5อุปสรรคของการรักษามะเร็งตับด้วยยา HCC tumor biology (พันธ์ดื้อ)disruption in p53 pathway : resistance to apoptosisDNA topoisomerase alpha over-expressed/ up-regulated : resistance to Topoisomerase inhibitorsintrinsic drug resistance mediated by an enhanced cellular drug efflux mechanism – MDR1, p-gp, MRPPharmacokinetic properties of cirrhotic liver (ตับไม่เอื้อ)total liver mass is reduceddistortion 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.
6ตัวอย่างของการศึกษาที่ใช้ยาเคมีบำบัด ในการรักษามะเร็งตับ ChemotherapyStudyNอัตราการตอบสนอง, %ระยะเวลาที่รอดชีวิต,เดือนCisplatin, DoxorubicinLee et al.3718.97.3Cisplatin, Interferon,Doxorubicin, 5-FU (PIAF)Yeo et al.9120.98.6GemcitabineYang et al2817.84.6CapecitabinePatt et al.1110.1Gemcitabine, OxaliplatinLouafi et al.34186.3Capecitabine, OxaliplatinBoige et al.5069.3FOLFOX 4Quin et al.1848.26.4Doxorubicin1872.7P 0.024.9P 0.085
7การใช้ยา Sorafenib NCCN 2013 APASL 2009 JSH 2010 For Unresectable HCC (tumor extent or location, liver function reserves), Child A or BAPASL 2009for 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 2010Sorafenib is the first choice of treatment as a standard of care in Extrahepatic spread with Child-Pugh A liver functionSorafenib is also a treatment of choice for TACE refractory patients with Child-Pugh A liver function.
8การศึกษาอ้างอิงที่ใช้ยา Sorafenib รักษามะเร็งตับ SHARP1Asia-Pacific21.001.00Sorafenib (n=299)Median: 10.7 monthsSorafenib (n=150) Median: 6.5 months0.750.75Placebo (n=303)Median: 7.9 monthsPlacebo (n=76)Median: 4.2 monthsSurvival Probability0.50Survival Probability0.500.250.25HR (S/P): 0.6995% CI:P=HR (S/P): 0.6895% CI:P=0.0144812162048121620Months from RandomizationMonths from Randomization1. Llovet JM, et al. N Engl J Med. 2008;359(4):2. Cheng AL, et al. Lancet Oncol. 2009;10:25-34.
9การศึกษาอ้างอิงที่ใช้ยา Sorafenib รักษามะเร็งตับ Sorafenib vs. placeboGIDEON(ASCO 2011)SHARPAsia-PacificHBV/HCV/others19/28/5371/11/1937/32/39BCLC stage A/B/ C (%)0/ 18/820/ 5/ 957/19/ 54Child-Pugh A /B (%)95/597/361/ 23ECOG PS 0 / 1 +2 (%)54/4625/ 7540 / 43OS (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
10GIDEON study: Child-Pugh A vs. B % of nChild-Pugh A (n=957)Child-Pugh B (n=367)Median treatment duration, weeks149Median daily dose, mg‡680721AEs (all Grades)8289SAEs†2956Drug-related SAEs‡815Permanent discontinuation of sorafenib due to AE§2438Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with SorafenibASCO 2011
11Sorafenib 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 cyclesPatients with AE (%)CycleHTN, hypertension1 cycle = 6 weeksHutson TE, et al. Eur J Cancer 2010;46:2432–40.1111
12อาการข้างเคียงจากการรักษาของ Sorafenib ในการศึกษาอ้างอิง SHARP & AP trial Incidence by grade (%)SHARP1Asia Pacific2Sorafenib (n=297)Placebo (n=302)Sorafenib (n=149)Placebo (n=75)AE*Any3-43–4Overall incidence805281.938.7Diarrhoea39811225.56.05.3Fatigue22416320.13.48.01.3HFSR21<145.010.72.7Rash/desquamation10.76.7Alopecia1424.8–Anorexia12.8Nausea11.4Hypertension518.82.0Nexavar was generally well tolerated with manageable AEsAEs associated with Nexavar were predominantly mild–moderate, and gastrointestinal, constitutional or dermatological in natureMost common drug-related AEs were HFSR, diarrhoea, alopecia, fatigue, rash/desquamation, hypertension, anorexia and nauseaAEs (NCI-CTCAE v3.0) that occurred in at least 10% of patients in either study arm are listed.Nexavar® was generally well tolerated with manageable AEs (predominantly grade 1 or 2)the most common drug-related AEs were HFSR, diarrhoea, alopecia, fatigue, rash/desquamation, hypertension, anorexia and nauseathis is a similar AE profile to that seen in the SHARP Trial.Grade 3–4 drug-related AEs that were reported more frequently in the Nexavar® group than in the placebo group included HFSR (10.7 vs 0%, respectively) and diarrhoea (6 vs 0%).Cheng A-L, et al. Efficacy and safety of sorafenib in patients in the Asia–Pacificregion with advanced hepatocellular carcinoma: a phase III randomised,double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25–34.*AEs, as defined by CTCAE version 3.0 that occurred in at least 10% of patients in either study group1. Llovet JM, et al. N Engl J Med. 2008;359(4):2. Cheng AL, et al. Lancet Oncol. 2009;10:25-34.
13Supportive measures (control callus, cream, cushion) Suggested Interventions for skin toxicity(Sorafenib 800 mg/day)Grade 1Grade 2Grade 3Supportive measures (control callus, cream, cushion)Topical therapyDecrease dose to 400mg/d for 7-28 daysIf symptoms resolve, increase to full doseIf symptoms persist, interrupt treatment for 7 daysResume tx at 400mg QD when toxicity < grade 113
14Supportive measures (control callus, cream, cushion) Suggested Interventions for skin toxicityGrade 1Grade 2Grade 3Supportive measures (control callus, cream, cushion)Topical therapyInterrupt treatment for 7 daysResume tx at 400mg/d when toxicity < grade 1Consider further dose reduction if symptoms recurIf toxicity < grade 1 for 7-28 days, may increase by one dose level14
15N = 868 Patients with advanced HCC treated with SOR Prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced HCCN = 868 Patients with advanced HCC treated with SORUrea-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)ResultsAll-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<0.001.Ren et al. J Clin Oncol 30, 2012 (suppl; abstr 4008)
16Sorafenib unanswered questions The mechanism of action of sorafenib in HCC that mediates clinical benefitsBenefits/Safety in patients with Child BOptimal doseThe mechanism of resistance
17Phase III trials in advanced HCC First-lineSorafenib/Doxorubicin vs Sorafenib/PlaceboSorafenib/Erlotinib vs Sorafenib/PlaceboSorafenib vs Sunitinib (failed, ASCO 2011)Sorafenib vs BrivanibSorafenib vs LinifanibSecond-lineBrivanib vs BSC (failed, EASL 2012)Everolimus vs BSCRamucirumab vs BSCADI-PEG 20 vs BSC
18Conclusion : Systemic therapy for HCC Sorafenib is the only approved systemic agent for the treatment of HCCMany other molecular-targeted agents are at the early stages of development in HCCRational design clinical trial with combination therapy holds promise to improve outcome and remain to be seen
19Systemic Therapy for Advanced Cholangiocarcinoma
20Challenges of systemic therapy in Cholangiocarcinoma Heterogeneous diseaseGall bladder cancerCholangiocarcinomaIntrahepatic cholangiocarcinoma(Peripheral type, mass forming)Extrahepatic cholangiocarcinomaDifferent location are truly the same pathology and biology ?
21Challenges to define standard chemotherapy for cholangiocarcinoma ? Lack of well conducted randomized controlled trialMost studies are small, non randomized phase IIMany studies comprise a mix of BTC, GBC and either PC or HCC.
22Chemo :FELv, FLv (age >60,PS <70) Overall survival :Chemo VS BSC6 M VS 2.5 M, P <0.016 M VS 2.5 M, P=0.05, N=53 : PCA6.5 M VS 2.5 M, P=0.1, N=37 : CCAFavorable QOL outcome :Chemo VS BSC – 36%VS10%,P <0.01both sitesQuality adjusted survival :Chemo VS BSC –4 M VS 1M,P <0.01FELv/FLvChemo :FELv, FLv (age >60,PS <70)
24104 trials (3 randomized, 112 trial arms), N = 2810 From January 1985 to July 200615% trials published 1993 – 199985% trials published after 2000No. 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 monthsOS 8.2 months
25Comparison of Regimens 2-drug VS 1-drugHigher RR 28.0 vs 15.3%, P=0.000Higher TCR 61.0 vs 50.4%, P=0.000Higher TTP 4.4 vs 3.4 months, P=0.015Higher OS 9.3 vs 7.5 months, P=0.0613 or more-drug VS 2-drugLower RR 19.1 vs 28.0%, P=0.000no difference in OS 9.0 vs 9.3 months3 or more-drug VS 1-drugHigher TCR 58.9 vs 50.4%, P=0.028Higher TTP 5.2 vs 3.4 months, P=0.016Trend OS 9.0 vs 7.5 months, P=0.086
26Gemcitabine (G) combined with P (cisplatin or oxaliplatin) the highest increases RR and TCRprovide best possible evidence that this combination chemotherapy may improve survival in these diseasesSubgroup analysis concerning the three most important drugs demonstrated thatG alone is not superior to FUPlatinums increase the activity of both G and FUgreater with G compared with the addition to FU
27Gemcitabine 1250 mg/m2 in a 30-min infusion on d 1 and 8 Cisplatin mg/m2 on d1, 21-d cycle
34Target agents in development N RR PFS OSSingle target agentErlotinib 39 BTC 25% Progression free at 6 MPhilip et al. JCO HCC 35% Progression free at 6 MLapatinib 17 BTC 0% MRamanathan et al.ASCO 2006,abs HCC 12% MSorafenib 31 BTC/GB 6% 2 M 6 MEl-Khoueiry et al. ASCO 2007,abs 4639Double target agentsErlotinib + Bevacizumab 6 GB 20% (20 evaluable)Holen et al. ASCO 2008, abs CCATarget agent + ChemotherapyBevacizumab+ GemOX 10 BTC 27% (11 evaluable)Clark et al. ASCO 2007, abs GBCetuximab + GemOx 22 BTC 58% (19 evaluable)Gruenberger et al. ASCO2008, abs 4586
35Conclusion : Systemic Therapy for CCA Chemotherapy is the standard for advanced cholangiocarcinomaLevel 1 evidence is gemcitabine and cisplatinOther combination regimens also have activityThe future in this disease should lie in targeted therapies (which agent ?, combination?)