Global Perspectives on Emerging Options in HCC

Global Perspectives on Emerging Options in HCC

Five important talks delivered the morning of January 19 during the 2018 Gastrointestinal Cancers Symposium covered diverse topics that provide insight into future diagnostic, management, and research directions in hepatocellular carcinoma (HCC).

Impact of New HCV Treatments on HCC

Infection with hepatitis C virus (HCV) is a prime risk factor for the development of HCC. Direct-acting antiviral therapies (DAAs) have transformed the treatment of chronic hepatitis C, leading to sustained virologic suppression in more than 95% of individuals with a relatively short course of therapy and reducing all-cause mortality. However, it is unclear whether the risk of cancer persists after viral cure or whether the risk may actually be exacerbated by DAAs.

Massimo Colombo, MD, of the Humanitas Research Hospital, in Italy, described the emerging trickle-down effects that DAAs are having the occurrence and recurrence of HCC based on early data.

Initial retrospective studies conducted among HCV-infected individuals treated with DAAs hinted at an increased incidence of de novo HCC after treatment. However, large retrospective and prospective studies, as well as a meta-analysis, conducted in the wake of these findings counter this notion. The findings suggest that DAAs likely protect against de novo HCC while also decreasing patient mortality.

Patients with early-stage HCC treated with curative intent require follow-up treatment with DAAs to prevent early hepatic decompensation that leads to mortality. The evidence to date does not suggest that subsequent DAA therapy increases the risk of recurrence in these individuals. However, accumulating evidence does show that DAAs may accelerate the time to recurrence. The mechanisms driving this process are not well understood.

Dr. Colombo indicated that dedicated studies are needed to better understand and confirm how DAAs modify the incidence and patterns of HCC recurrence.

mRECIST and LI-RADS Criteria for Assessing Response in HCC

The role of response criteria in oncology is to provide a surrogate for evaluating prolonged survival or improved quality of life—the clinical outcomes of true meaning to the patient. Response criteria also offer a tool for objective evaluation and comparison of treatment response in clinical trials.

Dr. Richard Do speaks during General Session 5.
Richard K.G. Do, MD, PhD, of Memorial Sloan Kettering Cancer Center, discussed the response criteria currently available to evaluate the effects of HCC therapy. Clinicians have a few different response criteria at their disposal, he explained, including the widely recognized Response Evaluation Criteria in Solid Tumors (RECIST), which focus solely on shrinkage of the entire tumor. However, these criteria often fail to recognize the benefit of nonenhancing lesions that reflect tissue devascularization achieved with many locoregional therapies. To account for ischemic necrosis in tumors induced by transarterial interventions, the modified RECIST (mRECIST) were created.

mRECIST emphasize arterial enhancement when determining response. “Intuitively, it makes sense to apply measurements only to the enhancing components of the liver,” Dr. Do said. The reproducibility of mRECIST scoring is high across different observers; accumulating data support the value of the criteria and indicate that they may improve survival prediction. “It’s just a matter of time, in my opinion, before mRECIST will supplant RECIST 1.1 when it comes to systemic therapies for clinical trials,” Dr. Do said.

Nevertheless, there are some challenges that mRECIST still need to overcome. Most notably, as useful as these criteria might be in clinical trials, they are not particularly useful in daily clinical practice. That is exactly the gap that the Liver Imaging Reporting and Data System (LI-RADS) is seeking to address, Dr. Do said.

LI-RADS, created by the American College of Radiology, features both standardized terminology and a classification system to describe the imaging findings of liver lesions. LI-RADS includes five different diagnostic categories that describe the severity of HCC (e.g., LR-1, definitely benign, to LR-5, definitely HCC), with two additional categories to describe probably or definitely malignant disease that may not necessarily be HCC (LR-M), as well as disease that features tumor in the vein (LR-TIV). There are also four different response categories applied after treatment (i.e., TRs) to describe nonevaluable, nonviable, equivocal, and viable disease. By reporting these categories in tandem with tumor size, ambiguity about the response to treatment should be reduced (e.g., LR-TR, viable 2.0 cm; previously LR-5, 5.1 cm).

Locoregional Therapy With Radioembolization

Although resection and liver transplantations remain the best curative treatment modalities for HCC, other locoregional options clearly are needed for patients with unresectable disease. Emerging data suggest that targeted delivery of internal radiotherapy could be used across the spectrum of HCC disease.

Arterial embolization disrupts the tumor blood supply to result in tumor ischemia/hypoxia; conversely, radioembolization works by administering radioactive particles through the hepatic artery into a tumor, where they become trapped at the precapillary level and emit lethal internal radiation. Yttrium-90 (Y90) is the radiotherapy of choice given its localized emission properties.

Dr. Edward Kim speaks during General Session 5.
“For radioembolization, there really is no level I evidence,” Edward Kim, MD, FSIR, of the Icahn School of Medicine at Mount Sinai, said. “The evidence that we discuss today will be mostly single-center, retrospective/prospective studies to see where, potentially, in clinical practice radioembolization can fit into the Barcelona Clinic Liver Cancer (BCLC) algorithm.”

Y90 radiation segmentectomy offers a treatment option to patients with early-stage HCC (BCLC A). This approach leverages microcatheter technology to selectively administer radioembolization, making it conceptually similar to anatomic surgical resection. Radiation segmentectomy has yielded median overall survival (OS) durations exceeding 2 to 4 years. Evidence suggests that it also yields outcomes similar to those of to transarterial chemoembolization (TACE) combined with microwave ablation for unresectable solitary lesions that measure 3 cm or less.

For patients with intermediate-stage disease (BCLC B), transarterial radioembolization (TARE) may be preferred to TACE on the basis of emerging data. A randomized, phase II trial demonstrated that Y90-TARE was superior to TACE for the primary endpoint of time to progression (TTP; > 26 vs. 6.8 months; p = 0.0012). Dr. Kim proposed that this dramatic delay in TTP may better bridge patients to transplantation given the 6-month waiting period mandated by the United Network for Organ Sharing. The bridge, in turn, could reduce attrition from the transplantation waitlist.

Radioembolization also may have a role to play in advanced HCC (BCLC C), specifically in patients with portal vein thrombosis (PVT). PVT does not bode well for patients with HCC because it decreases the tolerability of transarterial therapies and increases the likelihood of extrahepatic spread. When left untreated, median OS for individuals with PVT is 2.7 to 4.0 months. However, radioembolization with Y90-loaded glass microspheres can extend OS to 10 to 13 months. Y90-TARE also may offer better quality of life than sorafenib in patients with advanced HCC with or without PVT, according to results from two large randomized controlled trials, SARAH and SIRveNIB, although without gains in OS or progression-free survival (PFS).


External radiation therapy (RT) approaches have evolved substantially with time. Stereotactic body radiation therapy (SBRT) represents a sophisticated form of focal treatment that can deliver very high doses of radiation in few fractions while largely sparing normal tissue. Jinsil Seong, MD, PhD, of the Yonsei University College of Medicine, in South Korea, detailed the benefits that SBRT has to offer to select patients with HCC.

SBRT, Dr. Seong explained, offers a viable alternative to radiofrequency ablation (RFA) in inoperable HCC—for the right patients. SBRT is best reserved for patients with just a few small lesions (one to three lesions of cumulative size ≤ 6 cm) at least 1 cm removed from at-risk organs, a Child-Pugh score of A or B, no portal hypertension, and adequate liver reserve (≥ 700 to 800 mL of uninvolved liver) who are ineligible for transplantation.

When appropriate patients are selected and when conditions are optimized through use of motion reduction, tracking with radio-opaque markers, and imaging guidance for precise RT delivery, local control rates at 2 years after SBRT often reach 90% or higher. Retrospective data to compare SBRT with RFA suggest that SBRT yields comparable local control overall and offers better outcomes than RFA for tumors larger than 2 cm.

Another area in which SBRT demonstrates effectiveness is as a bridge to liver transplantation. In a study that compared patients treated with TACE, RFA, or SBRT while waiting for transplantation, SBRT showed 5-year rates of recurrence and OS similar to those of other modalities.

Use of SBRT in combination with immune checkpoint inhibitors also has the potential to increase tumor cell susceptibility to immune-mediated cell death. Radiation, in general, enhances cross-presentation of tumor antigens. Moreover, results from murine models illustrate that radiation combined with PD-L1 inhibition increases PD-L1 expression and the number of cytotoxic T cells within the tumor. It also suppresses tumor growth and increases survival of the animals. Preliminary data show that serum PD-L1 levels increase for up to 1 month after SBRT, which suggests to Dr. Seong that SBRT combined with a PD-L1 inhibitor might be more effective than SBRT alone and warrants clinical investigation.

Emerging Systemic Therapies for Advanced HCC

Since the introduction of sorafenib in 2007, there has been little change in the systemic therapies available for advanced HCC. However, the treatment landscape for patients with HCC is undergoing major change now—beginning last year with the approvals of the multikinase inhibitor regorafenib and the PD-1 inhibitor nivolumab, both in the second-line setting. Ann-Lii Cheng, MD, PhD, of the National Taiwan University Hospital, in Taiwan, detailed additional changes that may soon be used, pending approval of two new agents.

For more than a decade, sorafenib alone has been the standard of care for first-line treatment of advanced HCC. However, lenvatinib, an agent that targets multiple tyrosine kinases, may become a first-line option on the basis of results of the phase III REFLECT trial. This noninferiorty trial demonstrated similar median OS between lenvatinib and sorafenib in patients with advanced HCC (13.6 vs. 12.3 months; HR 0.92, 95% CI [0.79, 1.06]). However, lenvatinib excelled versus sorafenib in terms of median PFS (7.4 vs. 3.7 months; HR 0.66, 95% CI [0.57, 0.77]; p < 0.00001), median TTP (8.9 vs. 3.7 months; HR 0.63, 95% CI [0.53, 0.73]; p < 0.00001), and objective response rate (24% vs. 9%; p < 0.00001). The great majority of adverse events were similar between arms, although grade 3/4 hypertension was higher with lenvatinib than sorafenib (23% vs. 14%), and grade 3/4 hand-foot skin reaction was lower (3% vs. 11%).

Cabozantinib, also a multikinase inhibitor, is well positioned to join regorafenib and nivolumab as an option in the second-line setting according to favorable results of the phase III CELESTIAL trial. This study met the primary endpoint by showing a significant improvement in median OS with cabozantinib versus placebo (10.2 vs. 8.0 months; HR 0.76, 95% CI [0.63, 0.92]; p = 0.0049). Cabozantinib also demonstrated improvements compared with placebo for median PFS (5.2 vs. 1.9 months; HR 0.44, 95% CI [0.36, 0.52]; p < 0.0001), and objective response rate (4.0% vs. 0.4%; p = 0.0086).

Future changes highlighted by Dr. Cheng include possible approval of nivolumab in the first-line setting if the CheckMate-459 trial results are positive, as well as the introduction of pembrolizumab as a second-line option, pending results of KEYNOTE-224 and KEYNOTE-240.

–Kara Nyberg, PhD