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Transitioning Therapy
Key Concepts in HCC Treatment: Transitioning Patients From Locoregional to Systemic Therapy

Released: October 20, 2020

Expiration: October 19, 2021

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Since 2017, numerous systemic therapies have been approved for treating patients with advanced hepatocellular carcinoma (HCC) (including atezolizumab plus bevacizumab, cabozantinib, lenvatinib, nivolumab with or without ipilimumab, pembrolizumab, and ramucirumab), marking the first approvals for these patients since sorafenib in 2007, despite numerous clinical trials in the interim. With many active systemic therapy options now available, a key consideration in treating patients with HCC is timely initiation of systemic treatment to maximize therapeutic benefit. When should patients receiving locoregional therapies (eg, transarterial chemoembolization TACE) optimally be transitioned to systemic therapy? In this commentary, I discuss my thoughts on this question.

Key Concepts in Staging Patients With HCC
To begin, it is important to understand HCC staging and how this relates to treatment. HCC is staged using the Barcelona Clinic Liver Cancer algorithm, which includes 5 stages from 0 to D. On one side, we have patients with stage 0 and A: these include patients with early disease (who can potentially be cured with surgical options). On the other extreme, we have stage D, which includes less healthy patients with very advanced/terminal liver disease (Child-Pugh C, performance status 3/4) and advanced cancer for whom supportive care is indicated. Most patients who first present with HCC will be categorized as intermediate stage (stage B: multinodular HCC that is contained within the liver, with good liver function and performance status) or advanced stage (stage C). 

By definition, advanced stage C includes patients with relatively good liver function and performance status whose HCC has invaded the portal vasculature, whether within or outside the liver (ie, ”vascular invasion”) or whose tumor has spread beyond the liver. Patients who have large symptomatic tumor burdens in the liver may also be considered as having advanced-stage disease.

Stage Migration and Transitioning Patients Locoregional to Systemic Therapy
Patients who present with intermediate-stage disease are candidates for locoregional treatment, including TACE. Chemoembolization has been the backbone of treatment for these patients and has been shown to improve survival in this population. For patients with advanced disease, there are now randomized phase III data demonstrating improved survival with several systemic therapies. Patients with extensive infiltrative tumors throughout both lobes of the liver and patients with a tumor that is invading into the portal vasculature (macrovascular invasion) generally do not derive a significant benefit from TACE.

It is important to note that patients with intermediate-stage HCC will generally stage migrate, meaning that their HCC will eventually become refractory to TACE, necessitating a transition to systemic therapy. Before the arrival of active systemic treatments for HCC, patients who developed new HCC lesions or who experienced regrowth of a previously treated lesion while being treated with locoregional therapy might have been considered for further locoregional treatment. Now that active systemic treatments are available, it is very important that we reconsider when to transition patients from locoregional to systemic therapy. This is best done via a multidisciplinary discussion that includes a medical oncologist, hepatologist, and interventional radiologist. To maximize the benefit from the many active systemic treatments we have now, it is essential to transition patients to systemic therapy while they still have relatively good liver function. All of the phase III studies assessing now-approved systemic therapy options included patients with Child-Pugh A liver function and that it is in that context that we see the maximum benefit not only from frontline but also subsequent lines of therapy. It is important to keep in mind that every time a TACE procedure is performed, there is some compromise to liver function; as such, I believe it is hard to justify continued TACE for patients who meet the criteria for TACE refractory disease.

How do we decide that a patient is TACE refractory and should be considered for systemic therapy? The Japan Society of Hepatology has created perhaps the best criteria for clinical progression after TACE or “TACE refractoriness”: 

  • ≥ 2 consecutive ineffective responses within the treated tumors (viable lesion > 50%) after assessment of response 1-3 months after TACE
  • ≥ 2 consecutive progressions in the liver (including an increase in the number of tumors) after assessment of response 1-3 months after TACE
  • Continuous tumor marker elevation immediately following TACE (even if transient minor reduction observed)
  • Vascular invasion or extrahepatic spread

Patients meeting these criteria should be considered for systemic therapy.

Your Thoughts
At your institution, when do you recommend transitioning patients with HCC from locoregional to systemic therapy? What do you consider best practices in multidisciplinary care for patients who may be approaching or at this transition? Leave your comments below to join in the conversation.

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