Increasing the donor pool by live donation, using bridging therapy, and applying prioritization policies can help overcome this problem[ 22 ]. A MELD exception was developed to assign extra points to HCC patients due to their high dropout rate and mortality while on the waiting list. Although listing criteria for LTx currently depend on tumor number and size, the use of molecular markers and gene signatures for determining tumor behavior are under development[ 27 ].
The presence of vascular invasion, high AFP level, and transplant waiting time of more than 6 mo, are considered accurate predictive factors for poor survival and recurrence risk. In a large French multicenter study, incorporation of AFP in a prognostic score model for post-LTx outcome significantly improved the predictive performance of the Milan criteria in prioritization for LTx[ 29 ]. Tumor ablation can be obtained using either chemical alcohol and acetic acid or physical heating or cooling methods.
Multidisciplinary Treatment of Hepatocellular Carcinoma
The first technique used to locally treat HCC was PEI[ 32 ], which involves the intra-lesional injection of absolute alcohol. Temperature ablative techniques have advanced, including heating techniques such as RFA[ 33 ], microwave ablation MWA [ 34 ], laser ablation[ 35 ], and cryoablation[ 36 ]. RFA is superior to other local ablative therapies, and is currently the most commonly used ablative method, replacing PEI as the locoregional therapy of choice for early HCC[ 37 ].
RFA is considered the standard of care for patients with very early- and early-stage tumors, as well as those not suitable for or that refuse surgery. Three independent meta-analyses, including five RCTs, showed better results regarding local tumor control and survival benefits in patients treated with RFA, compared to ablation with PEI. Some groups have suggested that RFA should be considered as a first-line therapy, even when resection is possible, because it is associated with fewer side effects[ 39 ].
The main advantages compared to surgical intervention are that it is less invasive and provides an increased possibility for parenchymal sparing[ 39 , 43 ]. Whereas a Markov model analysis indicated that surgical resection was preferable to RFA in terms of overall survival[ 44 ], Peng et al[ 45 ] reported that RFA was better. Similarly, Wang et al[ 47 ] suggested that surgical resection was equivalent to RFA in terms of overall survival, and was associated with better disease-free survival.
However, RCTs with a large sample size are needed before ablation therapy can be confirmed as an alternative to surgery for potentially resectable HCC. Only one RCT[ 49 ] compared the effectiveness of MWA to RFA, which revealed a tendency to favor RFA with respect to rates of local recurrence and complications, likely due to the small volume of coagulation obtained with a single probe insertion[ 50 ]. However, newer devices may have overcome this limitation. One advantage of MWA over RFA is that treatment outcome is not affected by the heat-sink effect of vessels in proximity to the tumor[ 49 ].
Laser ablation refers to thermal tissue destruction by conversion of absorbed light into heat[ 51 ]. The only randomized prospective study comparing laser ablation with RFA reported no significant difference in overall survival rates, with cumulative rates of Cryoablation uses the extreme cold of liquid nitrogen or argon gas to destroy abnormal tissue[ 53 ]. Thus, the purpose of trans-arterial therapy is to block the blood supply and induce tumor necrosis, without significantly affecting hepatic blood supply[ 57 ].
Trans-arterial therapies include TACE, trans-arterial embolization, trans-arterial chemotherapy, and trans-arterial radioembolization[ 57 , 58 ]. TACE is currently the standard of care for patients with compensated liver function and large multifocal lesions without evidence of vascular invasion or extra-hepatic spread[ 3 ].
In Japan, TACE is recommended even for HCC patients with vascular invasion if radiologic portal invasion is distal to, or in the second-order branches of, the portal vein[ 59 ]. The main contraindications to TACE are extended portal vein thrombosis, diffuse tumor, extra-hepatic spread, and decompensated liver cirrhosis[ 22 , 60 ].
[Full text] The importance of a multidisciplinary approach to hepatocellular carci | JMDH
TACE improves survival compared to supportive care or suboptimal therapies[ 61 ], observed as an increase in the median survival of patients with intermediate-stage HCC to 20 mo[ 62 ]. However, a meta-analysis that included nine trials six trials assessing TACE and three trials assessing trans-arterial embolization has shown that trans-arterial therapy does not significantly increase survival in patients with unresectable HCC compared to controls[ 63 ].
Proper patient selection is crucial to prevent post-TACE-induced liver failure. BCLC-B includes disease ranging from variable tumor burden, which can be a multifocal HCC affecting both lobes, extending up to near replacement of the liver, and includes patients with a wide range of liver function impairment Child-Pugh score from 5 to 9. Substaging revealed decreasing survival for higher B substages, and thus TACE was recommended for early subgroups only[ 67 ].
Drug-eluting beads DEB -TACE involves the use of embolic microspheres with the ability to sequester and release chemotherapeutic agents in a controlled manner over a one-week period, which subsequently increases the local concentration of the drug with minimal systemic toxicity[ 68 ]. The use of locoregional options to induce tumor necrosis necessitated a refinement of the conventional criteria to evaluate treatment response.
Extent of tumor necrosis has been correlated with outcome after ablation, TACE and systemic therapy.
A modification of the response evaluation criteria in solid tumors modified RECIST takes into account the degree of tumor necrosis, evaluated by dynamic computed tomography or magnetic resonance imaging[ 70 ] and has been adopted by the latest EASL guidelines for evaluating locoregional therapies for HCC[ 3 ]. There is no established definition for TACE refractoriness, nor is there a consensus for when to consider TACE failure and refer the patient to an alternative therapy.
Despite the absence of solid evidence, however, panels of experts have proposed treatment migration to sorafenib downward treatment stage migration for intermediate-stage patients if they demonstrate disease progression or poor tolerance after first or second TACE[ 71 , 72 ]. The response to the first TACE and its effect on the underlying liver disease help in identifying patients at risk of adverse outcome with repeated TACE.
Radioembolization, or selective internal radiation therapy SIRT , has recently emerged as a therapeutic option for intermediate-stage HCC.
Multidisciplinary management of hepatocellular carcinoma
The procedure is well tolerated with survival rates similar to TACE. Moreover, it is as safe and effective as sorafenib in patients with more advanced-stage HCC, including patients with portal vein thrombosis and large tumor burden[ 76 - 79 ].
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In a study comparing radioembolization to TACE, radioembolization was associated with fewer side effects, better response rate, and longer time to progression Another study reported similar safety profile and response rates[ 76 ]. However, the cost associated with radioembolization may limit the applicability of this technique.
Stereotactic radiotherapy SRT allows the delivery of a high dose of radiation in a single radio-surgery or limited number hypo-fractionation of sessions, while sparing surrounding structures and healthy tissue[ 81 ]. Blomgren et al[ 82 ] first introduced SRT for liver tumors in , with treatment doses ranging from 15 to 45 Gy, in one to five fractions. The CyberKnife Radio-surgery System is able to deliver very high doses of radiation to both primary and metastatic liver tumors with extreme accuracy, and treatments can be completed in one to five sessions.
Louis et al[ 81 ] treated 25 patients with CyberKnife stereotactic radiotherapy using respiratory motion tracking, which enables the radiation beam to track tumor movement in real time and allows patients to breathe normally during their treatment sessions. CyberKnife and SRT though currently still very expensive offer a local therapy for HCC patients who are not eligible for surgery, embolization, chemotherapy or radiofrequency ablation, without significant complications. HCC is among the most chemoresistant tumors, and until , no systemic chemotherapy was recommended for patients with advanced tumors[ 3 ].
Moreover, these drugs are poorly tolerated in patients with underlying liver cirrhosis[ 85 - 87 ]. Interferon IFN therapy[ 87 ], anti-androgens, or tamoxifen[ 88 ] used in the treatment of advanced HCC show contradictory results without obvious benefit. A meta-analysis of seven RCTs, including patients, evaluated tamoxifen vs conservative management and showed neither anti-tumor effects nor survival benefits for tamoxifen[ 89 ]. Subsequent large RCTs reported negative results in terms of survival[ 90 , 91 ]. The median survival rate of the PIAF group did not significantly differ from the doxorubicin group 8.
Hepatocarcinogenesis is associated with epigenetic and genetic alterations that eventually lead to uncontrolled growth of hepatocytes.
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Signal transduction pathways, oncogenes, and growth factors and their receptors are considered new potential therapeutic targets for systemic targeted therapies, limiting widespread systemic toxicity[ 93 ]. Several targeted agents are currently in clinical development. Sorafenib is an orally administered multikinase inhibitor with antiproliferative and antiangiogenic activity[ 94 ]. Sorafenib mediates downregulation of anti-apoptotic proteins, leading to enhanced cytotoxicity of HCC cells to tumor necrosis factor-related apoptosis inducing ligand[ 95 ]. Two phase III randomized placebo-controlled trials, the SHARP multicenter trial[ 96 ] and the Asia-Pacific trial[ 97 ], reported improved overall survival and better outcome for patients who received sorafenib, which was generally well tolerated with mild toxicity.
Based on these findings, sorafenib was approved for treatment of advanced HCC, including patients with unresectable Child-Pugh A or B HCC with performance status and vascular invasion or distant metastasis[ 3 ], as well as for patients intolerant to TACE or in whom the procedure is technically difficult[ 98 , 99 ]. However, the prognosis for patients with this stage of HCC is still poor, with a median overall survival rate of 6. Sorafenib is currently being tested as an adjuvant after resection, with local ablation for early-stage HCC, in combination with chemoembolization for intermediate stages[ ], in combination with erlotinib or systemic doxorubicin in advanced stages.
Additionally, sorafenib was effective as a first-line treatment in Child-Pugh B patients with lower survival[ 3 ]. In a large retrospective study, the median survival with sorafenib was 5. Serious adverse events were more common in Child-Pugh class B patients[ , ]. This may be due to the fact that inhibition of a single signaling pathway can induce feedback activation of other pathways.
Therefore, combination therapies may demonstrate beneficial synergistic activity[ ]. The first phase III study of combination therapy in advanced HCC was SEARCH, a randomized trial testing sorafenib with the epithelial growth factor tyrosine kinase inhibitor erlotinib, which found no survival benefit over sorafenib alone[ ]. Persistence of chronic viral hepatitis in patients treated for HCC is associated with increased rates of recurrence and poor survival, thus control of hepatitis C virus HCV replication is an important factor for infected patients.
IFN therapy following successful ablation of HCC was shown to be safe and lead to a reduction in recurrence, and patients who continued IFN therapy after tumor ablation had better survival[ ]. Further improvement in prognosis may be expected with the higher efficacy of direct antiviral therapy. Patients with hepatitis B virus HBV -related HCC, even after successful treatment of the initial tumor, usually have multiple recurrences or metastases.
High viral load is one of the most important risk factors for HCC development and recurrence following surgical resection[ ]. In their study, Hann et al[ ] followed patients for 12 years who underwent local tumor ablation with or without concomitant antiviral therapy with lamivudine. No other modality has demonstrated equivalent effectiveness for decreasing recurrence after curative treatment of HCC as antiviral therapy has for viral hepatitis-related tumors.
HCC has diverse presentations that are compounded by the status of liver disease, and the multiple treatment options available make choosing the first line of treatment for a given patient a difficult task. Treatment of HCC patients should be undertaken by a multidisciplinary team that includes all the specialties involved in delivering the different therapies. In addition, simultaneous or sequential multi-modal therapies for patients with HCC show promise for improving patient outcome, further emphasizing the importance of a multidisciplinary approach to HCC management. The multidisciplinary team should include hepatologists, medical and surgical oncologists, transplant surgeons, diagnostic and interventional radiologists, radiation oncologists, and pathologists[ ].
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