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Advanced hepatocellular carcinoma: More treatments options ahead

Transarterial chemoembolization and external radiation therapy have been extensively investigated in combination for improved survival for this stage. However, recent trial shows that HCC patients with vascular invasion might benefit from such a combination as well.

Multimodality approach shows promising results against the portal-invasion type carcinoma

Transarterial chemoembolization and external radiation therapy have been extensively investigated in combination for improved survival for this stage. However, recent trial shows that HCC patients with vascular invasion might benefit from such a combination as well.

The separate application of transarterial chemoembolization and external radiation therapy has been the mainstay therapy for treatment of locally advanced hepatocellular carcinoma (HCC) without vascular invasion. Fresh research, however, hints at the benefits of to HCC patients with vascular invasion arising also from such a combination of these two applications.

Treatment of the locally advanced hepatocellular carcinoma (HCC) with a macrovascular invasion is a challenging problem. The survival rate in patients with a locally advanced HCC who have portal invasion is lower than in those without the vascular involvement. The only available guidelines-endorsed management modality for such patients is sorafenib, a nonspecific kinase inhibitor which acts on multiple tyrosine kinases including VEGF receptor, PDGF receptor, and RAF-family kinases. In the initial randomized controlled trial, it increased overall survival by 44% and prolonged the median survival from 7.9 to 10.7 months compared to placebo. These improvements, however, are achieved in the cost of numerous frequent side effects such as hypophosphatemia, hypokalemia, hypocalcemia, bleeding, myocardial ischemia, and other conditions which can be possibly fatal.

Transarterial chemoembolization (TACE) is one of the techniques used in patients with a locally advanced disease without the macrovascular involvement as a palliative treatment. This procedure combines transarterial chemotherapy and transarterial chemoembolization: the chemotherapeutic agent is injected through the hepatic artery, and the tumor feeding arteries are then occluded with a lipid-containing embolization material. TACE decreases target lesions by 30% or more in 15%-55% of patients, improving the overall and progression-free survival. External beam radiotherapy is a promising treatment modality intended to be used in the same patient cohorts.

In the trial recently published in JAMA Oncology, a combination of these methods has shown a tremendous superiority over the sorafenib. This randomized, open-label clinical study involved 90 patients with locally advanced non-metastatic HCC and macrovascular invasion confirmed by CT scanning and normal liver functioning classified with a Child-Pugh score class A. The participants were divided into two equal groups to receive either combination of TACE and external beam radiation (TACE-RT group) or sorafenib. The primary outcome of the study was the 12-week progression-free survival rate.

At the endpoint, TACE-RT group showed an 86.7% survival rate compared to 34.3% in sorafenib group. The median time to progression was also significantly longer in TACE-RT group compared to sorafenib group. Five patients from the TACE-RT group responded so well that curative surgical resection became possible. Moreover, as the crossover was allowed in case of disease progression, 34 patients from the sorafenib group switched to TACE with radiation therapy.

The results of this trial are, to say the least, encouraging. It brings a real alternative to sorafenib which despite having a worrisome adverse effects profile occupies the niche for treatment of vaso-invasive locally advanced cancers solely. There are a few issues which do not diminish the value of the results, but rather point to the necessity of further investigations.

First of all, the allowed crossover makes interpretation of the intention-to-treat analysis difficult. Only 3 patients of the 45 who were assigned to the treatment with sorafenib have made it to the very end. The majority of the control treatment group, in fact, received a combination of sorafenib followed by a radiation beam therapy which could confound the result. Next, authors do not report a proportion of the patients who had cirrhosis while it is an important determinant of radiation therapy safety. Also, the majority of the patients had hepatitis B virus-induced HCC while it is known that sorafenib induces a poorer response in this cohort of patients.

Overall, a combination of the transarterial chemoembolization and external beam radiation appears to be a very promising treatment option. However, many patients who have macro-invasion of the tumor into the blood patients are likely to have a decreased liver function which does not qualify for Child-Pugh score class A, so patients with sub- or decompensated liver dysfunction are still without a proper alternative because radiation therapy can yield more risk for them. 

Other approaches, such as stereotactic body radiotherapy followed by sorafenib, are under investigation and can potentially compete with the presented one in terms of survival rate and adverse effects profile. Also, checkpoint inhibitors, such as nivolumab, step on the toes of the multimodality treatments qualifying for the stage 3 trial with a satisfactory safety profile. 

 Sources:

  1. Yoon S, Ryoo B, Lee S et al. Efficacy and Safety of Transarterial Chemoembolization Plus External Beam Radiotherapy vs Sorafenib in Hepatocellular Carcinoma With Macroscopic Vascular Invasion. JAMA Oncol. 2018;4(5):661. doi:10.1001/jamaoncol.2017.5847.
  2. Heimbach J, Kulik L, Finn R et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2017;67(1):358-380. doi:10.1002/hep.29086.
  3. Verslype C, Rosmorduc O, Rougier P. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology. 2012;23(suppl 7):vii41-vii48. doi:10.1093/annonc/mds225.
  4. Costentin C, Ferrone C, Arellano R, Ganguli S, Hong T, Zhu A. Hepatocellular Carcinoma with Macrovascular Invasion: Defining the Optimal Treatment Strategy. Liver Cancer. 2017;6(4):360-374. doi:10.1159/000481315.
  5. El-Khoueiry A, Sangro B, Yau T et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. The Lancet. 2017;389(10088):2492-2502. doi:10.1016/s0140-6736(17)31046-2.
  6. Galle P, Forner A, Llovet J et al. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018. doi:10.1016/j.jhep.2018.03.019.