Systemic therapy for Advanced Hepatoma & Cholagiocarcinoma

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

2. รักษาประคับ ประคอง แนวทางการรักษามะเร็งตับ(ระยะโรค, ความแข็งแรงผู้ป่วย, ความแข็งแรงของตับ) HCC Stage DPST >2, Child–Pugh C Stage 0PST 0, Child–Pugh A Stage A–CPST 0–2, Child–Pugh A–B Very early stage (0) 1 HCC <2cmCarcinoma in situ Early stage (A) 1 HCC or 3 nodules<3cm, PST 0 Intermediate stage (B) Multinodular,PST 0 Advanced stage (C)Portal invasion, N1, M1, PST 1–2 End stage (D) 1 HCC 3 nodules < 3 cm Portal pressure/bilirubin Increased Associated diseases Normal No Yes ยา Resection Transplantation Ablation TACE มีโอกาสหายขาด ระงับหรือบรรเทาโรค Adapted from Llovet JM, et al. J Natl Cancer Inst 2008;100:698-711

4. Yau et al. Cancer 2008.

5. อุปสรรคของการรักษามะเร็งตับด้วยยาอุปสรรคของการรักษามะเร็งตับด้วยยา • 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. ตัวอย่างของการศึกษาที่ใช้ยาเคมีบำบัดในการรักษามะเร็งตับตัวอย่างของการศึกษาที่ใช้ยาเคมีบำบัดในการรักษามะเร็งตับ

7. การใช้ยาSorafenib 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. การศึกษาอ้างอิงที่ใช้ยาSorafenibรักษามะเร็งตับการศึกษาอ้างอิงที่ใช้ยาSorafenibรักษามะเร็งตับ SHARP1 Asia-Pacific2 1.00 1.00 Sorafenib (n=299) Median: 10.7 months Sorafenib (n=150)Median: 6.5 months 0.75 0.75 Placebo (n=303) Median: 7.9 months Placebo (n=76) Median: 4.2 months Survival Probability Survival Probability 0.50 0.50 0.25 0.25 HR (S/P): 0.69 95% CI: 0.55-0.87 P=0.00058 HR (S/P): 0.68 95% CI: 0.50-0.93 P=0.014 0 0 4 8 12 16 20 4 8 12 16 20 0 0 Months from Randomization 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.

9. การศึกษาอ้างอิงที่ใช้ยาSorafenibรักษามะเร็งตับการศึกษาอ้างอิงที่ใช้ยาSorafenibรักษามะเร็งตับ GIDEON : Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib

10. GIDEON study: Child-Pugh A vs. B Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib ASCO 2011

11. Sorafenib long-term data: Initial presentation of treatment-related AEs (any grade) by cycle Most Sorafenib-treated patients first experienced HFSR and other common AEs within the first two treatment cycles Patients with AE (%) Cycle 1 cycle = 6 weeks HTN, hypertension Hutson TE, et al. Eur J Cancer 2010;46:2432–40.

12. อาการข้างเคียงจากการรักษาของ Sorafenibในการศึกษาอ้างอิง SHARP & AP trial *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.

13. 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

14. 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 7-28 days, may increase by one dose level

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<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)

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. 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

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. Systemic Therapy for Advanced Cholangiocarcinoma

20. Challenges of systemic therapy inCholangiocarcinoma • 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 <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 sites Quality adjusted survival : Chemo VS BSC –4 M VS 1M,P <0.01 both sites FELv /FLv Chemo :FELv, FLv (age >60,PS <70)

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% - 24.2%) 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/m2 in a 30-min infusion on d 1 and 8 Cisplatin 75 mg/m2 on d1, 21-d cycle

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 usinggemcitabine 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.

32. Randomized clinical trials usinggemcitabine 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.

34. Target agents in development N 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 HCC12% 1.8 M Sorafenib 31 BTC/GB 6% 2 M 6 M El-Khoueiryet al. ASCO 2007,abs 4639 Double target agents Erlotinib + Bevacizumab 6 GB 20% (20 evaluable) Holen et al. ASCO 2008, abs 4522 27 CCA Target agent + Chemotherapy Bevacizumab+ GemOX 10 BTC 27% (11 evaluable) Clark et al. ASCO 2007, abs 46259 GB Cetuximab + GemOx 22 BTC 58% (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?)