晚期原发性肝癌内科治疗进展
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摘要
原发性肝癌是中国发病率和死亡率均较高的恶性肿瘤。目前临床上晚期原发性肝癌的治疗以全身系统性药物治疗为主,主要包括系统化疗、分子靶向治疗以及免疫治疗等。该文就近年来晚期原发性肝癌的内科治疗研究进展作一综述。
Hepatocellular carcinoma(HCC)is a cancer with high morbidity and mortality in China.Systemic medical therapy,including systemic chemotherapy,molecular targeted therapy and immunotherapy,is the main treatment for advanced HCC. This article reviews the progress in medical treatment of HCC in recent years.
Hepatocellular carcinoma(HCC)is a cancer with high morbidity and mortality in China.Systemic medical therapy,including systemic chemotherapy,molecular targeted therapy and immunotherapy,is the main treatment for advanced HCC. This article reviews the progress in medical treatment of HCC in recent years.
引文
[1]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[2]Sciarrino E,Simonetti RG,Le Moli S,et al.Adriamycin treatment for hepatocellular carcinoma.Experience with109 patients[J].Cancer,1985,56:2751-2755.
[3]Lai CL,Wu PC,Chan GC,et al.Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma.Aprospective randomized trial[J].Cancer,1988,62:479-483.
[4]Fuchs CS,Clark JW,Ryan DP,et al.A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma[J].Cancer,2002,94:3186-3191.
[5]Patt YZ,Hassan MM,Aguayo A,et al.Oral capecitabine for the treatment of hepatocellular carcinoma,cholangiocarcinoma,and gallbladder carcinoma[J].Cancer,2004,101(3):578-586.
[6]Qin S,Bai Y,Lim HY,et al.Randomized,multicenter,open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia[J].JClin Oncol,2013,31:3501-3508.
[7]Leung TW,Patt YZ,Lau WY,et al.Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma[J].Clin Cancer Res,1999,5:1676-1681.
[8]Yeo W,Mok TS,Zee B,et al.A randomized phase IIIstudy of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil(PIAF)combination chemotherapy for unresectable hepatocellular carcinoma[J].J Natl Cancer Inst,2005,97(20):1532-1538.
[9]McDermott U,Sharma SV,Dowell L,et al.Identification of genotype correlated sensitivity to selective kinase inhibitors by using high throughput tumor cell line profiling[J].USA Proc Natl Acad Sci,2007,104:19936-19941.
[10]Jelic S,Sotiropoulos GC.Hepatocellular carcinoma:ESMOClinical Practice Guidelines for diagnosis,treatment and follow-up[J].Ann Oncol,2010,21(Suppl 5):v59-v64.
[11]Uovet J,Ricci S,Mazzaferro V,et a1.Sorafenib in advanced hepatocellular carcinoma[J].N Engl J Med,2008,359(4):378-390.
[12]Cheng AL,Kang Y,Chen Z,et al.Randomized phaseⅢtrial of sorafenib versus placebo in Asian patients with advanced hepatocellular carcinoma[J].J Clin Oncol,2008,26(19 Suppl):4509.
[13]Theysohn JM,Schlaak JF,Müller S,et al.Selective internal radiation therapy of hepatocellular carcinoma:potential hepatopulmonary shunt reduction after sorafenib administration[J].J Vasc Interv Radiol,2012,23:949-952.
[14]Richly H,Schultheis B,Adamietz IA,et al.Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma:results from a phaseⅠextension trial[J].Eur J Cancer,2009,45:579-587.
[15]Ghassan K,Abou-Alfa,Donna Niedzwieski,et al.PhaseⅢrandomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma(HCC):CALGB 80802(Alliance)[J].J Clin Oncol,2016,1:21-23.
[16]Liu GY,Liu Y,Zhang YW.TACE combined with sorafenib in the treatment of advanced HCC preliminary evaluation of the efficacy and safety[J].Electronic Journal of Liver Tumor,2018,5(2):19-23.[刘广宇,刘影,张跃伟.TACE联合索拉非尼治疗中晚期肝细胞肝癌疗效及安全性初步评价[J].肝癌电子杂志,2018,5(2):19-23.]
[17]Zhang YF,Wei W,Wang JH,et al.Transarterial chemoembolization combined with sorafenib for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus[J].Onco Targets Ther,2016,9:4239-4246.
[18]Ikeda K,Kudo M,Kawazoe S,et al.Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma[J].J Gastroenterol,2017,52(4):512-519.
[19]Cheng AL,Finn RS,Qin SK,et al.PhaseⅢtrial of lenvatinib(LEN)vs sorafenib(SOR)in first-line treatment of patients(pts)with unresectable hepatocellular carcinoma(uHCC)[R].Chicago:ASCO,2017.Abstr 4001.
[20]Bruix J,Tak WY,Gasbarrini A,et al.Regorafenib as econdline therapy for intermediate or advanced hepatocellular carcinoma:multicentre,open-label,phaseⅡsafety study[J].Eur J Cancer,2013,49(16):3412-3419.
[21]Bruix J,Merle P,Granito A,et al.Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma(HCC)progressing on sorafenib:results of the international,randomized phase 3 RESORCE trial[J].Ann Oncol,2016,27:140-141.
[22]Lilly announces CYRAMZA誖(ramucirumab)phase 3REACH-2 study in second-line hepatocellular carcinoma patients met overall survival endpoint[EB/OL].https://investor.lilly.com/news-releases/news-release-details/lilly-announces-cyramzar-ramucirumab-phase-3-reach-2-study,2018-04-04.
[23]Zhu AX,Baron AD,Malfertheiner P,et al.Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma:analysis of REACH trial results by Child-Pugh score[J].JAMA Oncol,2016,22:4115.
[24]Chau I,Peck-Radosavljevic M,Borg C,et al.Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib:patient-focused outcome results from the randomised phaseⅢREACH study[J].Eur J Cancer,2017,81:17-25.
[25]Abou-Alfa GK,Meyer T,Cheng AL,et al.Cabozantinib(C)versus placebo(P)in patients(pts)with advanced hepatocellular carcinoma(HCC)who have received prior sorafenib:results from the randomized phaseⅢCELESTIALtrial[R].San Francisco:ASCO-GI,2018.Abstr 207.
[26]Kelley RK,Gane E,Assenat E,et al.A phase 2 study of galunisertib(TGF-βR1 inhibitor)and sorafenib in patients with advanced hepatocellular carcinoma(HCC)[R].Chicago:ASCO,2017.Abstr 4097.
[27]Qin SK,Kim TY,Lim HY,et al.PhaseⅠb trial of tepotinib in Asian patients with advanced hepatocellular carcinoma(HCC):final data including long-term outcomes[R]Chicago:ASCO,2017.Abstr 4087.
[28]Santoro A,Rimassa L,Borbath I,et al.Tivantinib for second-line treatment of advanced hepatocellular carcinoma:a randomised,placebo-controlled phase 2 study[J].Lancet Oncol,2013,14(1):55-63.
[29]Rimassa L,Assenat E,Peck-Radosavljevic M,et al.Secondline tivantinib(ARQ 197)vs placebo in patients(Pts)with MET-high hepatocellular carcinoma(HCC):results of the METIV-HCC phaseⅢtrial[R].Chicago:ASCO,2017.Abstr4000.
[30]Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy[J].Nat Rev Cancer,2012,12(4):252-264.
[31]El-Khoueiry AB,Sangro B,Yau T,et al.Nivolumab in patients with advanced hepatocellular carcinoma(CheckMate040):an open-label,non-comparative,phase 1/2 dose escalation and expansion trial[J].Lancet,2017,389(10088):2492-2502.
[32]Sangro B,Park JW,Dela Cruz C,et al.A randomized,multicenter,phase 3 study of nivolumab vs sorafenib as first-line treatment in patients(pts)with advanced hepatocellular carcinoma(HCC):CheckMate-459[R].Chicago:ASCO,2016.Abstr 4147.
[33]Zhu AX,Finn RS,Cattan S,et al.KEYNOTE-224:pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib[J].J Clin Oncol,2018,36(4 Suppl):209.
[34]Stein S,Pishvaian MJ,Lee MS,et al.Safety and clinical activity of 1L atezolizumab+bevacizumab in a phaseⅠb study in hepatocellular carcinoma(HCC)[J].J Clin Oncol,2018,36(15 Suppl):4074.
[35]Ikeda M,Sung MW,Kudo M,et al.A phase 1b trial of lenvatinib(LEN)plus pembrolizumab(PEM)in patients(pts)with unresectable hepatocellular carcinoma(uHCC)[J].J Clin Oncol,2018,36(15 Suppl):4076.
[36]Xu JM,Zhang Y,Jia R,et al.Anti-programmed death-1antibody SHR-1210(S)combined with apatinib(A)for advanced hepatocellular carcinoma(HCC),gastric cancer(GC)or esophagogastric junction(EGJ)cancer refractory to standard therapy:a phase 1 trial[J].J Clin Oncol,2018,36(15 Suppl):4075.
[2]Sciarrino E,Simonetti RG,Le Moli S,et al.Adriamycin treatment for hepatocellular carcinoma.Experience with109 patients[J].Cancer,1985,56:2751-2755.
[3]Lai CL,Wu PC,Chan GC,et al.Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma.Aprospective randomized trial[J].Cancer,1988,62:479-483.
[4]Fuchs CS,Clark JW,Ryan DP,et al.A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma[J].Cancer,2002,94:3186-3191.
[5]Patt YZ,Hassan MM,Aguayo A,et al.Oral capecitabine for the treatment of hepatocellular carcinoma,cholangiocarcinoma,and gallbladder carcinoma[J].Cancer,2004,101(3):578-586.
[6]Qin S,Bai Y,Lim HY,et al.Randomized,multicenter,open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia[J].JClin Oncol,2013,31:3501-3508.
[7]Leung TW,Patt YZ,Lau WY,et al.Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma[J].Clin Cancer Res,1999,5:1676-1681.
[8]Yeo W,Mok TS,Zee B,et al.A randomized phase IIIstudy of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil(PIAF)combination chemotherapy for unresectable hepatocellular carcinoma[J].J Natl Cancer Inst,2005,97(20):1532-1538.
[9]McDermott U,Sharma SV,Dowell L,et al.Identification of genotype correlated sensitivity to selective kinase inhibitors by using high throughput tumor cell line profiling[J].USA Proc Natl Acad Sci,2007,104:19936-19941.
[10]Jelic S,Sotiropoulos GC.Hepatocellular carcinoma:ESMOClinical Practice Guidelines for diagnosis,treatment and follow-up[J].Ann Oncol,2010,21(Suppl 5):v59-v64.
[11]Uovet J,Ricci S,Mazzaferro V,et a1.Sorafenib in advanced hepatocellular carcinoma[J].N Engl J Med,2008,359(4):378-390.
[12]Cheng AL,Kang Y,Chen Z,et al.Randomized phaseⅢtrial of sorafenib versus placebo in Asian patients with advanced hepatocellular carcinoma[J].J Clin Oncol,2008,26(19 Suppl):4509.
[13]Theysohn JM,Schlaak JF,Müller S,et al.Selective internal radiation therapy of hepatocellular carcinoma:potential hepatopulmonary shunt reduction after sorafenib administration[J].J Vasc Interv Radiol,2012,23:949-952.
[14]Richly H,Schultheis B,Adamietz IA,et al.Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma:results from a phaseⅠextension trial[J].Eur J Cancer,2009,45:579-587.
[15]Ghassan K,Abou-Alfa,Donna Niedzwieski,et al.PhaseⅢrandomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma(HCC):CALGB 80802(Alliance)[J].J Clin Oncol,2016,1:21-23.
[16]Liu GY,Liu Y,Zhang YW.TACE combined with sorafenib in the treatment of advanced HCC preliminary evaluation of the efficacy and safety[J].Electronic Journal of Liver Tumor,2018,5(2):19-23.[刘广宇,刘影,张跃伟.TACE联合索拉非尼治疗中晚期肝细胞肝癌疗效及安全性初步评价[J].肝癌电子杂志,2018,5(2):19-23.]
[17]Zhang YF,Wei W,Wang JH,et al.Transarterial chemoembolization combined with sorafenib for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus[J].Onco Targets Ther,2016,9:4239-4246.
[18]Ikeda K,Kudo M,Kawazoe S,et al.Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma[J].J Gastroenterol,2017,52(4):512-519.
[19]Cheng AL,Finn RS,Qin SK,et al.PhaseⅢtrial of lenvatinib(LEN)vs sorafenib(SOR)in first-line treatment of patients(pts)with unresectable hepatocellular carcinoma(uHCC)[R].Chicago:ASCO,2017.Abstr 4001.
[20]Bruix J,Tak WY,Gasbarrini A,et al.Regorafenib as econdline therapy for intermediate or advanced hepatocellular carcinoma:multicentre,open-label,phaseⅡsafety study[J].Eur J Cancer,2013,49(16):3412-3419.
[21]Bruix J,Merle P,Granito A,et al.Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma(HCC)progressing on sorafenib:results of the international,randomized phase 3 RESORCE trial[J].Ann Oncol,2016,27:140-141.
[22]Lilly announces CYRAMZA誖(ramucirumab)phase 3REACH-2 study in second-line hepatocellular carcinoma patients met overall survival endpoint[EB/OL].https://investor.lilly.com/news-releases/news-release-details/lilly-announces-cyramzar-ramucirumab-phase-3-reach-2-study,2018-04-04.
[23]Zhu AX,Baron AD,Malfertheiner P,et al.Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma:analysis of REACH trial results by Child-Pugh score[J].JAMA Oncol,2016,22:4115.
[24]Chau I,Peck-Radosavljevic M,Borg C,et al.Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib:patient-focused outcome results from the randomised phaseⅢREACH study[J].Eur J Cancer,2017,81:17-25.
[25]Abou-Alfa GK,Meyer T,Cheng AL,et al.Cabozantinib(C)versus placebo(P)in patients(pts)with advanced hepatocellular carcinoma(HCC)who have received prior sorafenib:results from the randomized phaseⅢCELESTIALtrial[R].San Francisco:ASCO-GI,2018.Abstr 207.
[26]Kelley RK,Gane E,Assenat E,et al.A phase 2 study of galunisertib(TGF-βR1 inhibitor)and sorafenib in patients with advanced hepatocellular carcinoma(HCC)[R].Chicago:ASCO,2017.Abstr 4097.
[27]Qin SK,Kim TY,Lim HY,et al.PhaseⅠb trial of tepotinib in Asian patients with advanced hepatocellular carcinoma(HCC):final data including long-term outcomes[R]Chicago:ASCO,2017.Abstr 4087.
[28]Santoro A,Rimassa L,Borbath I,et al.Tivantinib for second-line treatment of advanced hepatocellular carcinoma:a randomised,placebo-controlled phase 2 study[J].Lancet Oncol,2013,14(1):55-63.
[29]Rimassa L,Assenat E,Peck-Radosavljevic M,et al.Secondline tivantinib(ARQ 197)vs placebo in patients(Pts)with MET-high hepatocellular carcinoma(HCC):results of the METIV-HCC phaseⅢtrial[R].Chicago:ASCO,2017.Abstr4000.
[30]Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy[J].Nat Rev Cancer,2012,12(4):252-264.
[31]El-Khoueiry AB,Sangro B,Yau T,et al.Nivolumab in patients with advanced hepatocellular carcinoma(CheckMate040):an open-label,non-comparative,phase 1/2 dose escalation and expansion trial[J].Lancet,2017,389(10088):2492-2502.
[32]Sangro B,Park JW,Dela Cruz C,et al.A randomized,multicenter,phase 3 study of nivolumab vs sorafenib as first-line treatment in patients(pts)with advanced hepatocellular carcinoma(HCC):CheckMate-459[R].Chicago:ASCO,2016.Abstr 4147.
[33]Zhu AX,Finn RS,Cattan S,et al.KEYNOTE-224:pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib[J].J Clin Oncol,2018,36(4 Suppl):209.
[34]Stein S,Pishvaian MJ,Lee MS,et al.Safety and clinical activity of 1L atezolizumab+bevacizumab in a phaseⅠb study in hepatocellular carcinoma(HCC)[J].J Clin Oncol,2018,36(15 Suppl):4074.
[35]Ikeda M,Sung MW,Kudo M,et al.A phase 1b trial of lenvatinib(LEN)plus pembrolizumab(PEM)in patients(pts)with unresectable hepatocellular carcinoma(uHCC)[J].J Clin Oncol,2018,36(15 Suppl):4076.
[36]Xu JM,Zhang Y,Jia R,et al.Anti-programmed death-1antibody SHR-1210(S)combined with apatinib(A)for advanced hepatocellular carcinoma(HCC),gastric cancer(GC)or esophagogastric junction(EGJ)cancer refractory to standard therapy:a phase 1 trial[J].J Clin Oncol,2018,36(15 Suppl):4075.