、水腫或潰瘍，但可進食或吞嚥

3 需要靜脈輸注補充水分的疼痛性血腫、水腫或潰瘍

4 嚴重潰瘍或病患需要腸外（parenteral）或腸內（enteral）營養補充支持治療或者預防性插管

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應告知病患其他潛在的化療相關不良反應

• 嘔吐

– 24小時內超過一次

• 噁心

– 缺乏食慾、每日食物攝取量較平時大幅減少

• 發燒或感染

– 體溫38°C以上或其他感染症狀

• 胸痛

– 胸部中央位置疼痛，尤其在運動時

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• 您應該建議病患避免– 長時間將手、腳浸泡於熱水中– 曬太陽– 讓腳從事過度用力或摩擦的活動（例如長途步行）– 從事會長時間對手施加壓力的活動（例如使用工具）– 接觸洗衣精或家用清潔產品

預防手足症候群

www.cancer.net. Accessed on 15 May 2009

• 您應建議病患– 使用冰袋或冷敷（cool compress）的方式冷卻手

腳– 在坐姿或臥姿時將手腳抬高– 清洗後小心拍乾皮膚– 擦拭溫和的護膚乳液以保持雙手溼潤– 穿著寬鬆、透氣的鞋子與衣物

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預防腹瀉

• 您應建議病患避免

– 飲用或食用咖啡因、酒類、乳製品、脂肪、纖維、柳橙汁、梅汁以及辛辣食物

– 使用瀉藥與軟便劑


• 您應建議病患– 少量多餐– 每天至少喝2公升的水以預防脫水

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預防口炎

• 您應建議病患避免

– 食用酸、辛辣、鹹、粗糙或乾燥的食物


• 您應建議病患

– 使用含氟牙膏輕輕刷牙

– 使用牙線輕輕剔牙

– 移除假牙

– 選擇咀嚼不費力或不需咀嚼的食物

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管理不良反應

• 常規病患追蹤程序（電訪或額外回診檢查）可協助確保不良反應管理達到佳效果

– 特別是首次服用Xeloda的病患

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中斷Xeloda治療• 發生中度（第2級）或更嚴重的出血性不良反

應時，應中斷Xeloda治療

– 手足症候群

– 腹瀉

– 口炎

中斷

Xeloda治療

痊癒後重新開始治療

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中斷Xeloda治療不是病患唯一能採取的做法！

• 應在發生中度或更嚴重的不良反應時，告知病患停用Xeloda是正確的做法，但不是唯一的選擇

– 病患必須進一步徵詢您或其醫師之建議！

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管理手足症候群

• 應在發生中度或更嚴重程度的手足症候群時，建議病患

– 停用Xeloda，並徵詢其腫瘤科護士／腫瘤科醫師之建議

– 使用潤膚劑／乳液

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Taxan mechanism

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Docetaxel/ Paclitaxel

• 施打前之預防藥物:– Dexamathsone: 4-8 mg x 3 (給藥前晚上, 早

上以及傍晚)

• 目的﹕– 延遲體液滯留發生的時間及嚴重程度。– 降低過敏反應的發生率。– 可能降低嚴重皮膚反應的發生率

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副作用及注意事項 (1)過敏反應雖然使用口服類固醇前處理藥物可降低過敏反應的

頻率及嚴重程度﹐護理人員仍應該警覺可能發生的過敏反應。輸注期間若觀察到嚴重過敏反應﹐應該立即停止給藥﹐並即時給予適當治療。下列急診用藥在治療過敏反應發生時應能隨時取用diphenhydramine, 50 mg, IVnoradrenaline, 1 ml, 1/1000, IVmethylprednisolone, 125 mg, IVdexamethasone, 10 mg, IVsalbutamol nebules and nebulizer

為了降低過敏反應的發生率﹐建議輸注的前5分鐘輸注速度變慢﹐然後持續依照既定速度輸注1小時。

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副作用及注意事項 (2)

• 血管外滲不會引起全身性毒性。– 腫脹及/或輕微疼痛– 紅斑– 靜脈輸注部位無血液回流

• 外滲(extravasation)的處理– 立即停給藥﹐– 抽吸IV注射針﹐– 移除IV注射針﹐– 在輸注部位冰敷15~20分鐘﹐並告知病患回家後接

下來的72小時﹐每4~6小時重複一次。或依照一般原則立即處理及告知病患回家後處理方式。

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• 嗜中性白血球減少症Neutropenia– 嗜中性白血球減少症的發生迅速( 低點的中數

在第8天)且恢復快速(通常在1週內)。– 嗜中性白血球減少症可能發生在病患回家以後。

因此﹐病患應該被告知發生感染的可能性﹐若病患感覺不適即應該監測體溫。若體溫高於38℃﹐則應該告知其治療中心。

– 當病患服用類固醇和處在嗜中性白血球減少症的危機中﹐更應該特別注意口腔衛生。

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• 體液滯留Fluid retention– 體液滯留並非是危及生命的不良反應﹔它與累

積劑量有關。通常發生在數個治療周期之後(發生之累積劑量中數為797 mg/m2)﹐類固醇前處理藥物明顯降低體液滯留的發生率﹑嚴重程度並延後症狀之發生。

– 體液滯留可觀察到病患有水腫﹑體重增加﹐少數病患會有胸肋膜滲出液﹑腹水或心包膜滲出液。

– 若有體液滯留情況發生時﹐根據體液滯留嚴重情況加上furosemide或spironolactone。長期使用利尿劑應該小心。

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副作用及注意事項 (5)• 皮膚﹑神經學及胃腸方面的反應

– 若有皮膚乾燥或潮濕脫皮現象﹐病患應被建議採取溫水浴﹐採用無香水的香皂﹐並在乾燥皮膚區域敷上水性乳霜。若有皮膚癢的情況﹐可用抗組織胺作症狀處理。

– 曾有報告顯示pyridoxine, 口服﹐50 mg﹐每天三次﹐可減輕改善感覺遲鈍觸痛等現象。

– 胃腸方面的副作用﹐確定病患出院時有開立適當的止吐劑﹐止瀉劑。

– 勸導病患密切注意口腔衛生﹐使用軟質牙刷及處方的牙膏製品。

– 若口腔有傷口﹐勸導病患避免太辣太鹹的食物。

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• 無力﹑關節痛及肌肉痛

– 無力感發在三分之二的病患﹐約有12 %的案例為程度嚴重。

– 關節痛及肌肉痛一般為輕度至中度。病患應被告知使用時﹐因為這些症狀病患的生活品質可能會有所影響。使用輕度止痛劑便可有效減輕關節痛及肌肉痛。

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Oxaliplatin Mechanism

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Oxaliplatin

• 須給病人適當止吐藥（and/or）。

5‐HT3 antagonist: Aloxi, setoral, kytril… Dexamethasone Primperan：Gastro‐T Novamin 5 mg

• 如病人因疑慮而產生咽喉感覺異常時

抗焦慮藥品可能對病人有幫助。

• 神經毒性：

Cal. Gluconate (1 gm) + MgSo4 (1 gm) in D5W 100 cc run 15‐30 mins before & after Oxaliplatin

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副作用及注意事項 (1)周圍感覺神經異常1. 常見的副作用，與個人的體質、治療的劑量、

治療時間的長短有關。2. 當進行治療時，四肢末端以及（或）口腔周圍可

能會產生刺痛感或感覺變得較不敏銳。而這些症狀通常在數小時或數天後便會自動緩解。

3. 較冷的環境，可能會引發或是加劇上述的副作用。應盡量避免暴露於寒冷的環境下。

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週邊感覺神經異常

• 如發生神經毒性，請詢問病人以下問題：症狀型態：

感覺異常、遲鈍、過敏，疼痛，麻木，肌肉收縮，虛弱等等。

症狀發生的位置：肢端，口腔周圍的區域。

症狀與低溫的關聯性。症狀持續的時間：

開始時間與Oxaliplatin輸注時間的關聯性，症狀持續的時間(暫時性或持續性)。

症狀的嚴重度：是否伴隨著功能的障礙。 120

Oxaliplatin的神經毒性急性暫時性神經病變蓄積性感覺神經病變

作用機轉

Oxaliplatin代謝物oxalate，可能經與鈣離子鉗合會阻擋鈉離子通道。

機轉不清楚，由急性暫時性神經病變逐漸衍生而來。

發生率

輕微遠端及/或口腔周圍皮膚感覺異常以及/或感覺遲鈍：85-95 %暫時性咽喉感覺遲鈍，導致感覺呼吸困難或吞嚥困難：10-20 %

10-18 %

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急性暫時性神經病變蓄積性感覺神經病變

經歷

發生於第一次治療大部分累積性毒性會經歷急性症狀感覺遲鈍或異常等症狀在兩次治療週期間會持續存在

症狀

肢體末梢以及/或是口腔周圍的感覺異常

進一步進展成功能性障礙：精細的感覺、運動協調性失常，感覺失調

誘因

低溫會引發或讓副作用情況更加惡化

累積劑量780-850mg/m2

Oxaliplatin 130 mg/m2q3w 6 cyclesOxaliplatin 85 mg/m2 q2w 9 cycles

時間

數小時或數天症狀便會消失

治療停止後3-5個月，75 %會回復至第一級蓄積性神經病變或更輕微症狀。

Oxaliplatin的神經毒性

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嚴重症狀

輸注過程或結束：1.偶發咽喉感覺異常、敏感度降低

2.暫時感覺呼吸或吞嚥困難（不會發生呼吸困難）

3.肌肉收縮：痙攣或抽筋，手腳僵硬感，

手掌握拳後無法張開，有時影響腿或導致下巴收縮。

使用Oxaliplatin治療的病人不曾有過麻痺或癱瘓報告。

約<15 %病人會發生感覺功能障礙。

原因臨床類似強直性痙攣，運動神經元過度興奮及脊椎抑制性神經元間突觸釋放神經傳導物質時出現異常造成。

神經的過度興奮或是肌肉的過度興奮所造成。


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解決方式

輸注時間由2小時延長至6小時治療停止後會逐漸改善或消失

其他劑量為130mg/m2時，比Oxaliplatin的劑量85mg/m2發生的機率高。

治療計劃的時間表無關


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神經毒性之處理方式• 調整劑量

• Vitamin B12 ?• Vitamin C 400 mg daily ?• 鈉離子通道阻斷劑對多種神經性疾病都有減低神經元傷害的治療用途* Cal. Gluconate (1 Amp) + MgSo4 (0.5 Amp) in D5W 100 cc run 15-30 mins before & after * 鈉離子通道阻斷劑 : Carbamazepine * 抗癲癇藥品，增加GABA的釋放：Gabapentin

• Glutathione ?125

週邊感覺神經異常病患接受化學治療後五日內應注意下列各事項：1. 避免暴露於寒冷或強風的環境。在冷空氣中，可

使用口罩或圍巾保護口、鼻。2. 需注意保暖，感覺冷時，可穿戴毛衣、圍巾、手

套。在室內時可用溫水暖手。3. 避免用冷水洗手。4. 避免碰觸冷的東西或物体。從冰箱中拿取食物時，

好穿戴手套。當病人的這些症狀持續發生或變得更加嚴重，應該向醫師反應，請醫師替病患調整藥品的使用劑量。

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Summary

• Early diagnosis, Early treatment • Adjuvant chemotherapy is beneficial, but managing side effect is team work.

• Stage IV is not “ terminal” , prolong life is possible.

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Thanks for your attentions

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胃癌gastric cancer 鑑古知今from past to future

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