New Developments in the Treatment of Hepatocellular Carcinoma: The Concept of Adjuvant and Neoadjuvant Chemotherapy

Abstract

Hepatocellular carcinoma (HCC) is the commonest liver malignancy, and its annual incidence has been estimated to be 2.8 per 100,000 population in India.1Kumar A. Acharya S.K. Singh S.P. et al.INASL Taskforce on Hepatocellular Carcinoma2019 Update of Indian national association for study of the liver consensus on prevention, diagnosis, and management of hepatocellular carcinoma in India: the puri II recommendations.J Clin Exp Hepatol. 2020 Jan-Feb; 10: 43-80https://doi.org/10.1016/j.jceh.2019.09.007Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar There is evidence to suggest that the incidence and prevalence of HCC are rising because of the raging epidemic of nonalcoholic fatty liver disease, and the condition is likely to become the leading cause of cancer in India in near future.2Three-year report of PBCR 2012-2014. http://ncdirindia.org/NCRP/ALL_NCRP_REPORTS/PBCR_REPORT_2012_2014/ALL_ CONTENT/Printed_Version.htm. Accessed August 12, 2018.Google Scholar The situation is similar in the Western world too.3Younossi Z. Stepanova M. Ong J.P. et al.Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2019; 17 (e3): 748-755https://doi.org/10.1016/j.cgh.2018.05.057Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar The prognosis of HCC is dismal because of several reasons. Most cases in India are diagnosed at an advanced stage (BCLC-A: 13%; BCLC-B: 39%; BCLC-C 23%; BCLC-D: 13%).4Acharya S.K. Epidemiology of hepatocellular carcinoma in India.J Clin Exp Hepatol. 2014; 4: S27-S33https://doi.org/10.1016/j.jceh.2014.05.013Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Moreover, the curative treatments are often out of the economic reach of an average man. A conventional oncological approach (with systemic chemotherapy, external radiotherapy, or plain surgery) does not work for HCC because of associated cirrhosis and portal hypertension in most patients. Therefore, a wide range of new approaches, ranging from drastic to minimally invasive ones, were tried and soon became popular. These include treatment with curative intent such as liver transplantation (LT), resection or ablative techniques (such as percutaneous radiofrequency ablation [RFA], percutaneous ethanol injection, microwave ablation [MWA], cryoablation [CA], irreversible electroporation) in early stages of HCC (BCLC-0 and BCLC-A). In addition, one also has locoregional treatments with palliative intent such as transarterial chemoembolization (TACE) or chemoembolization with drug-eluting beads and, more recently, local endovascular radiotherapy via transarterial delivery of beta-emitting microparticles (selective internal radiation therapy) for later stages of HCC (BCLC-B and BCLC-C).5Inchingolo R. Posa A. Mariappan M. Spiliopoulos S. Locoregional treatments for hepatocellular carcinoma: current evidence and future directions.World J Gastroenterol. 2019; 25: 4614-4628https://doi.org/10.3748/wjg.v25.i32.4614Crossref PubMed Scopus (38) Google Scholar Attempts have also been made to downstage the incurable or late-stage tumors to make them amenable to curative treatment.6European Association for the Study of the LiverEASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2018; 69: 182-236Abstract Full Text Full Text PDF PubMed Scopus (2789) Google Scholar Thus, treatment of HCC remains complex and enigmatic. In this issue of the journal, there are two reports concerning the treatment of HCC. Kedarisetty et al7Kedarisetty C.A. Bal S. Parida S. et al.Role of N-acetyl cysteine in post-transarterial chemoembolization transaminitis in hepatocellular carcinoma: a single-center experience.J Clin Exp Hepatol. 2021; 11: 299-304https://doi.org/10.1016/j.jceh.2020.10.007Abstract Full Text Full Text PDF Scopus (1) Google Scholar have described a prospective, single-center experience with treatment of 112 patients with HCC treated with TACE. They have shown that early initiation of N-acetyl cysteine in those with post-TACE embolization syndrome reduces the transaminase level significantly. It is basically a proof-of-concept study for use of N-acetyl cysteine in post-TACE transaminitis, although the period of hospitalization was not different with this treatment. On the other hand, Kalra et al8Kalra N. Gupta P. Jugpal T. et al.Percutaneous cryoablation of liver tumors: initial experience from a tertiary care center in India.J Clin Exp Hepatol. 2021; 11: 305-311https://doi.org/10.1016/j.jceh.2020.10.005Abstract Full Text Full Text PDF Scopus (3) Google Scholar have reported the initial experience with percutaneous CA for early-stage liver tumors. Technical success was achieved in all 9 patients. Complete response was achieved in 7 (77.8%) patients. There was no local tumor progression and no death during the median follow-up period of 7 months. There was no procedure-related complication. The study demonstrates the feasibility and safety of this ablative technique; however, no attempt has been made to compare it with the more popular RFA. In the succeeding paragraphs, the changing approach to locoregional therapies in overall management of HCC in the wake of new developments is briefly reviewed. Firstly, there is a rich experience of using heat-based tumor ablation therapies such as RFA and MWA, but experience with freezing the tumor tissue is relatively limited.9Hinshaw J.L. Lubner M.G. Ziemlewicz T.J. Lee F.T. Brace C.L. Percutaneous tumor ablation tools: microwave, radiofrequency, or cryoablation – what should you use and why?.Radiographics. 2014; 34: 1344-1362Crossref PubMed Scopus (190) Google Scholar RFA has technical limitations such as impedance from charred tissue and relative tissue susceptibility to heat sink effects. CA causes cell damage by freezing intracellular and extracellular fluid and subsequent cell death.10Dendy M.S. Ludwig J.M. Stein S.M. Kim H.S. Locoregional therapy, immunotherapy and the combination in hepatocellular carcinoma: future directions.Liver Canc. 2019 Oct; 8 (Epub 2019 Jan 16. PMID: 31768343; PMCID: PMC6873025): 326-340https://doi.org/10.1159/000494843Crossref PubMed Scopus (18) Google Scholar CA has the advantage of reduced rates of gallbladder or bowel injury and less painful procedure in superficial lesions, although relatively longer freezing times, as well as the need for multiple cryoprobes, may be cited as a limitation.11Xu J. Noda C. Erickson A. et al.Radiofrequency ablation vs. Cryoablation for localized hepatocellular carcinoma: a propensity-matched population study.Anticancer Res. 2018 Nov; 38: 6381-6386https://doi.org/10.21873/anticanres.12997Crossref PubMed Scopus (11) Google Scholar CA may be the modality of choice when precision is needed for tumors near vulnerable structures such as blood vessels because the ablation zone can be monitored in real time on intraprocedural computed tomography. A lot more needs to be learned about relative merits of various ablative treatments in HCC. Second, TACE remains the most widely available and popular therapy for intermediate-stage HCC and is well supported by evidence.12Palmer D.H. Malagari K. Kulik L.M. Role of locoregional therapies in the wake of systemic therapy.J Hepatol. 2020 Feb; 72 (PMID: 31954492): 277-287https://doi.org/10.1016/j.jhep.2019.09.023Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar There is robust evidence that TACE can prolong life in BCLC stage B, but it is considered a palliative treatment. TACE sessions when repeated over time lead to progressive deterioration of liver function, making patients unfit later even for systemic therapy.13Peck-Radosavljevic M. Kudo M. Raoul J.-L. et al.Outcomes of patients (pts) with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE): global OPTIMIS final analysis.J Clin Oncol. 2018; 36: 4018Crossref Google Scholar Deteriorating liver functions also significantly reduce the survival benefits of systemic therapy. Therefore, the optimum timing for giving up TACE and starting systemic therapy has been a matter of debate, and various scores have been developed to have clearer guidelines with limited benefit.14Sieghart W. Hucke F. Pinter M. et al.The ART of decision making: retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma.Hepatology. 2013; 57: 2261-2273Crossref PubMed Scopus (222) Google Scholar,15Kadalayil L. Benini R. Pallan L. et al.A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer.Ann Oncol. 2013; 24: 2565-2570Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar It has been suggested that the hypoxic environment created by the TACE procedure stimulates induction of vascular endothelial growth factor (VEGF) and other angiogenic pathways, promoting revascularization, neoangiogenesis, and growth of the residual viable tumor.16Wang B. Xu H. Gao Z.Q. Ning H.F. Sun Y.Q. Cao G.W. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization.Acta Radiol. 2008; 49: 523-529Crossref PubMed Scopus (199) Google Scholar,17Fernández M. Semela D. Bruix J. Colle I. Pinzani M. Bosch J. Angiogenesis in liver disease.J Hepatol. 2009; 50: 604-620Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar Third, exciting developments have taken place on the systemic therapy front. The development of the molecular-targeted agent sorafenib that improved survival in late-stage HCC is old news now.18Llovet J.M. Ricci S. Mazzaferro V. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (8043) Google Scholar In the last 3–4 years, a series of new drugs have become available for clinical use, which are as good as or even better than sorafenib and work through several mechanisms including inhibition of angiogenesis.19Bruix J. Qin S. Merle P. et al.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo controlled, phase 3 trial.Lancet. 2017; 389: 56-66Abstract Full Text Full Text PDF PubMed Scopus (1701) Google Scholar, 20Abou-Alfa G.K. Meyer T. Cheng A.L. et al.Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.N Engl J Med. 2018; 379: 54-63Crossref PubMed Scopus (842) Google Scholar, 21Zhu A.X. Kang Y.K. Yen C.J. et al.Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2019; 20: 282-296Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar Another recent trial (IMbrave150)22Finn R.S. Qin S. Ikeda M. et al.Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med. 2020; 382: 1894-1905Crossref PubMed Scopus (1087) Google Scholar demonstrated that atezolizumab plus bevacizumab improves overall survival and all other efficacy outcomes when compared with those obtained with sorafenib monotherapy. Time was now ripe to combine locoregional therapies with systemic therapies to see if one can achieve a miraculous summation of results.23Geschwind J.-F. Kudo M. Marrero J.A. et al.TACE treatment in patients with sorafenib-treated unresectable hepatocellular carcinoma in clinical practice: final analysis of GIDEON.Radiology. 2016; 279: 630-640Crossref PubMed Scopus (78) Google Scholar,24Strebel B.M. Dufour J.-F. Combined approach to hepatocellular carcinoma: a new treatment concept for nonresectable disease.Expert Rev Anticancer Ther. 2008; 8: 1743-1749Crossref PubMed Scopus (79) Google Scholar Several schedules were tried aiming to minimize the angiogenic upsurge induced by TACE and to maximize synergy.12Palmer D.H. Malagari K. Kulik L.M. Role of locoregional therapies in the wake of systemic therapy.J Hepatol. 2020 Feb; 72 (PMID: 31954492): 277-287https://doi.org/10.1016/j.jhep.2019.09.023Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Initial attempts to combine TACE with sorafenib failed to show exciting results.25Bruix J. Takayama T. Mazzaferro V. et al.Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Oncol. 2015; 16 ([cited 2020 Sep 28] Available from:): 1344-1354https://pubmed.ncbi.nlm.nih.gov/26361969/Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar However, some studies confirmed the feasibility and demonstrated a positive effect on survival in BCLC stage C disease.12Palmer D.H. Malagari K. Kulik L.M. Role of locoregional therapies in the wake of systemic therapy.J Hepatol. 2020 Feb; 72 (PMID: 31954492): 277-287https://doi.org/10.1016/j.jhep.2019.09.023Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Because many of these were retrospective analyses, the results were not particularly convincing.26Kudo M. Recent advances in systemic therapy for hepatocellular carcinoma in an aging society: 2020 update.Liver Canc. 2020 Dec; 9 (Epub 2020 Nov 17. PMID: 33442538; PMCID: PMC7768150): 640-662https://doi.org/10.1159/000511001Crossref PubMed Scopus (1) Google Scholar Use of drugs other than sorafenib, for example, thalidomide, bevacizumab, and brivanib did not change the outcome much. However, more recently, a prospective study, the “TACTICS trial” has shown highly promising results.27Kudo M. Ueshima K. Ikeda M. et al.Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.Gut. 2020; 69: 1492-1501Crossref PubMed Scopus (117) Google Scholar It has been shown that TACE plus sorafenib in patients with unresectable HCC significantly improved PFS over TACE alone. Combining TACE with immunotherapy is also an attractive option. LRT on its own can drive antitumor immune responses as it can release tumor antigens (DAMPs), activate the innate immune system, and generate sustained T-cell immunity. It can also lead to checkpoint blockade to maintain T-cell effector function. Patients treated with TACE show greater TAA-specific CD8+ T-cell responses. One can hypothesize that CPI therapy given in a highly immunogenic environment will increase the chance of overcoming local tumor-mediated immune suppression.12Palmer D.H. Malagari K. Kulik L.M. Role of locoregional therapies in the wake of systemic therapy.J Hepatol. 2020 Feb; 72 (PMID: 31954492): 277-287https://doi.org/10.1016/j.jhep.2019.09.023Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar,28Restrepo C.R. Field D.H. Kim A.Y. Current state of combination of locoregional therapies with immune checkpoint inhibition.J Vasc Intervent Radiol. 2020 Nov; 31 (e9) (Epub 2020 Oct 2. PMID: 33019993): 1740-1744https://doi.org/10.1016/j.jvir.2020.07.011Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Replacing TACE with other locoregional therapies such as TARE is also an interesting option. LRT is also used to downstage HCC beyond Milan criteria to consider the curative option of LT in patients with the intermediate-stage disease. Whether combination therapies can make downstaging more efficient remains to be seen. There is a compelling argument to use systemic therapy before rather than after tumor ablation or surgery. In animal models, it has been shown that immunotherapy could improve survival if the primary tumor was in situ as it leads to enhanced tumor-specific CD8+ T-cell activation.29Liu J. Blake S.J. Yong M.C.R. et al.Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease.Canc Discov. 2016 Dec; 6: 1382-1399Crossref PubMed Scopus (312) Google Scholar Thus, immunotherapy before tumor resection can induce an effect like a vaccine, resulting in sustained systemic immune surveillance.30Pinato D.J. Fessas P. Sapisochin G. Marron T.U. Perspectives on the neoadjuvant use of immunotherapy in hepatocellular carcinoma.Hepatology. 2020 Dec 28; (Epub ahead of print. PMID: 33369758)https://doi.org/10.1002/hep.31697Crossref Scopus (4) Google Scholar Several other studies have also shown that systemic therapy in the neoadjuvant setting leads to enhanced therapeutic benefit by adequate maturing of Baft3+ dendritic cells (which are the most potent cross-presenters of TAA to CD8+ T cells) and by stimulating immune-exhausted tumor-infiltrating lymphocytes, expansion of Tcf1+ PD-1+ stem–like subsets, and proliferation of subdominant T-cell clones.30Pinato D.J. Fessas P. Sapisochin G. Marron T.U. Perspectives on the neoadjuvant use of immunotherapy in hepatocellular carcinoma.Hepatology. 2020 Dec 28; (Epub ahead of print. PMID: 33369758)https://doi.org/10.1002/hep.31697Crossref Scopus (4) Google Scholar, 31Siddiqui I. Schaeuble K. Chennupati V. et al.Intratumoral Tcf1 + PD-1 + CD8 + T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy.Immunity. 2019 Jan 15; 50 (e10, [cited 2020 Sep 28]. Available from:): 195-211https://pubmed.ncbi.nlm.nih.gov/30635237/Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar, 32Liu J. Rozeman E.A. O'Donnell J.S. et al.Batf3 + DCs and type I IFN are critical for the efficacy of neoadjuvant cancer immunotherapy.Oncoimmunology. 2019 Feb 1; 8 (Available from:)https://pubmed.ncbi.nlm.nih.gov/30713806/Crossref Scopus (15) Google Scholar There is also evidence to show that a certain period of time is crucial between use of immunotherapy and surgery among metastatic mouse tumor models as IFN-γ secretion from tumor antigen–specific T cells may be affected.33Liu J. O'Donnell J.S. Yan J. et al.Timing of neoadjuvant immunotherapy in relation to surgery is crucial for outcome.Oncoimmunology. 2019 May 4; 8e1581530Crossref PubMed Scopus (27) Google Scholar Evidence is accumulating that use of immune checkpoint inhibitors (ICIs) as a neoadjuvant therapy in tumors other than HCC (e.g., melanoma, lung cancer, bladder cancer, head and neck squamous cell carcinoma, and so on)12Palmer D.H. Malagari K. Kulik L.M. Role of locoregional therapies in the wake of systemic therapy.J Hepatol. 2020 Feb; 72 (PMID: 31954492): 277-287https://doi.org/10.1016/j.jhep.2019.09.023Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar,34Forde P.M. Chaft J.E. Smith K.N. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018 May 24; 378 ([cited 2020 May 14]. Available from:): 1976-1986http://www.nejm.org/doi/10.1056/NEJMoa1716078Crossref PubMed Scopus (745) Google Scholar, 35Hellmann M.D. Chaft J.E. William W.N. et al.Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.Lancet Oncol. 2014; vol. 15 ([cited 2020 Sep 28]. Available from:)https://pubmed.ncbi.nlm.nih.gov/24384493/Abstract Full Text Full Text PDF Scopus (187) Google Scholar, 36Shu C.A. Gainor J.F. Awad M.M. et al.Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020 Jun 1; 21 ([cited 2020 Sep 28] Available from:): 786-795https://pubmed.ncbi.nlm.nih.gov/32386568/Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar gives higher response rates, although larger studies are needed to confirm these findings. Neoadjuvant studies indicate that the peak benefit of this therapy may be seen within the first week.37Huang A.C. Orlowski R.J. Xu X. et al.A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma.Nat Med. 2019 Mar 1; 25 ([cited 2020 Sep 28]. Available from:): 454-461https://pubmed.ncbi.nlm.nih.gov/30804515/Crossref PubMed Scopus (217) Google Scholar It is interesting to note that in a subset of patients, tumors can undergo significant downstaging within a short period of time, which may permit less morbid resection.38Uppaluri R. Campbell K.M. Egloff A.M. et al.Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus–Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial.Clin Cancer Res [Internet]. 2020 Jul 14; ([cited 2020 Sep 28])Crossref Scopus (44) Google Scholar However, the adverse effects of currently available therapies remain a major limiting factor.39Martins F. Sofiya L. Sykiotis G.P. et al.Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.Nat Rev Clin Oncol. 2019 Sep; 16 (PMID: 31092901): 563-580https://doi.org/10.1038/s41571-019-0218-0Crossref PubMed Scopus (459) Google Scholar The concept of neoadjuvant immunotherapy, if proven, will be beneficial even for patients being treated with a curative intent by resection and ablation. Such patients presently have higher risk of recurrence than LT.40Ahn K.S. Kang K.J. Appropriate treatment modality for solitary small hepatocellular carcinoma: radiofrequency ablation vs. resection vs. transplantation?.Clin Mol Hepatol. 2019; 25: 354-359Crossref PubMed Scopus (17) Google Scholar,41Portolani N. Coniglio A. Ghidoni S. et al.Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications.Ann Surg. 2006 Feb; 243 (cited 2020 Sep 30): 229-235Crossref PubMed Scopus (567) Google Scholar The risk factors of such a high recurrence are well known, and such patients may be the candidate for neoadjuvant therapy.42Takeishi K. Maeda T. Tsujita E. et al.Predictors of intrahepatic multiple recurrences after curative hepatectomy for hepatocellular carcinoma.Anticancer Res. 2015 May 1; 35 ([cited 2020 Sep 28]): 3061-3066PubMed Google Scholar Preliminary data have suggested that the neoadjuvant approach to downstage may be feasible in intrahepatic cholangiocarcinoma.43Le Roy B. Gelli M. Pittau G. et al.Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma.Br J Surg. 2018 Jun 1; 105 ([cited 2020 Nov 25] Available from:): 839-847https://pubmed.ncbi.nlm.nih.gov/28858392/Crossref PubMed Scopus (92) Google Scholar Similar innovative approaches with systemic therapy upfront in intermediate-stage HCC followed by TACE are also being tried.44Kudo M. A new treatment option for intermediate-stage hepatocellular carcinoma with high tumor burden: initial Lenvatinib therapy with subsequent selective TACE.Liver Canc. 2019 Oct; 8 (Epub 2019 Sep 18. PMID: 31768341; PMCID: PMC6872999): 299-311https://doi.org/10.1159/000502905Crossref PubMed Scopus (36) Google Scholar It is presumed that a multikinase inhibitor such as lenvatinib, if given early, may exert an antitumor effect, normalize tumor vessels, and improve drug delivery. Lenvatinib will also inhibit hypoxia-inducible cytokines such as VEGF and angiopoietin-2 later when TACE is given subsequently (see Figure 1). Finally, with the development of a new ICI for HCC, its neoadjuvant use may become a preferred choice before other forms of therapy soon. A fair number of trials of such combination therapy both in the advanced-stage HCC and in the early- and intermediate-stage HCC are underway.45Kudo M. Recent advances in systemic therapy for hepatocellular carcinoma in an aging society: 2020 update.Liver Canc. 2020 Dec; 9 (Epub 2020 Nov 17. PMID: 33442538; PMCID: PMC7768150): 640-662https://doi.org/10.1159/000511001Crossref PubMed Scopus (28) Google Scholar The authors have none to declare.