Systemic therapy for
Advanced Hepatoma & Cholagiocarcinoma
นายแพทย์ ชัยยุทธ เจริญธรรม
หน่วยมะเร็งวิทยา ภาควิชาอายุรศาสตร์
1
แนวทางการรักษามะเร็งตับ
(ระยะโรค, ความแข็งแรงผูป้ ่ วย, ความแข็งแรงของตับ)
HCC
Stage 0
Stage A–C
PST 0, Child–Pugh A
PST 0–2, Child–Pugh A–B
Stage D
PST >2,
Child–Pugh C
Very early stage (0)
Early stage (A)
Intermediate stage (B)
Advanced stage (C)
1 HCC <2cm
Carcinoma in situ
1 HCC or 3 nodules
<3cm, PST 0
Multinodular,
PST 0
Portal invasion,
N1, M1, PST 1–2
1 HCC
3 nodules < 3 cm
Portal pressure/
bilirubin
Increased
Normal
Resection
End stage (D)
Associated diseases
No
Transplantation
มีโอกาสหายขาด
Yes
Ablation
TACE
ยา
ระงับหรือบรรเทาโรค
รักษาประคับ
ประคอง
Adapted from Llovet JM, et al. J Natl Cancer Inst 2008;100:698-711
2
3
Patient characteristics
Ascites
Point
Yes
2
No
0
Yes
2
No
0
Yes
2
Not Amendable to Locoregional Therapy
No
0
Prognosis
C
5
B
2
A
0
Serum alkaline
phosphatase
(ALP), int. unit/L
>200
3
≤200
0
Total bilirubin
>50 int. unit/L (2.9 mg/dL)
Abdominal pain
Weight loss
Child-Pugh grade
โอกาสการมีชีวิตรอดอย่างน้ อย 3 เดือน
Patients With Advanced HCC
0-2
>81
3-6
72-80
7-8
66-69
9
63
3
10-12
51-59
>33 - ≤50 int. unit/l (1.9 - 2.9 mg/dL)
1
≤33 int unit/L (1.9 mg/dL)
13-14
42-47
0
>8.9 mmol/L (>25 mg/dL)
2
15
38
≤8.9 mmol/L (≤25 mg/dL)
0
16
33
17-19
21-29
20-22
10-17
≥23
<10
Tumor characteristics
Portal vein thrombosis
Tumor size
Lung metastases
Serum alpha-fetoprotein
(AFP), ng/mL
อัตราการมีชีวิตที่ 3 เดือน,
%
Good
Biochemistry
Urea
Score
Yes
3
No
0
Diffuse
4
>5 cm
3
≤5 cm
0
Yes
3
No
0
>400
4
≤400
0
Intermediate
Poor
Yau et al. Cancer 2008.
4
อุปสรรคของการรักษามะเร็งตับด้วยยา
 HCC tumor biology (พันธ์ดือ
้ )
– disruption in p53 pathway : resistance to apoptosis
– DNA topoisomerase alpha over-expressed/ up-regulated :
resistance to Topoisomerase inhibitors
– intrinsic drug resistance mediated by an enhanced cellular drug
efflux mechanism – MDR1, p-gp, MRP
 Pharmacokinetic properties of cirrhotic liver (ตับไม่เอื้อ)
– total liver mass is reduced
– distortion of the liver architecture leads to significant intra-hepatic
shunting and reduced extraction of protein-bound substances.
– affects the absorption, plasma protein binding, distribution and
renal excretion of drugs.
5
ตัวอย่างของการศึกษาที่ใช้ยาเคมีบาบัด
ในการรักษามะเร็งตับ
Chemotherapy
Study
N
อัตราการ
ตอบสนอง,
%
ระยะเวลาที่
รอดชีวิต,
เดือน
Cisplatin, Doxorubicin
Lee et al.
37
18.9
7.3
Cisplatin, Interferon,
Doxorubicin, 5-FU (PIAF)
Yeo et al.
91
20.9
8.6
Gemcitabine
Yang et al
28
17.8
4.6
Capecitabine
Patt et al.
37
11
10.1
Gemcitabine, Oxaliplatin
Louafi et al.
34
18
6.3
Capecitabine, Oxaliplatin
Boige et al.
50
6
9.3
FOLFOX 4
Quin et al.
184 8.2
6.4
Doxorubicin
Quin et al.
187 2.7
P 0.02
4.9
P 0.085
6
การใช้ยา Sorafenib
 NCCN 2013
– For Unresectable HCC (tumor extent or location, liver function
reserves), Child A or B
 APASL 2009
– for advanced stage patients who are not suitable for locoregional therapy and who have Child-Pugh liver function class
A. (Grade A)
– may be used with caution in patients with Child-Pugh liver
function class B. (Grade C)
 JSH 2010
– Sorafenib is the first choice of treatment as a standard of care
in Extrahepatic spread with Child-Pugh A liver function
– Sorafenib is also a treatment of choice for TACE refractory
patients with Child-Pugh A liver function.
7
การศึกษาอ้างอิงที่ใช้ยา Sorafenib รักษามะเร็งตับ
SHARP1
Asia-Pacific2
1.00
1.00
0.75
Placebo (n=303)
Median: 7.9 months
0.50
0.25
HR (S/P): 0.69
95% CI: 0.55-0.87
P=0.00058
0
0
4
8
12
16
20
Months from Randomization
Sorafenib (n=150)
Median: 6.5 months
Survival Probability
Survival Probability
Sorafenib (n=299)
Median: 10.7 months
0.75
Placebo (n=76)
Median: 4.2 months
0.50
0.25
HR (S/P): 0.68
95% CI: 0.50-0.93
P=0.014
0
0
4
8
12
16
20
Months from Randomization
1. Llovet JM, et al. N Engl J Med. 2008;359(4):378-390.
2. Cheng AL, et al. Lancet Oncol. 2009;10:25-34.
8
การศึกษาอ้างอิงที่ใช้ยา Sorafenib รักษามะเร็งตับ
Sorafenib vs. placebo
SHARP
Asia-Pacific
GIDEON
(ASCO 2011)
HBV/HCV/others
19/28/53
71/11/19
37/32/39
BCLC stage A/B/ C (%)
0/ 18/82
0/ 5/ 95
7/19/ 54
Child-Pugh A /B (%)
95/5
97/3
61/ 23
ECOG PS 0 / 1 +2 (%)
54/46
25/ 75
40 / 43
OS (months)
10.7 (S)
7.9 (P)
6.5 (S)
4.2 (P)
10.3 (C-P A)
4.8 (C-P B)
TTP (months)
5.5 (S)
2,8 (P)
2.8 (S)
1.4 (P)
4.2 (C-P A)
3.6 (C-P B)
GIDEON : Global Investigation of Therapeutic Decisions in Hepatocellular
Carcinoma and of its Treatment with Sorafenib
9
GIDEON study: Child-Pugh A vs. B
Child-Pugh A
(n=957)
Child-Pugh B
(n=367)
Median treatment
duration, weeks
14
9
Median daily dose, mg‡
680
721
AEs (all Grades)
82
89
SAEs†
29
56
Drug-related SAEs‡
8
15
Permanent
discontinuation of
sorafenib due to AE§
24
38
% of n
Global Investigation of Therapeutic Decisions in Hepatocellular
Carcinoma and of its Treatment with Sorafenib
ASCO 2011
10
Sorafenib long-term data: Initial presentation of
treatment-related AEs (any grade) by cycle
Patients with AE (%)
Most Sorafenib-treated patients first experienced HFSR and other
common AEs within the first two treatment cycles
Cycle
HTN, hypertension
1 cycle = 6 weeks
Hutson TE, et al. Eur J Cancer 2010;46:2432–40.
11
อาการข้างเคียงจากการรักษาของ Sorafenib ในการศึกษา
อ้างอิง SHARP & AP trial
Incidence by grade (%)
SHARP1
Asia Pacific2
Sorafenib (n=297) Placebo (n=302)
AE*
Any
3-4
Any
3-4
52
Sorafenib
(n=149)
Any
3–4
81.9
Placebo (n=75)
Any
3–4
Overall incidence
80
38.7
Diarrhoea
39
8
11
2
25.5
6.0
5.3
0
Fatigue
22
4
16
3
20.1
3.4
8.0
1.3
HFSR
21
8
3
<1
45.0
10.7
2.7
0
Rash/desquamation
16
1
11
0
20.1
0.7
6.7
0
Alopecia
14
0
2
0
24.8
–
1.3
–
Anorexia
14
<1
3
1
12.8
0
2.7
0
Nausea
11
<1
8
1
11.4
0.7
10.7
1.3
Hypertension
5
2
2
1
18.8
2.0
1.3
0
*AEs, as defined by CTCAE version 3.0 that occurred in at least 10% of patients in either study group
1. Llovet JM, et al. N Engl J Med. 2008;359(4):378-390.
2. Cheng AL, et al. Lancet Oncol. 2009;10:25-34.
12
Suggested Interventions for skin toxicity
(Sorafenib 800 mg/day)
Grade 1
Grade 2
Grade 3
Supportive measures (control callus, cream, cushion)
Topical therapy
Decrease dose to 400mg/d
for 7-28 days
If symptoms resolve,
increase to full dose
If symptoms persist,
interrupt treatment
for 7 days
Resume tx at 400mg
QD when toxicity <
grade 1
13
Suggested Interventions for skin toxicity
Grade 1
Grade 2
Grade 3
Supportive measures (control callus, cream, cushion)
Topical therapy
Interrupt treatment for
7 days
Resume tx at 400mg/d
when toxicity < grade 1
Consider further dose
reduction if symptoms
recur
If toxicity < grade 1 for 728 days, may increase
by one dose level
14
Prophylactic effect of urea-based cream on the hand-foot
skin reaction associated with sorafenib in advanced HCC
 N = 868 Patients with advanced HCC treated with SOR
 Urea-based cream was given twice daily for up to 12
weeks starting on Day 1 (Arm A) vs BSC was at the
physician’s discretion and excluded urea-based
creams. (Arm B) (1:1)
 Results
– All-grade HFSR - lower in Arm A (56.0%) vs Arm B (73.6%);
p<0.0001.
– Grade ≥2 HFSR tended to be lower in Arm A (21.9%) vs Arm B
(29.2%), p=0.1638.
– The median time to the first HFSR event was 2.5 fold longer in
Arm A (84 days, 95% CI 45-93 days) vs Arm B; (34 days, 95% CI
29-43 days) , p<0.001.
Ren et al. J Clin Oncol 30, 2012 (suppl; abstr 4008)
15
Sorafenib unanswered questions
 The mechanism of action of sorafenib in HCC that
mediates clinical benefits
 Benefits/Safety in patients with Child B
 Optimal dose
 The mechanism of resistance
16
Phase III trials in advanced HCC
 First-line
– Sorafenib/Doxorubicin
vs Sorafenib/Placebo
– Sorafenib/Erlotinib
vs Sorafenib/Placebo
– Sorafenib
vs Sunitinib (failed, ASCO 2011)
– Sorafenib
vs Brivanib
– Sorafenib
vs Linifanib
 Second-line
– Brivanib
vs BSC (failed, EASL 2012)
– Everolimus
vs BSC
– Ramucirumab
vs BSC
– ADI-PEG 20
vs BSC
17
Conclusion : Systemic therapy for HCC
 Sorafenib is the only approved systemic agent for
the treatment of HCC
 Many other molecular-targeted agents are at the
early stages of development in HCC
 Rational design clinical trial with combination
therapy holds promise to improve outcome and
remain to be seen
18
Systemic Therapy for
Advanced Cholangiocarcinoma
19
Challenges of systemic therapy in
Cholangiocarcinoma
• Heterogeneous disease
— Gall bladder cancer
— Cholangiocarcinoma
•
Intrahepatic cholangiocarcinoma
(Peripheral type, mass forming)
•
Extrahepatic cholangiocarcinoma
— Different location are truly the same pathology and
biology ?
Challenges to define standard
chemotherapy for cholangiocarcinoma ?
• Lack of well conducted randomized controlled
trial
• Most studies are small, non randomized phase II
• Many studies comprise a mix of BTC, GBC and
either PC or HCC.
Overall survival :
Chemo VS BSC
6 M VS 2.5 M, P <0.01
FELv
/FLv
6 M VS 2.5 M, P=0.05, N=53 : PCA
6.5 M VS 2.5 M, P=0.1, N=37 : CCA
Favorable QOL outcome :
Chemo VS BSC – 36%VS10%,P <0.01
both sites
Quality adjusted survival :
Chemo VS BSC –4 M VS 1M,P <0.01
both sites
Chemo :FELv, FLv (age >60,PS <70)
Chemotherapy in Cholangiocarcinoma
• ยาเดี่ยว
— Fluoropyrimidine : 5-FU, capecitabine, tegafur, S1
— Platinums : Cisplatin, carboplatin, oxaliplatin
— Antimetabolites : Gemcitabine, MMC
— Anthracyclines : Doxorubicin, Epirubicin
— Topoisomerase I inhibitors : Irinotecan
— Taxanes : Paclitaxel, Docetaxel
• สูตรยาคู่
— FU + Platinums/ Gemcitabine
— Gemcitabine + Platinums/ FU
• สูตรผสมที่ใช้ยาตัง้ แต่ 3 ตัวร่วมกัน – ECF, FAM, PIAF
• 104 trials (3 randomized, 112 trial arms), N = 2810
• From January 1985 to July 2006
— 15% trials published 1993 – 1999
— 85% trials published after 2000
• No. pt range from 5 – 65/trial (mean 25.1)
• Pooled RR = 22.6% (95% CI 21.0% - 24.2%)
• Pooled TCR (tumor control rate=CR+PR+SD) = 57.3%
• TTP 4.1 months
• OS 8.2 months
Comparison of Regimens
• 2-drug VS 1-drug
— Higher RR 28.0 vs 15.3%, P=0.000
— Higher TCR 61.0 vs 50.4%, P=0.000
— Higher TTP 4.4 vs 3.4 months, P=0.015
— Higher OS 9.3 vs 7.5 months, P=0.061
•
3 or more-drug VS 2-drug
— Lower RR 19.1 vs 28.0%, P=0.000
— no difference in OS 9.0 vs 9.3 months
• 3 or more-drug VS 1-drug
— Higher TCR 58.9 vs 50.4%, P=0.028
— Higher TTP 5.2 vs 3.4 months, P=0.016
— Trend OS 9.0 vs 7.5 months, P=0.086
• Gemcitabine (G) combined with P (cisplatin or
oxaliplatin)
— the highest increases RR and TCR
— provide best possible evidence that this
combination chemotherapy may improve survival
in these diseases
• Subgroup analysis concerning the three most
important drugs demonstrated that
— G alone is not superior to FU
— Platinums increase the activity of both G and FU
•
greater with G compared with the addition to FU
Gemcitabine
Cisplatin
1250 mg/m2 in a 30-min infusion on d 1 and 8
75 mg/m2 on d1, 21-d cycle
RR 21%, TCR 52%, TTP 8.5 M, OS 10.5 M
Randomized studies of chemotherapy
in biliary tract cancer
Randomized clinical trials using
gemcitabine and cisplatin for advanced biliary tract cancer
Randomized :
gemcitabine 1000 mg/m2+ cisplatin 25 mg/m2 vs. gemcitabine 1000 mg/m2 alone
Valle JW, et al. J Clin Oncol 2009;27(15s).
Okusaka T,et al. Br J Cancer 2010;103(4):469–74.
Randomized clinical trials using
gemcitabine and cisplatin for advanced biliary tract cancer
Randomized :
gemcitabine 1000 mg/m2+ cisplatin 25 mg/m2 vs. gemcitabine 1000 mg/m2 alone
Valle JW, et al. J Clin Oncol 2009;27(15s).
Okusaka T,et al. Br J Cancer 2010;103(4):469–74.
Target agents in development
Single target agent
Erlotinib
Philip et al. JCO 2006
Lapatinib
Ramanathan et al.ASCO 2006,abs4010
Sorafenib
N
RR
PFS
39 BTC
35 HCC
17 BTC
17 HCC
31 BTC/GB
25% Progression free at 6 M
35% Progression free at 6 M
0%
1.8 M
12%
1.8 M
6%
2M
6M
El-Khoueiry et al. ASCO 2007,abs 4639
Double target agents
Erlotinib + Bevacizumab
6 GB
Holen et al. ASCO 2008, abs 4522
27 CCA
Target agent + Chemotherapy
Bevacizumab+ GemOX
10 BTC
Clark et al. ASCO 2007, abs 4625
9 GB
Cetuximab + GemOx
22 BTC
Gruenberger et al. ASCO2008, abs 4586
20% (20 evaluable)
27% (11 evaluable)
58% (19 evaluable)
OS
Conclusion : Systemic Therapy for CCA
• Chemotherapy is the standard for advanced
cholangiocarcinoma
• Level 1 evidence is gemcitabine and cisplatin
• Other combination regimens also have activity
• The future in this disease should lie in targeted
therapies (which agent ?, combination?)