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 ตัวอย่างของการศึกษาที่ใช้ยาเคมี บำบัด ในการรักษามะเร็งตับ ChemotherapyStudyN อัตราการ ตอบสนอง, % ระยะเวลา ที่ รอดชีวิต, เดือน Cisplatin, DoxorubicinLee et al.3718.97.3 Cisplatin, Interferon, Doxorubicin, 5-FU (PIAF) Yeo et al.9120.98.6 GemcitabineYang et al2817.84.6 CapecitabinePatt et al.371110.1 Gemcitabine, OxaliplatinLouafi et al.34186.3 Capecitabine, OxaliplatinBoige et al.5069.3 FOLFOX 4Quin et al.1848.26.4 DoxorubicinQuin et al.1872.7 P 0.02 4.9 P 0.085
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.
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 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 ‡ 680721 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 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 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 incidence805281.938.7 Diarrhoea39811225.56.05.30 Fatigue22416320.13.4 8.0 1.3 HFSR2183<145.010.72.70 Rash/desquamation16111020.10.76.70 Alopecia1402024.8–1.3– Anorexia14<13112.802.70 Nausea11<18111.4 0.710.71.3 Hypertension522118.82.0 1.30 *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. อาการข้างเคียงจากการรักษาของ Sorafenib ในการศึกษาอ้างอิง SHARP & AP trial
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 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 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
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/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 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
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 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) FELv /FLv
•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 1250 mg/m 2 in a 30-min infusion on d 1 and 8 Cisplatin 75 mg/m 2 on d1, 21-d cycle
Target agents in development NRR PFS OS Single target agent Erlotinib39 BTC25% Progression free at 6 M Philip et al. JCO 2006 35 HCC35% Progression free at 6 M Lapatinib17 BTC 0% 1.8 M Ramanathan et al.ASCO 2006,abs4010 17 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 4522 27 CCA Target agent + Chemotherapy Bevacizumab+ GemOX10 BTC27% (11 evaluable) Clark et al. ASCO 2007, abs 4625 9 GB Cetuximab + GemOx22 BTC58% (19 evaluable) Gruenberger et al. ASCO2008, abs 4586
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?)