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1 Systemic therapy for Advanced Hepatoma & Cholagiocarcinoma นายแพทย์ ชัยยุทธ เจริญธรรม หน่วยมะเร็งวิทยา ภาควิชาอายุรศาสตร์

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งานนำเสนอเรื่อง: "1 Systemic therapy for Advanced Hepatoma & Cholagiocarcinoma นายแพทย์ ชัยยุทธ เจริญธรรม หน่วยมะเร็งวิทยา ภาควิชาอายุรศาสตร์"— ใบสำเนางานนำเสนอ:

1 1 Systemic therapy for Advanced Hepatoma & Cholagiocarcinoma นายแพทย์ ชัยยุทธ เจริญธรรม หน่วยมะเร็งวิทยา ภาควิชาอายุรศาสตร์

2 2 Ablation Stage 0 PST 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 TACE Resection รักษาประคับ ประคอง มีโอกาสหายขาดระงับหรือบรรเทาโรค Associated diseases YesNo 3 nodules < 3 cm Increased Normal 1 HCC Portal pressure/ bilirubin Stage D PST >2, Child–Pugh C HCC Intermediate stage (B) Multinodular, PST 0 Stage A–C PST 0–2, Child–Pugh A–B Adapted from Llovet JM, et al. J Natl Cancer Inst 2008;100: ยา แนวทางการรักษามะเร็งตับ ( ระยะโรค, ความแข็งแรงผู้ป่วย, ความแข็งแรง ของตับ )

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4 4 Patient characteristics Point AscitesYes2 No0 Abdominal painYes2 No0 Weight lossYes2 No0 Child-Pugh gradeC5 B2 A0 Biochemistry Serum alkaline phosphatase (ALP), int. unit/L >2003 ≤2000 Total bilirubin>50 int. unit/L (2.9 mg/dL)3 >33 - ≤50 int. unit/l ( 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 thrombosisYes3 No0 Tumor sizeDiffuse4 >5 cm3 ≤5 cm0 Lung metastasesYes3 No0 Serum alpha-fetoprotein (AFP), ng/mL >4004 ≤4000 โอกาสการมีชีวิตรอดอย่าง น้อย 3 เดือน Patients With Advanced HCC Not Amendable to Locoregional Therapy PrognosisScore อัตราการมีชีวิตที่ 3 เดือน, % Good0-2> Intermediate Poor ≥23<10 Yau et al. Cancer 2008.

5 5 อุปสรรคของการรักษา มะเร็งตับด้วยยา  HCC tumor biology ( พันธ์ดื้อ ) –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.

6 6 ตัวอย่างของการศึกษาที่ใช้ยาเคมี บำบัด ในการรักษามะเร็งตับ ChemotherapyStudyN อัตราการ ตอบสนอง, % ระยะเวลา ที่ รอดชีวิต, เดือน Cisplatin, DoxorubicinLee et al Cisplatin, Interferon, Doxorubicin, 5-FU (PIAF) Yeo et al GemcitabineYang et al CapecitabinePatt et al Gemcitabine, OxaliplatinLouafi et al Capecitabine, OxaliplatinBoige et al FOLFOX 4Quin et al DoxorubicinQuin et al P P 0.085

7 7 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 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.

8 8 Months from Randomization Survival Probability Sorafenib (n=299) Median: 10.7 months Placebo (n=303) Median: 7.9 months HR (S/P): % CI: P= SHARP 1 Sorafenib (n=150) Median: 6.5 months Placebo (n=76) Median: 4.2 months HR (S/P): % CI: P= Asia-Pacific 2 Months from Randomization Survival Probability 1. Llovet JM, et al. N Engl J Med. 2008;359(4): Cheng AL, et al. Lancet Oncol. 2009;10: การศึกษาอ้างอิงที่ใช้ยา Sorafenib รักษามะเร็งตับ

9 9 Sorafenib vs. placebo GIDEON (ASCO 2011) SHARPAsia-Pacific HBV/HCV/others19/28/5371/11/1937/32/39 BCLC stage A/B/ C (%)0/ 18/820/ 5/ 957/19/ 54 Child-Pugh A /B (%)95/597/361/ 23 ECOG PS 0 / 1 +2 (%)54/4625/ 7540 / 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 การศึกษาอ้างอิงที่ใช้ยา Sorafenib รักษามะเร็งตับ

10 10 GIDEON study: Child-Pugh A vs. B % of n Child-Pugh A (n=957) Child-Pugh B (n=367) Median treatment duration, weeks 149 Median daily dose, mg ‡ AEs (all Grades)8289 SAEs † 2956 Drug-related SAEs ‡ 815 Permanent discontinuation of sorafenib due to AE § 2438 ASCO 2011 Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib

11 11 Sorafenib long-term data: Initial presentation of treatment-related AEs (any grade) by cycle Patients with AE (%) 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, hypertension 1 cycle = 6 weeks

12 12 Incidence by grade (%) SHARP 1 Asia Pacific 2 Sorafenib (n=297)Placebo (n=302) Sorafenib (n=149) Placebo (n=75) AE* Any3-4Any3-4Any 3–4Any3–4 Overall incidence Diarrhoea Fatigue HFSR2183< Rash/desquamation Alopecia –1.3– Anorexia14< Nausea11< Hypertension *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): Cheng AL, et al. Lancet Oncol. 2009;10: อาการข้างเคียงจากการรักษาของ Sorafenib ในการศึกษาอ้างอิง SHARP & AP trial

13 13 Grade 1 Grade 2 Grade 3 Supportive measures (control callus, cream, cushion) 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 Suggested Interventions for skin toxicity (Sorafenib 800 mg/day) Topical therapy

14 14 Interrupt treatment for 7 days Grade 1 Grade 2 Grade 3 Supportive measures (control callus, cream, cushion) Suggested Interventions for skin toxicity If toxicity < grade 1 for 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

15 15 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< –Grade ≥2 HFSR tended to be lower in Arm A (21.9%) vs Arm B (29.2%), p= –The median time to the first HFSR event was 2.5 fold longer in Arm A (84 days, 95% CI days) vs Arm B; (34 days, 95% CI days), p< Ren et al. J Clin Oncol 30, 2012 (suppl; abstr 4008)

16 16 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

17 17 Phase III trials in advanced HCC  First-line –Sorafenib/Doxorubicin vs Sorafenib/Placebo –Sorafenib/Erlotinibvs Sorafenib/Placebo –Sorafenibvs Sunitinib (failed, ASCO 2011) –Sorafenibvs Brivanib –Sorafenibvs Linifanib  Second-line –Brivanib vs BSC (failed, EASL 2012) –Everolimusvs BSC –Ramucirumabvs BSC –ADI-PEG 20vs BSC

18 18 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

19 19 Systemic Therapy for Advanced Cholangiocarcinoma

20 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 ?

21 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.

22 Overall survival : Chemo VS BSC 6 M VS 2.5 M, P < 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) FELv /FLv

23 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 • สูตรผสมที่ใช้ยาตั้งแต่ 3 ตัวร่วมกัน – ECF, FAM, PIAF

24 •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% %) •Pooled TCR (tumor control rate=CR+PR+SD) = 57.3% •TTP 4.1 months •OS 8.2 months

25 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

26 •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

27 Gemcitabine 1250 mg/m 2 in a 30-min infusion on d 1 and 8 Cisplatin 75 mg/m 2 on d1, 21-d cycle

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

30 Randomized studies of chemotherapy in biliary tract cancer

31 Randomized clinical trials using gemcitabine 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. Randomized : gemcitabine 1000 mg/m 2 + cisplatin 25 mg/m2 vs. gemcitabine 1000 mg/m 2 alone

32 Randomized clinical trials using gemcitabine 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. Randomized : gemcitabine 1000 mg/m 2 + cisplatin 25 mg/m2 vs. gemcitabine 1000 mg/m 2 alone

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34 Target agents in development NRR PFS OS Single target agent Erlotinib39 BTC25% Progression free at 6 M Philip et al. JCO HCC35% Progression free at 6 M Lapatinib17 BTC 0% 1.8 M Ramanathan et al.ASCO 2006,abs HCC12% 1.8 M Sorafenib31 BTC/GB 6% 2 M6 M El-Khoueiry et al. ASCO 2007,abs 4639 Double target agents Erlotinib + Bevacizumab 6 GB20% (20 evaluable) Holen et al. ASCO 2008, abs CCA Target agent + Chemotherapy Bevacizumab+ GemOX10 BTC27% (11 evaluable) Clark et al. ASCO 2007, abs GB Cetuximab + GemOx22 BTC58% (19 evaluable) Gruenberger et al. ASCO2008, abs 4586

35 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?)


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