New Approaches to the Detection and Treatment of HCC With Portal Vein Thrombosis

¹

An estimated 10% to 40% of patients with HCC will present with PVT at the time of diagnosis. Portal vein thrombosis is an independent predictor of mortality, and, when left untreated, patients with HCC and PVT have a median overall survival (OS) of just 2 to 4 months.²Using the Barcelona Clinic Liver Cancer (BCLC) staging, most patients with PVT are classified as having advanced-stage disease (class C). As such, treatments are extremely limited, and curative options, such as liver transplantation and surgical resection, are generally contraindicated or controversial, and not performed in most centers.³

Sorafenib (Nexavar) currently remains the only therapy specifically recommended for HCC with PVT by the American Association for the Study of Liver Diseases (AASLD). In the pivotal phase III SHARP trial, sorafenib demonstrated a median OS of 10.7 months versus 7.9 months with placebo, a benefit that was maintained across subgroups of patients with aggressive disease.⁴Because of the relatively short survival expectancy, ongoing efforts have continued in the detection and development of locoregional therapeutic options for patients with HCC and PVT.

Insights Into the Novel Detection of PVT

Accurate and timely assessment of patients with malignant PVT in HCC is vital for both tumor staging and subsequent treatment selection. A relatively novel detection technique, gadoxetic acid‒enhanced magnetic resonance imaging (MRI), represents one potential option for the evaluation of thrombosis in HCC.

In a recently published retrospective study, Jae H. Kim, MD, and colleagues, Seoul National University College of Medicine, South Korea, reported their analysis of patients with HCC and PVT using gadoxetic acid-enhanced MRI in the January 14, 2016, issue ofRadiology.⁵

Current imaging techniques used to evaluate HCC include dynamic computed tomography (CT) and nonspecific extracellular contrast material (ECCM)‒enhanced liver MRI. Both have shown clinical accuracy in diagnosis of PVT with HCC, though study cohorts have been small and did not include non-PVT control groups.^6,7

Previous reports have indicated that MRI with gadoxetic acid had superior diagnostic sensitivity and specificity for HCC in patients eligible for liver transplantation compared with dynamic CT or MRI with ECCM.⁸Whether MRI with gadoxetic acid was useful and advantageous for the evaluation of PVT was unknown.

Gadoxetic acid is a liver-specific contrast agent that exhibits certain characteristics that are beneficial for evaluating liver lesions. Hepatocytes take up nearly half of the injected dose of gadoxetic acid with a delayed enhancement that lasts for about 2 hours.⁹After administration, normal liver tissues demonstrate T1 shortening, but focal liver lesions typically do not, increasing the likelihood of HCC tumor detection through this exclusion. Tumors as small as 2 cm have been detected with this agent. Meta-analysis of gadoxetic acid‒enhanced MRI studies has shown 91% sensitivity and 94% specificity for HCC detection, rates that are higher than dynamic CT and ECCM MRI.⁸

In the present study, 183 patients with malignant (n = 134) or benign (n = 49) PVT were matched with patients without PVT for age and sex. Of those with PVT, 125 patients had a complete occlusion and 58 had a partial occlusion. PVT was located in either the major portal vein (n = 159) or segmental portal vein (n = 24). Most patients, whether positive or negative for PVT, were classified as Child-Pugh A status.

Gadoxetic acid‒enhanced MR images were analyzed for sensitivity, specificity, and accuracy in the detection and characterization of PVT by location (major vs segmental) and type (complete vs partial). Two radiologists who were blinded to clinical and pathologic information analyzed images independently.

Patients with PVT exhibited a number of characteristics that were consistent with a worse clinical prognosis. Compared with those without PVT, patients with PVT had a significantly higher rate of liver cirrhosis (81% vs 66%;P<.0001), larger HCC diameters (7.15 cm &plusmn; 4.90 vs 5.32 cm &plusmn; 2.92;P<.0001), and a higher incidence of multiple tumors (52% vs 21%;P<.0001).

The diagnostic performance of gadoxetic acid‒enhanced MRI demonstrated comparable rates of sensitivity, specificity, and accuracy in PVT detection as when used to detect HCC. Using MRI with gadoxetic acid, reviewers were able to detect PVT with a sensitivity of 70% to 84%, specificity of 89% to 96%, and accuracy of 83% to 87%. The sensitivity of detection with gadoxetic acid for malignant PVT was 81% to 93%, with similar sensitivity of detection for the segmental and major branches. The sensitivity for benign PVT was significantly lower (41%-60%;P<.0001).

The sensitivity for detecting partial PVT was significantly lower than the detection of complete PVT (36%-59% vs 86%-96%, respectively;P<.0001). Similarly, sensitivity was significantly lower for patients eligible for liver transplantation than for other treatments, and in patients with Child-Pugh class B or C cirrhosis. The researchers hypothesized that these results may have been due to portal hypertension and weaker enhancement of the portal vein, the higher likelihood of partial benign PVTs in those groups, or the potential for severe hepatic dysfunction to impair the diagnostic performance.

The detection of characteristic imaging features of malignant PVT was common; detection of tumor continuity, vessel expansion, enhancement, increased T2 signal intensity, and diffusion restriction was found in more than 76% of patients for each reviewer. Conversely, these characteristics were rare, 10% or less, in patients with benign PVT. Importantly, MRI with gadoxetic acid distinguished malignant and benign PVT with accuracies of 92% to 95%.

A randomized trial compared gadoxetic acid‒enhanced MRI with ECCM MRI and contrast-enhanced CT as a first-line imaging method in patients suspected of having colorectal cancer with liver metastases (mCRC). Investigators concluded that diagnostic confidence was higher for MRI with gadoxetic acid than with the other 2 methodologies because additional imaging was not required prior to surgery. Fewer imaging tests ultimately resulted in similar overall costs among the imaging strategies evaluated.¹⁰

Christoph Zech, MD, University of Basel, Switzerland, the lead researcher of the study commented, &ldquo;The potential clinical benefits shown at similar costs suggest that gadoxetic acid-enhanced MRI should be the preferred procedure to evaluate hepatic resectability in patients with colorectal cancer liver metastases."¹¹

Taken together, these results indicate the utility of gadoxetic acid‒enhanced MRI in HCC with PVT, and also in secondary metastases to the liver. Accurate diagnosis of HCC can help to improve treatment strategies and guide optimal clinical management of this progressive disease.

Ablation Techniques in the Clinical Management of HCC With PVT

For unresectable HCC, local ablation is considered a suitable alternative nonsurgical therapy option. Thermal ablation techniques effectively induce solid tumor cell death by raising the temperature above a lethal threshold. The technique is used in the treatment of many different tumor types, and is considered a favorable alternative to surgery because of its minimal invasiveness, acceptable tolerability and safety profile, efficacy, and cost-effectiveness. Furthermore, surgery is often an unsuitable treatment option for HCC with main portal vein involvement.¹²

The 2 most commonly used thermal ablation techniques are microwave ablation (MWA) and radiofrequency ablation (RFA). They differ in their energy sources: non-ionizing electromagnetic fields with a frequency of 1 GHz are typically used with MWA, and alternating electric currents with a frequency of 400-500 kHz are typically used with RFA. In patients with HCC tumors less than 3 cm, RFA is effective and has shown a 5-year OS rate of nearly 40%.¹³Conversely, MWA is better suited for HCC tumors larger than 3 cm. Multiple reports have indicated complete ablation rates greater than 90% and OS rates greater than 50% at 3 years, although response rates often correlate directly with the size of the lesion.¹³

Despite promising OS rates with ablation techniques, the recurrence rates of larger HCCs is still high. As such, combination therapies, such as MWA with transarterial chemoembolization (TACE), have been investigated. Not only does TACE create an ischemic environment that increases the local effect of the chemotherapeutic agent, it also creates synergy with thermal ablation by enhancing the sensitivity of tumor cells to hyperthermia.¹²A limited number of studies have examined the clinical efficacy of MWA with TACE in the setting of HCC with PVT, which may be attributed in part to concerns of hepatic necrosis and worsening liver function.¹⁴

A recent prospective analysis examined the use of MWA following TACE in patients with HCC with malignant PVT. Jian Long, MD, and colleagues at Capital Medical University in Beijing, China, reported their findings in the January 7, 2016, issue ofHepatology International.¹⁵

In this study, the clinical characteristics, survival outcomes, and complications of patients treated with MWA after TACE (n = 60) were compared with those treated with TACE alone (n = 54), using data from a previous retrospective study. All patients in the prospective cohort had BCLC stage C disease, with one-half having more than 1 tumor. The mean size of the largest tumor was over 6.0 cm.

Compared with those treated with TACE alone, patients who were treated with MWA plus TACE showed improvement in 1- and 3-year OS rates (48% vs 33%, 1-year OS; 23% vs 20%, 3-year OS). Similarly, median survival times were also improved with combination therapy (13.5 months vs 9.5 months, respectively). Comparatively, in previous studies of patients with HCC and PVT treated with sorafenib, the 3-year survival rate was 15% and median survival was 4.3 months.^16,17

Additionally, changes in bioclinical markers were significantly associated with patient survival. Changes in the neutrophil-to-lymphocyte ratio (NLR; HR, 0.331;P=.031), Cancer of the Liver Italian Program (CLIP) score (HR, 2.632;P=.025), and treatment efficacy (HR, 36.848;P=.000) were all prognostic indicators of survival, indicating that these factors may be clinically useful predictors of patient outcomes in the context of HCC with PVT. Patients who were treated with MWA plus TACE and who had a decrease in NLR posttreatment showed improved survival compared with those with increased NLR. Within 4 weeks of treatment, no patients developed posttreatment hepatic failure, a significant finding given the controversial nature of MWA use with TACE. Other complications were rare, and only pneumothorax (n=2) and biliary tract injury (n=5) were noted posttreatment.

Although data are limited, these results were consistent with a previous study that showed improved clinical outcomes for patients who were treated with TACE followed by MWA compared with TACE alone in patients with unresectable, large-sized HCC. Superior tumor reduction rates (88% vs 39%) and longer survival times (11.6 vs 6.1 months) were observed.¹⁸

Arthur Winer, MD, NYU Langone Medical Center, New York City, and colleagues presented a retrospective study of the comparative effectiveness of combination therapy of TACE plus ablation (RFA/MWA) versus TACE monotherapy in patients with HCC, at the 2016 ASCO Gastrointestinal Cancers Symposium. The 5-year survival rates for combination therapy, TACE, and ablation were 42.1%, 11.9%, and 13.3%, respectively. Similarly, survival at 5 years, as determined by Kaplan Meier analysis, was significantly longer with combination therapy than with ablation or TACE alone (P=.0006).¹⁹

Although the latter studies did not evaluate the subpopulation of patients with HCC patients and PVT specifically, they demonstrated the potential clinical efficacy in an advanced HCC setting. The positive clinical results of the study by Long et al¹⁵may be of particular interest because of the large mean tumor size and multinodularity among patients. These clinical characteristics have traditionally been difficult to treat effectively, especially in patients with PVT.

&ldquo;The great progress of oncology over the past few years now permits the treatment of more patients with advanced disease who were previously considered unfit for surgery, or indeed, any kind of palliative treatment. Locoregional treatments such as RFA and MWA constitute the backbone of interventional treatment in HCC, a malignancy that affects up to a million people per year worldwide,&rdquo; wrote Loukia Poulou, MD, PhD, National and Kapodistrian University of Athens, Greece, and colleagues. Poulou added, &ldquo;The evolution of devices and instruments coupled with the progress of multidisciplinary patient management may allow a better stratification that would maximize treatment benefit.&rdquo;²⁰

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