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Combination Therapy in Intermediate-Stage Hepatocellular Carcinoma: Do We Need to Know about Microvascular Invasion?

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See also the article by Peng and Chen et al in this issue.


Transarterial chemoembolization (TACE) is the standard of care for the treatment of primary and recurrent intermediate-stage hepatocellular carcinoma (HCC). Patients with intermediate-stage HCC who are not treated have a median survival of 16 months. TACE alone only modestly extends survival to a median of 19–20 months. This variability in survival and response to treatment reflects the heterogeneous nature of intermediate-stage HCC with respect to tumor biology and extent of disease (1).

Tumor recurrence after initial resection of HCC often manifests as intermediate-stage Barcelona Clinic Liver Cancer stage B HCC (multinodular pattern without macrovascular invasion). Outcomes of intermediate-stage disease are variable and range from 11 months in untreated patients to 36–45 months in the best cohort of treatment responders.

The optimal treatment of patients with intermediate-stage HCC with recurrent disease is unclear and multiple investigators have reported beneficial results with variations of TACE (ie, bland embolization, drug-eluting beads, and transarterial chemoinfusion), selective internal radiation therapy, and combination therapy of TACE with percutaneous ablation and TACE combined with antiangiogenic agents. Microvascular invasion (MVI) and tumor grade at histologic analysis of hepatic resection specimens are important prognostic indicators for recurrence of HCC. The likelihood of MVI dramatically increases when a lesion has exceeded 2 cm in diameter and is manifest in most lesions larger than 5 cm.

TACE with sorafenib, an inhibitor to vascular endothelial growth factor, is an attractive approach because of the relatively common finding of MVI in resected specimens larger than 2 cm in diameter and the likelihood that the immediate, postembolic localized hypoxic effect from TACE results in increased levels of vascular endothelial growth factor. In a meta-analysis of six studies with 1254 patients, Zhang et al (2) reported an improvement in overall survival, time to progression, and objective response rate in patients with intermediate or advanced stage HCC who were treated with a combination of TACE with sorafenib. In their analysis of the pooled data, there was a 35% reduction in risk of death and 32% reduction in time to progression in patients treated with combination therapy. Current European Association for the Study of Liver Disease clinical practice guidelines, however, recognize an acceptable safety profile associated with the combination of TACE and antiangiogenic agents but state that conclusive efficacy of combination therapy has not been established (1). Hence, the optimal use of combination therapy in intermediate-stage HCC, although widely studied, remains controversial.

In this issue of Radiology, Peng et al (3) evaluated 260 patients with recurrent intermediate-stage HCC and found a survival benefit in patients with lesions positive for MVI (n = 127) who were treated with a combination of sorafenib with TACE versus TACE alone. The combination treatment group had a longer median overall survival (17.2 vs 12.1 months, respectively; P = .02) and longer progression-free survival (17.0 months vs 11.0 months, respectively; P = .02) than did the TACE cohort. Patients who did not have MVI-positive lesions (n = 133) did not demonstrate a significant difference in overall or progression-free survival between the two treatment groups.

In the overall cohort, multivariable analysis demonstrated the following three variables each to be independent predictors of both overall survival and progression-free survival: presence of three intrahepatic tumors, absence of MVI, and combination treatment. Response rates were better for the combination therapy group but were not significantly different than in the TACE group. For the MVI-positive cohort, combination therapy resulted in 34.5% complete response and 38.1% partial response versus 20.8% complete response and 29.2% partial response for the TACE-only group. Objective response (complete response and partial response) was 40% for combination therapy versus 36% for TACE only. An interaction analysis between MVI and the treatment groups demonstrated that when MVI was positive for the lesion, the combination treatment was associated with better overall survival (interaction between MVI and treatment hazard ratio, 3.8; 95% confidence interval: 1.6, 9.3, P = .003) and progression-free survival (interaction between MVI and treatment hazard ratio, 3.3; 95% confidence interval:1.4,7.4; P = .005).

Whereas the antiangiogenic effect of sorafenib may inhibit the potential upregulation of vascular endothelial growth factor caused by TACE-induced local hypoxia (4), prolonged administration of antiangiogenic agents before hepatic transarterial therapy may decrease the efficacy of TACE and lead to complications during treatment. There has been substantial variability in dosing protocols for sorafenib in combination therapy. The Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Aorafenib (known as GIDEON) observational registry (5) evaluated TACE therapy both before and concomitantly with sorafenib treatment and documented global variability in the timing of sorafenib. The performance of TACE before initiation of sorafenib therapy was more common in Japan and in Asian countries. The overall results demonstrated the safety of combination therapy but also noted better results in patients treated concomitantly with TACE and sorafenib versus those who underwent the treatments separately.

The current report by Peng et al (3) incorporated a concomitant sorafenib treatment regimen that started 1–3 days before TACE and continued after TACE with a standard de-escalation protocol to accommodate for the development of drug-related adverse events. With this approach, there were no unexpected adverse events, no treatment-related deaths, and no significant difference in adverse events between the MVI-positive and MVI-negative groups. This approach is consistent with the positive results for concomitant treatment in the GIDEON registry. In the study by Peng et al, the inclusion criteria of patients with intermediate-stage, postresection recurrent HCC with good performance status may have contributed to its success. The median duration of treatment with sorafenib lasted more than 15 months for all patients treated with combination therapy. The negative data from other studies that evaluated combination treatment with sorafenib and TACE may have been in part because of the inclusion of patients with advanced disease with poor performance status who were unable to tolerate sorafenib for at least 6 months (5).

Matching the response to treatment with individual tumor types in HCC currently requires histologic-level evaluation of tumor grade and MVI. Full analysis of these criteria is only reliable by histologic examination of postresection specimens because percutaneous biopsy specimens are limited in the determination of histologic grade and MVI due to sampling error. Establishment of imaging surrogates for MVI is an area of significant interest for research. Studies have proposed imaging criteria that correlate with MVI such as nonsmooth margins and two-trait predictor of venous invasion (ie, presence of venous invasion and hypoattenuating haloes and peritumoral enhancement). Nodules that show at least two of these three imaging criteria are considered to be positive for MVI(5). MRI studies that use diffusion kurtosis imaging have shown that higher mean kurtosis values combined with irregular circumferential enhancement are potential imaging biomarkers for MVI in patients with HCC (7). In addition, promising data have been published in the field of radiomics. Investigators have validated nomograms, which use a combination of imaging criteria and clinical data, to create a radiomics signature for the preoperative prediction of MVI in patients with HCC (8). As the ability to more accurately characterize tumor biology noninvasively improves, the importance of the outcomes reported in the current report by Peng et al increases.

In conclusion, the validation of a positive response to combination therapy of transarterial chemoembolization with sorafenib in a specific cohort of patients with MVI has treatment implications for patients who have undergone resection and potentially for patients who by noninvasive techniques can be determined to have MVI. The use of vascular endothelial growth factor inhibitors in the treatment of HCC has long been considered theoretically attractive, but the widespread adoption of this approach has been limited by inconclusive data involving more diverse groups of patients. In this study, MVI that is present at initial resection was correlated with a positive treatment response to combination therapy. In conjunction with the findings of the current report by Peng et al (3), newer imaging techniques and the development of radiomics signatures that reflect tumor biology may further expand the treatment options for patients with intermediate-stage HCC.

Disclosures of Conflicts of Interest: P.C.M. disclosed no relevant relationships.


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Article History

Received: Apr 22 2019
Revision requested: Apr 25 2019
Revision received: Apr 25 2019
Accepted: Apr 29 2019
Published online: May 28 2019
Published in print: July 2019