Doctors Debate: Is Systemic or Liver-Directed Therapy Best for Hepatocellular Carcinoma?

Sunyoung S. Lee, MD, PhD

The field of hepatocellular carcinoma (HCC) is brimming with available treatment options, including surgery, transplant, liver-directed therapy, and systemic therapy. Selecting the optimal therapy for HCC from among these options is dependent upon disease setting and patient characteristics. Liver-directed and systemic therapy share a subset of patients with similar qualifiers and therefore generate discussion among medical and interventional oncologists about which treatment is most favorable for patients with HCC.^1,2

Beau Toskich, MD

As part of the virtual 17th Annual Meeting of the International School of Gastrointestinal Oncology (ISGIO), a debate ensued around whether liver-directed or systemic therapy is best for the treatment of patients with HCC. Sunyoung S. Lee, MD, PhD, a gastrointestinal medical oncologist and clinical faculty member in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston argued in favor of systemic therapy, whereas Beau Toskich, MD, an interventional oncologist at the Mayo Clinic in Jacksonville, Florida argued in favor of liver-directed therapy.

Ultimately, the 2 physicians found more common ground than disagreement.

Factors to Consider for Systemic and Liver-Directed Therapy in HCC

In the ongoing question of what treatment type is the gold standard for HCC, some experts have stated that it should be standard for HCC disease management to be a multidisciplinary process. The field is headed in this direction, according to both Lee and Toskich.

In a review of cases and clinical trials in HCC, it was shown that treatment strategies that were multimodal achieved better resection rates in patients eligible for surgery, more successful transplants, and longer survival following treatment compared with studies that used one form of therapy over the other. The authors of the study led by Dekey Lhewa, MD, of Oregon Health & Science University in the Department of Medicine, Division of GI & Hepatology,held that many justifications for multimodal therapy in HCC exist, some of which include decreased time to initial treatment choice and administration, maximizing patient confidence in care, creating a roadmap of treatment for all healthcare providers involved, improved survival in patients, and help with clinical trial enrollment.³ 

Similar opinions were shared during the ISGIO debate between Lee and Toskich.

Lee told Targeted Oncology, in an interview: “Liver-directed therapy and systemic treatments have their roles in each case of patient care. I do not think that local therapy or systemic therapy is better or inferior. For the treatment of HCC, they are complementary to each other and have a synergistic effect. If a patient has a local disease or slightly advanced disease, liver-directed therapy is effective. More data suggest that adding liver-directed therapy to systemic therapy was clinically beneficial even in patients with advanced HCC.”

Research has shown that in the current HCC landscape, liver-directed therapies and utilization of tyrosine kinase inhibitors work hand-in-hand and for some patients for whom toxicity of TKIs such as sorafenib (Nexavar) is of concern, liver-directed therapy may delay the need for systemic therapy. On the other hand, liver-directed therapy may negatively impact liver function in select patients and for these patients, treatment with systemic therapy may be more appropriate.⁴

“Patients can have deterioration of liver function after certain locoregional therapies, and this must be a priority consideration when designing your liver-directed treatment approach. There are aspects of local therapy that don’t address the total volume of disease due to limitations in imaging or serologic staging, and there certainly are disease presentations that benefit from having the whole body treated,” Toskich told Targeted Oncology, in an interview.

“It is also import to avoid premature enthusiasm for a new therapy, and have it encroach on other options that may be more effective without adequate evidence, just because of differences in patient access. That’s why I rely on the multidisciplinary model; because it ensures patient exposure to the best ideas and talent pools for this extremely challenging disease,” Toskich added.

Systemic Therapy

In relation to the debate of systemic therapy versus liver-directed therapy, Lee reviewed a large pool of agents that make the case for systemic therapy use in HCC, but he explained during the interview that neither approach is better than the other.

“The most important point is that HCC needs multidisciplinary care, and medical oncologists need to know when to add liver-directed therapy, and interventional radiologists or radiation oncologists need to know the indication when systemic therapy needs to be added. More and more data suggest that multidisciplinary care is more beneficial in HCC. This is the key takeaway,” he said.

FDA Approved Systemic Therapies

Systemic agents and systemic therapy combinations for HCC includes kinase inhibitors, monoclonal antibodies, and immune checkpoint inhibitors. The promise of systemic therapy was first confirmed in 2007, when the FDA granted approval to sorafenib after the agent significantly improved survival in patients with HCC treated in the phase 2 SHARP clinical trial (NCT00105443). The median overall survival (OS) was 10.7 months with sorafenib in the study compared with 7.9 months with placebo (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.55- 0.87; P <.001). Sorafenib also showed a median time to radiologic progression of 5.5 months compared with 2.8 months in patients given a placebo (P<.001).⁵

A year later, lenvatinib (Lenvima) was granted FDA approval for the first-line treatment of patients with unresectable HCC based on outcomes from a non-inferiority study (REFLECT, NCT01761266) in which the agent significantly improved OS compared with sorafenib HR. 0.92; 95% CI: 0.79-1.06). The median OS observed with lenvatinib was 3.6 months compared with sorafenib, which showed a median OS of 12.3 months in the REFLECT study. The was also a statistically significant improvement in PFS with lenvatinib versus sorafenib of 7.3 months versus 3.6 months in the sorafenib arm (HR, 0.64; 95% CI, 0.55-0.75; P<.001).⁶

In later studies of systemic therapy, survival and response to treatment either was consistent or continued to be approved upon as newer regimens received FDA approval. These therapies included the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) from the phase 3 IMbrave150 clinical trial (NCT03434379), as well as the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as assessed in the phase 1/2 CheckMate-040 trial (NCT01658878). Single agents that were granted FDA approval after showing favorable efficacy in various HCC populations included cabozantinib (Cabometyx), regorafenib (Stivarga), and ramucirumab (Cyramza).

According to Lee’s presentation, the combination of nivolumab and ipilimumab achieved the longest survival of 23 months, and ramucirumab monotherapy achieved the shortest at only 8.5 months. The highest ORR was observed with atezolizumab in combination with bevacizumab at 33.2%, but nivolumab/ipilimumab was not far behind at 32%. The lowest ORR was observed with sorafenib at 2%. Most of the systemic therapies in the HCC paradigm had similar PFS, but the longest was achieved with lenvatinib followed by atezolizumab/bevacizumab. The shortest PFS was seen with single-agent ramucirumab.¹

“Between 2007 and 2017, there was only one medication, sorafenib. Patients who received sorafenib and progressed didn’t have options until nivolumab and regorafenib were approved. Sorafenib, lenvatinib, atezolizumab plus bevacizumab and nivolumab are available options in the front-line setting. Nivolumab, pembrolizumab (Keytruda), nivolumab plus ipilimumab, cabozantinib, regorafenib, and ramucirumab are options approved for in the second-line setting.” Lee stated during his presentation.

“Most recently, atezolizumab plus bevacizumab was approved by the FDA and has a promising response rate and survival, proving that combination therapy has better efficacy and survival benefit,” Lee said..

Emerging Systemic Therapy Combinations

In the early stages of research, 2 systemic therapy combinations are showing promising for patients with HCC. First, lenvatinib in combination with pembrolizumab led to a high number of responses and long survival in patients with unresectable HCC.

According to published data from the phase 1b study of lenvatinib plus pembrolizumab, in a cohort of 104 patients, the ORR was 36.0% (95% CI, 26.6%-46.2%) per RECIST v1.1 at a median follow-up of 10.6 months (95% CI, 9.2-11.5). The median PFS was 8.6 months per RECIST v1.1 and there was a 22-month median OS. The combination was also tolerable in the unresectable HCC population with no new safety signals observed.⁷

Another study of tremelimumab (formerly ticilimumab, CP-675,206) in combination with durvalumab (Imfinzi) showed efficacy, tolerability and biomarker activity in a pool of 332 patients with advanced HCC who received the combination in 4 different treatment arms.⁸

For the 75 patients who received tremelimumab 300 mg with durvalumab 1500 mg, the ORR was 22.7% (95% CI, 13.8-33.8), with a median duration of response (DOR) not reached. The median OS was 18.7 months (95% CI, 10.8 to not reached [NR]). Eighty-four patients received tremelimumab 75 mg combined with durvalumab 1500 mg, and the ORR for this arm was 11.3 (95% CI, 4.2-17.9) with a 13.2-month median DOR. The median OS was 11.3 months (8.4-14.6).

In the other 2 arms of the study, 104 patients were treated with durvalumab monotherapy, and 69 patients received tremelimumab monotherapy. In the single-agent durvalumab arm, the ORR was 9.5% (95% CI, 14.7-17.0) and the median DOR was 14.8 months. Durvalumab also achieved a 11.7-month median OS (95% CI, 8.5-16.9). With tremelimumab alone, the ORR was 7.2% (95% CI, 2.4-16.1) with responses lasting for a median duration of 24.0 months. The median OS in this arm was 17.1 months (95% CI, 10.9-NR).

Overall, the data for the novel combination are encouraging. The combination showed a tolerable safety profile, and the data also suggest that better outcomes can be achieved with the higher dose (300 mg) of tremelimumab compared with the lower dose (75 mg).

In regard to the role of systemic therapy in HCC, Toskich agrees that it is still an important modality, even though liver-directed therapy is sometimes preferred. He explained during the interview that part of his job as an interventional oncologist is not precluding a patient’s chance to receive systemic therapy after local therapy.

Liver-Directed Therapy

The case for liver-directed therapy over systemic therapy in HCC began with an explanation of the ill-balance between 2 disciplines, oncology and radiation oncology. Toskich explained that there are more than 12,000 oncologists in the United States, while there are less than a third as many interventional radiologists. Related to this imbalance, clinical trials often study multiple permutations of systemic therapy, and head-to-head trials that include a procedural arm are difficult to conduct.

“For decades, transarterial chemoembolization (TACE) was the standard of care for intermediate stage HCC. Thermal ablation has made its way into guidelines as a curative treatment for very early-stage disease. Expanding the role of energy therapeutics such as ablative radioembolization or charged-particle radiation, to engage tumors that are conventionally challenging for thermal ablation is where we’ve seen our most promising results recently”, Toskich told Targeted Therapies in Oncology.

Toskich made his argument according to disease status in patients with HCC. First, for BCLC stage 0 disease, he stated that ablation was the recommended treatment in the front-line setting for patients with BCLC stage 0 HCC who were ineligible for transplant or who have portal hypertension. No evidence has shown benefit of using systemic therapy for this patient population, Toskich explained by quoting a 2018 paper authored by Dr. Lee on immunomodulation in HCC.⁹

For BCLC stage A disease, research from multiple angles has shown that liver-directed therapy is beneficial for patients, but efficacy is dependent upon factors such as tumor size, tumor location, hepatic and extrahepatic patient conditions, as well as cirrhosis. A prospective randomized trial from 2006 showed that percutaneous local ablative therapy was equivalent to surgical resection in patients with small, solitary, HCC.¹⁰ In addition, Toskich explains that ablation better preserves hepatic parenchyma, has lower adverse events (AEs), and is a more cost-effective treatment. However, patients with larger solitary tumors that have preserved liver function will have better outcomes with tumor resection, Toskich noted.

New research from a cohort of the LEGACY study shows that radiation may be effective in larger tumors up to 8 cm. Utilizing Y90 glass microspheres in patients with solitary HCC, the treatment achieved complete pathologic necrosis in 67% or patients, and this response was elevated to 100% when the treatment dose was increase to >400 Gy.¹¹

Systemic therapy with sorafenib does not have a role for the treatment of BCLC stage A HCC, according to data observed in the STORM trial (NCT00692770). The study showed that adjuvant sorafenib is not an effective intervention for HCC following either tumor resection or ablation.¹² “Although prior adjuvant kinase inhibitor trials were negative, there are several trials evaluating the role of immunotherapy as a locoregional adjuvant and vice versa, which hold promise due to a conceptual synergy in these modalities” Toskich added.

TACE remains the gold standard frontline therapy for patients with intermediate stage disease. HCC guidelines do recommend that systemic therapy is used in patients with BCLC stage B disease who progressed after 2 TACE treatments or for patients who cannot have local therapy.

Toskich stated during his presentation, “the reality of BCLC stage B HCC is that it is heterogenous. This has led to sub stratifications which may allow us to better allocate treatment in this overworked tumor stage.”

Finally, for BCLC stage C HCC, clinical trials have shown that low dose radioembolization using a currently outdated body surface area dose methodology does not improve survival when compared to sorafenib. Results of the SIRveNIB and SARAH trials showed improvements over sorafenib in terms response, AEs, and quality of life, but not survival.^13,14

However, recent results from a randomized study of standard dose radioembolization compared to personalized dose radioembolization with a target tumor threshold of >205 Gy in patients with locally advanced HCC demonstrated an overall survival improvement of 10.7 vs 26.6 months.¹⁵”

Overall, data appear to show benefit of both liver-directed and systemic therapy in HCC.

Lee supported Toskich’s presentation stating in an interview: “Liver-directed therapy is ideal for patients with a limited disease, smaller tumors, fewer number of tumors in the liver. Once again, HCC treatment is multidisciplinary. I agree with Dr. Toskich about his points. Once again, surgical oncology, medical oncology, radiation oncology, and interventional radiology work together.”

_References:

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_{2. Toskich B. Liver-Directed Therapy. Presented at: 17th Annual International School of Gastrointestinal Oncology; October 2–3, 2020.}

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_{4. Viveiros P, Riaz A, Lewandowski RJ, et al. Cancers (Basel). 2019l11(8):1085. doi: 10.3390/cancers11081085}

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_{7. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020; 38(26 ): 2960-2970. doi: 10.1200/JCO.20.00808}

_{8. Kelley RK, Sangro B, Harris WP, et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J Clin Oncol. 2020;38(suppl 15): 4508-4508. doi: 10.1200/JCO.2020.38.15_suppl.4508}

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_{10. Chen MS, Li JQ, Zheng Y, et al. A Prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg. 2006;243(3): 321–328. doi: 10.1097/01.sla.0000201480.65519.b8}

_{11. Salem R, Johnson GE, Riaz A, et al. 992P Yttrium-90 glass microspheres in the treatment of early and advanced hepatocellular carcinoma: The LEGACY study. Ann Oncol. 2020; 31(4): S692-S693. 10.1016/j.annonc.2020.08.1108}

_{12. Bruix J, Takayama T, Mazzferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015;16(13):1344-54. doi: 10.1016/S1470-2045(15)00198-9.}

_{13. Vilgrain V, Pereira H, Assenat E, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624-1636.doi: 10.1016/S1470-2045(17)30683-6.}

_{14. Chow PK, Gandhi M, Tan SB, et al. SIRveNIB: Selective internal radiation therapy versus sorafenib in asia-pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36(19):1913-1921. doi: 10.1200/JCO.2017.76.0892.}

_{15. Garin E, Tselikas L, Guiu B, et al. DOSISPHERE-01 Study Group. Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial. Lancet Gastroenterol Hepatol. 2021;6(1):17-29. doi: 10.1016/S2468-1253(20)30290-9.}