During the same time period that the combination of immunotherapy and antiangiogenics was demonstrating benefits in advanced-stage HCC, interventional radiology studies began to examine the potential of combining locoregional therapies like TACE with systemic therapies in intermediate- stage HCC. In the TACE 2 trial,5


313


patients with intermediate-stage HCC were randomized to drug-eluting bead transarterial chemoembolization (DEB- TACE) with sorafenib or DEB-TACE with placebo. The results of TACE 2 showed no improvement in time to progression for sorafenib and DEB-TACE compared to DEB-TACE alone. In addition, a phase II randomized controlled trial was performed comparing conventional TACE to TACE plus bevacizumab in 32 predominantly intermediate-stage HCC patients.6


Median survival was worse


in the study arm with bevacizumab (5.3 vs 13.7 months). No improvement in radiologic tumor response or overall survival was observed in patients in either group at 3, 6 or 12 months.


With the failure of enhanced overall survival in intermediate stage HCC patients with the combination TACE with TKIs or antiangiogenics, a lingering question remains: Can the overall survival of TACE be improved by adding immunotherapy? Studies conducted in the post-TACE tumor immune microenvironment (TIME) can shed some light on the subject. In the pre- and post- TACE tumor microenvironment, immune modulating cytokines are present. One study of 142 HCC patients treated with TACE7 looked at pre/post serum levels of the T cell cytokines (IL-1, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A,


1990


SIR publishes the first issue of the Journal of Vascular and Interventional Radiology.


Multiple treatments are introduced:


• Percutaneous extraction of gallbladder stones


• Radiofrequency ablation (RFA) technique for liver tumors


• Treatment of bone and kidney tumors by embolization


• RFA for soft tissue tumors, i.e., bone, breast, kidney, lung and liver cancer.


sirweb.org/irq | 13


IL-22, IFN- and TNF-). Results revealed that patients with undetectable levels of IL-6 and high levels of IL-22 pre TACE had better overall survival than the converse. Likewise, patients with increased IFN/ IL 10 ratio post-TACE demonstrated increased survival compared to those with a decreased ratio. Another study in 51 intermediate-stage patients with HCC showed that high levels of circulating Th-17 T cells 30 days post TACE was associated with improved overall survival compared to those with low levels.8


Thus, if locoregional


therapies like TACE can affect the tumor immune microenvironment, TACE and immunotherapy could potentially improve survival by at least two mechanisms. At best, the necrosis caused by locoregional therapy could provide antigens and cytokines favorable for the function of immunotherapeutic drugs. At worst, debulking tumors with locoregional therapy could result in a lower tumor burden, potentially making the immunotherapy more effective.


Doublet and triplet combinations Given what we know from combination medical therapies in advanced- stage HCC, it would be vital for IRs to test the effects of “doublet” and even “triplet” combinations of TACE and immunotherapy, TKIs and antiangiogenics. Agents being considered for study include durvalumab (anti PD-1), pembrolizumab (anti PD-1), nivolumab (anti PD-1), ipilimumab (anti CTLA-4), lenvatinib (TKI) and bevacizumab (anti-angiogenic). In fact, four new trials are currently underway, exploring combinations of TACE and immunotherapy in intermediate-stage HCC patients.


in 10 YEARS


WHAT COMES NEXT?


I look forward to the expansion of independent IR practice; so many


physicians are out there proving that an IR practice is viable and rewarding. I’m also looking forward to seeing a more diverse IR workforce. And I am hopeful many of the battles that we are fighting now—for coverage, reimbursement and recognition—will be resolved and IR will continue to innovate, grow and thrive.


— MERIDITH J. ENGLANDER, MD, FSIR


1991


Abdominal aortic stent grafts are created.


1992


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