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Systemic therapy for Advanced Hepatoma & Cholagiocarcinoma

นายแพทย� ชัยย�ทธ เจริ�ญธริริมนายแพทย� ชัยย�ทธ เจริ�ญธริริมหน�วยมะเริ�งว�ทยา ภาคว�ชัาอาย�ริศาสตริ�หน�วยมะเริ�งว�ทยา ภาคว�ชัาอาย�ริศาสตริ�

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Ablation

Stage 0PST 0, Child–Pugh A

Very early stage (0) 1 HCC <2cm

Carcinoma in situ

Early stage (A)1 HCC or 3 nodules

<3cm, PST 0

Advanced stage (C) Portal invasion, N1, M1, PST 1–2

End stage (D)

Transplantation TACEResection ริกษาปริะคบปริะคองม#โอกาสหายขาด ริะงบหริ'อบริริเทาโริค

Associated diseases

YesNo

3 nodules < 3 cm

Increased

Normal

1 HCC

Portal pressure/bilirubin

Stage DPST >2,

Child–Pugh C

HCC

Intermediate stage (B)Multinodular,

PST 0

Stage A–CPST 0–2, Child–Pugh A–B

Adapted from Llovet JM, et al. J Natl Cancer Inst 2008;100:698-711

ยา

แนวทางการิริกษามะเริ�งตบ(ริะยะโริค, ความแข�งแริงผู้)*ป+วย, ความแข�งแริงของตบ)

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4

Patient characteristics Point

Ascites Yes 2

No 0

Abdominal pain Yes 2

No 0

Weight loss Yes 2

No 0

Child-Pugh grade C 5

B 2

A 0

Biochemistry

Serum alkaline phosphatase (ALP), int. unit/L

>200 3

≤200 0

Total bilirubin >50 int. unit/L (2.9 mg/dL) 3

>33 - ≤50 int. unit/l (1.9 - 2.9 mg/dL) 1

≤33 int unit/L (1.9 mg/dL) 0

Urea >8.9 mmol/L (>25 mg/dL) 2

≤8.9 mmol/L (≤25 mg/dL) 0

Tumor characteristics

Portal vein thrombosis Yes 3

No 0

Tumor size Diffuse 4

>5 cm 3

≤5 cm 0

Lung metastases Yes 3

No 0

Serum alpha-fetoprotein (AFP), ng/mL

>400 4

≤400 0

โอกาสการิม#ชั#ว�ตริอดอย�างน*อย 3 เด'อนPatients With Advanced HCC

Not Amendable to Locoregional Therapy

Prognosis Score อตริาการิม#ชั#ว�ตท#, 3 เด'อน, %

Good 0-2 >81

3-6 72-80

7-8 66-69

Intermediate 9 63

10-12 51-59

13-14 42-47

15 38

Poor 16 33

17-19 21-29

20-22 10-17

≥23 <10

Yau et al. Cancer 2008.Yau et al. Cancer 2008.

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อ�ปสริริคของการิริกษามะเริ�งตบด*วยยา

HCC tumor biology (พนธ�ด'-อ)– 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 (ตบไม�เอ'-อ)– 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.

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ตวอย�างของการิศ/กษาท#,ใชั*ยาเคม#บ1าบดในการิริกษามะเริ�งตบ

Chemotherapy Study N อตริาการิตอบ

สนอง, %

ริะยะเวลาท#,

ริอดชั#ว�ต, เด'อน

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 2.7P 0.02

4.9P 0.085

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การิใชั*ยา 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 loco-

regional 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.

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Months from Randomization

Surv

ival

Pro

babi

lity

Sorafenib (n=299)Median: 10.7 months

Placebo (n=303)Median: 7.9 months

HR (S/P): 0.6995% CI: 0.55-0.87P=0.00058

0.25

0.50

0.75

1.00

00

4 8 12 16 20

SHARP1

Sorafenib (n=150)Median: 6.5 months

Placebo (n=76)Median: 4.2 months

HR (S/P): 0.68 95% CI: 0.50-0.93P=0.014

0.25

0.50

0.75

1.00

00

4 8 12 16 20

Asia-Pacific2

Months from Randomization

Surv

ival

Pro

babi

lity

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.

การิศ/กษาอ*างอ�งท#,ใชั*ยา Sorafenib ริกษามะเริ�งตบ

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Sorafenib vs. placeboGIDEON

(ASCO 2011)SHARP Asia-Pacific

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 SorafenibGIDEON : Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib

การิศ/กษาอ*างอ�งท#,ใชั*ยา Sorafenib ริกษามะเริ�งตบ

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GIDEON study: Child-Pugh A vs. B

% of nChild-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

ASCO 2011ASCO 2011

Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with SorafenibGlobal Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib

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Sorafenib long-term data: Initial presentation of treatment-related AEs (any grade) by cycle

Pati

ents

wit

h A

E (

%)

Cycle

Most Sorafenib-treated patients first experienced HFSR and other common AEs within the first two treatment cycles

Hutson TE, et al. Eur J Cancer 2010;46:2432–40.

HTN, hypertensionHTN, hypertension 1 cycle = 6 weeks1 cycle = 6 weeks

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Incidence by grade (%)

SHARP1 Asia Pacific2

Sorafenib (n=297) Placebo (n=302) Sorafenib (n=149) Placebo (n=75)

AE* Any 3-4 Any 3-4 Any 3–4 Any 3–4

Overall incidence 80 52 81.9 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.

อาการิข*างเค#ยงจากการิริกษาของ Sorafenib ในการิศ/กษาอ*างอ�ง SHARP & AP trial

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Grade 1 Grade 2 Grade 3

Supportive measures (control callus, cream, cushion)

If symptoms resolve, increase to full dose

If symptoms persist, interrupt treatment for 7 days

Resume tx at 400mg QD when toxicity < grade 1

Suggested Interventions for skin toxicity(Sorafenib 800 mg/day)

Topical therapy

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Interrupt treatment for 7 days

Grade 1 Grade 2 Grade 3Supportive measures (control callus, cream, cushion)

Suggested Interventions for skin toxicity

If toxicity < grade 1 for 7-28 days, may increase by one dose level

Resume tx at 400mg/d when toxicity < grade 1

Topical therapy

Consider further dose reduction if symptoms recur

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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) Ren et al. J Clin Oncol 30, 2012 (suppl; abstr 4008)

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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

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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

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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

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Systemic Therapy for Advanced Cholangiocarcinoma

Challenges of systemic therapy inChallenges of systemic therapy inCholangiocarcinomaCholangiocarcinoma

• 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 Challenges to define standard chemotherapy for cholangiocarcinoma ?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 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 sitesQuality adjusted survival : Chemo VS BSC –4 M VS 1M,P <0.01

both sitesChemo :FELv, FLv (age >60,PS <70)

FELv/FLv

Chemotherapy in CholangiocarcinomaChemotherapy in Cholangiocarcinoma

• ยาเด#,ยว— Fluoropyrimidine : 5-FU, capecitabine, tegafur, S1— Platinums : Cisplatin, carboplatin, oxaliplatin— Antimetabolites : Gemcitabine, MMC— Anthracyclines : Doxorubicin, Epirubicin— Topoisomerase I inhibitors : Irinotecan— Taxanes : Paclitaxel, Docetaxel

• ส)ตริยาค)�— FU + Platinums/ Gemcitabine— Gemcitabine + Platinums/ FU

• ส)ตริผู้สมท#,ใชั*ยาต-งแต� 3 ตวริ�วมกน – 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 RR = 22.6% (95% CI 21.0% - 24.2%)

• Pooled TCR (tumor control rate=CR+PR+SD) = 57.3%Pooled TCR (tumor control rate=CR+PR+SD) = 57.3%

• TTP 4.1 monthsTTP 4.1 months

• OS 8.2 monthsOS 8.2 months

Comparison of RegimensComparison 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 1250 mg/m2 in a 30-min infusion on d 1 and 8 Cisplatin 75 mg/m2 on d1, 21-d cycle

RR 21%, TCR 52%, TTP 8.5 M, OS 10.5 M

Randomized studies of chemotherapy Randomized studies of chemotherapy

in biliary tract cancerin biliary tract cancer

RRandomized clinical trials usingandomized clinical trials usinggemcitabine and cisplatin for advanced biliary tract cancergemcitabine and cisplatin for advanced biliary tract cancer

Valle JW, et al. J Clin Oncol 2009;27(15s).Okusaka T,et al. Br J Cancer 2010;103(4):469–74.Valle JW, et al. J Clin Oncol 2009;27(15s).Okusaka T,et al. Br J Cancer 2010;103(4):469–74.

Randomized : Randomized : gemcitabine 1000 mg/mgemcitabine 1000 mg/m22+ + cisplatin 25 mg/m2 vs. gemcitabine 1000 mg/mcisplatin 25 mg/m2 vs. gemcitabine 1000 mg/m22 alo aloneneRandomized : Randomized : gemcitabine 1000 mg/mgemcitabine 1000 mg/m22+ + cisplatin 25 mg/m2 vs. gemcitabine 1000 mg/mcisplatin 25 mg/m2 vs. gemcitabine 1000 mg/m22 alo alonene

Randomized clinical trials usinggemcitabine and cisplatin for advanced biliary tract cancer

Valle JW, et al. J Clin Oncol 2009;27(15s).Okusaka T,et al. Br J Cancer 2010;103(4):469–74.Valle JW, et al. J Clin Oncol 2009;27(15s).Okusaka T,et al. Br J Cancer 2010;103(4):469–74.

Randomized : Randomized : gemcitabine 1000 mg/mgemcitabine 1000 mg/m22+ + cisplatin 25 mg/m2 vs. gemcitabine 1000 mg/mcisplatin 25 mg/m2 vs. gemcitabine 1000 mg/m22 alo aloneneRandomized : Randomized : gemcitabine 1000 mg/mgemcitabine 1000 mg/m22+ + cisplatin 25 mg/m2 vs. gemcitabine 1000 mg/mcisplatin 25 mg/m2 vs. gemcitabine 1000 mg/m22 alo alonene

Target agents in developmentTarget agents in developmentN RR PFS OS

Single target agent Erlotinib 39 BTC 25% Progression free at 6 M Philip et al. JCO 2006 35 HCC 35% Progression free at 6 M Lapatinib 17 BTC 0% 1.8 M Ramanathan et al.ASCO 2006,abs4010 17 HCC 12% 1.8 M Sorafenib 31 BTC/GB 6% 2 M 6 M El-Khoueiry et al. ASCO 2007,abs 4639 Double target agents Erlotinib + Bevacizumab 6 GB 20% (20 evaluable) Holen et al. ASCO 2008, abs 4522 27 CCATarget agent + Chemotherapy Bevacizumab+ GemOX 10 BTC 27% (11 evaluable) Clark et al. ASCO 2007, abs 4625 9 GB Cetuximab + GemOx 22 BTC 58% (19 evaluable) Gruenberger et al. ASCO2008, abs 4586

Conclusion : Systemic Therapy for CCAConclusion : 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?)