Is radioembolization appropriate for patients with limited extrahepatic spread?
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Yes.
There are four scenarios in which patients with HCC and extrahepatic disease (EHD) should be considered for locoregional therapy (LRT) in the form of radioembolization or other options (eg, ablation, external radiotherapy).
First, consider the patient for whom a large liver tumor results in bulging of the liver capsule, causing pain and obstructing the biliary ducts. Palliative treatment with LRTs, despite the presence of EHD, makes sense to achieve rapid response and biliary relief and to minimize the need for chronic pain management.
The second scenario relates to the patient with EHD who develops new, localized HCC in the liver, despite other disease being controlled with systemic therapy (ST). Because this is technically progressive disease, purists will argue for changing ST. To avoid premature conversion to another ST and to maximize its benefit, an alternative approach would be to maintain ST and apply LRT.
The third scenario relates to the application of LRT among patients with advanced disease and EHD at initial presentation. In this setting, it is possible for 99% of the disease to be hepatic, with 1% manifested as EHD (eg, lung nodule). In contradistinction, 1% could be hepatic (high-alpha-fetoprotein HCC) and 99% extrahepatic (multiple bilateral lung nodules). Although both scenarios represent advanced-stage disease, they are distinctly different. The former patient’s life expectancy is based on the liver burden and that patient may benefit from LRT with ST. The latter patient clearly will succumb to EHD, and ST is indicated. We must recognize that there is a wide spectrum of disease and, rather than simply labeling both patients as advanced and dogmatically applying ST, individualized and personalized care is warranted.
The fourth scenario relates to HCC with portal vein invasion. Although also advanced stage, only the LRTs have consistently downstaged patients to cure via resection or transplantation. In properly selected patients, LRT in the form of radioembolization should be considered, with or without ST, with the intent of achieving a curative outcome.
Those who aren’t in favor of LRT will counter there are insufficient data. Although this is technically true, it does not prevent clinicians from amalgamating all available data on LRTs and STs and individualizing care.
It also highlights the limited granular data presented in ST trials relating to index lesion size, tumor burden, tumor distribution, location of disease and pattern of progression. Because these are the variables used to personalize decision-making, they represent tangible weaknesses of level-one randomized controlled trials that will be quoted to argue against LRT. As a result, advanced stage is now recognized to be just as heterogeneous as intermediate stage, with insufficient granularity of data that permits individualized and personalized decision-making.
At the end of the day, purely compartmentalizing patients with EHD into STs without further considering the location and size of disease violates the very principles of personalized care and of tailoring treatment based on the individual characteristics. Simply declaring disease as advanced stage and extrahepatic provides insufficient detail to make broad recommendations. Like other malignancies for which a combination of systemic and local therapies is standard (eg, neuroendocrine, gynecologic), that approach is sure to represent the next evolution in the advanced HCC landscape.
- Riad Salem, MD, MBA, FSIR, is vice chair for image-guided therapy and chief of vascular and interventional radiology in the department of radiology at Northwestern Medicine and professor of radiology (vascular and interventional radiology), medicine (hematology and oncology) and surgery (organ transplantation) at Feinberg School of Medicine. He can be reached at Northwestern Memorial Hospital, 676 N. St. Clair St., Suite 800, Chicago, IL 60611; email: rsalem1@nm.org.
No.
Liver-directed therapies are a cornerstone of management of locally advanced, unresectable HCC, including ablative therapies, bland or chemoembolization, and selective internal radiation with yttrium-90 (SIRT Y-90) resin microspheres (SIR-Spheres, Sirtex Medical). Such treatment approaches are the usual first step in treating locally advanced and unresectable disease. Retrospective series and small randomized trials comparing supportive care with chemoembolization indicate survival benefits for liver-directed therapy.
However, comparison of liver-directed therapies with ST, including randomized trials employing SIRT Y-90, have failed to demonstrate survival benefits above ST alone. Three recent randomized controlled phase 3 trials addressed this issue head-on.
Vilgrain and colleagues of the SARAH trial randomly assigned patients with locally advanced, inoperable HCC to treatment with sorafenib or to up to two treatments with SIRT Y-90 microspheres. Of the 459 treated patients, nearly all had cirrhosis (90%) related to alcohol (59%) or hepatitis C (23%), nearly half (44%) had undergone prior unsuccessful transarterial chemoembolization, and 44% had a single hepatic lesion.
OS, the primary endpoint, did not significantly improve among patients who received SIRT Y-90 compared with sorafenib (8 months vs. 9.9 months; HR =1.15; 95% CI, 0.94-1.41), with no difference in 1-year OS (39.5% vs. 42.1%). No subgroup showed superior survival with SIRT Y-90. Not surprisingly, a higher response rate was seen with SIRT Y-90 compared with sorafenib (19% vs. 12%; P = .0421), but this did not translate to a PFS benefit (4.1 months vs. 3.7 months, HR = 1.03; 95% CI, 0.85-1.25).
Similar negative results for sorafenib vs. SIRT Y-90 were reported in the SIRveNIB trial targeting 360 patients in the Asia-Pacific region. Chow and colleagues reported no difference in OS comparing SIRT Y-90 with sorafenib (8.8 months vs. 10 months; HR = 1.1; 95% CI, 0.9-1.4).
In a third recent trial, SORAMIC, Ricke and colleagues also failed to show a survival benefit for the combination of liver-directed therapy with sorafenib compared with sorafenib alone (12.1 months vs. 11.4 months, HR = 1.01; 95% CI, 0.81-1.25).
The failure of these trials to demonstrate a survival benefit even in locally advanced disease completely undercuts the argument to use this therapy prior to ST among patients with EHD. The liver-directed therapy in these studies also is compared with sorafenib, arguably a modestly active therapy, which now has been displaced by use of atezolizumab and bevacizumab based on significantly improved OS, PFS and response.
Arguably, SIRT Y-90 therapy might prove inferior to new-generation treatments. In addition, the advent of multiple second-line therapy options — including regorafenib, ramucirumab and cabozantinib — further relegate the use of liver-directed therapies to a salvage option for patients with significant EHD.
We must individualize therapy to each patient and certainly consider liver-directed therapy for patients with limited EHD, or for patients in whom the short-term outlook may be determined by better control of liver disease. However, the expanding armamentarium of more active first-line and later-line therapies negates a blanket argument to use liver-directed therapies, including SIRT Y-90, as the preferred option over systemic agents. The next phase of development in locally advanced or unresectable disease should evaluate these new agents in combination with liver-directed therapies.
- References:
- Chow PKH, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.76.0892.
- Finn RS, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1915745.
- Llovet JM, et al. Lancet. 2002;doi:10.1016/S0140-6736(02)08649-X.
- Lo C-M, et al. Hepatology. 2002;doi:10.1053/jhep.2002.33156.
- Ricke J, et al. J Hepatol. 2019;doi:10.1016/j.jhep.2019.08.006.
- Vilgrain V, et al. Lancet Oncol. 2017;doi:10.1016/S1470-2045(17)30683-6.
- Villanueva A. N Engl J Med. 2019;doi:10.1056/NEJMra1713263.
- David H. Ilson, MD, PhD, is an attending physician at Memorial Sloan Kettering Cancer Center, professor of medicine at Weill Cornell Medicine and a HemOnc Today Editorial Board Member. He can be reached at Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., BAIC 1031, New York, NY 10065; email: ilsond@mskcc.
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