Neoadjuvant Radiotherapy Improves Outcomes in Patients With HCC and Portal Vein Tumor Thrombus

Treatment with 3D conformal radiotherapy prior to hepatectomy significantly improved post-operative outcomes compared with surgery alone in patients with resectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus, according to the results of a randomized study published in theJournal of Clinical Oncology.¹

At 1 year, the rate of overall survival (OS) in the neoadjuvant radiotherapy arm was 75.2% compared with 43.1% in the hepatectomy-alone arm. Significant increases in OS were seen in patients with both type II and type III portal vein tumor thrombus.

The study authors, led by Xubiao Wei, MD, noted that “despite progressive disease and adverse events in a small proportion of patients, neoadjuvant radiotherapy is effective in improving overall survival and disease-free survival rates in patients with hepatocellular carcinoma and portal vein tumor thrombus. IL-6 may act as a biomarker in predicting the response to radiation in these patients.”

Surgery is recommended for select patients with resectable HCC and portal vein tumor thrombus over nonsurgical treatments. A prior retrospective study, however, demonstrated that neoadjuvant radiotherapy significantly reduced the extent of portal vein tumor thrombus and improved long-term survival. The rates of HCC recurrence (HR, 0.36; 95% CI, 0.19-0.70) and HCC-related death (HR, 0.32; 95% CI, 0.18-0.57) were both improved with neoadjuvant radiotherapy.²

This study aimed to confirm the results of the retrospective study in a randomized fashion. The randomized, open-label, multicenter controlled trial randomized patients to either neoadjuvant radiotherapy followed by surgery (n = 82) or surgery alone (n = 82).¹

All patients had primary resectable HCC and Cheng’s type II or III portal vein tumor thrombus involving the right- or left-side branch or the main trunk of the portal vein. Patients were excluded if they had received a prior regimen for HCC within 1 year and if they had another malignancy, hepatitis C virus, or HIV infection.

Modified RECIST criteria were used to evaluate the effects of radiotherapy. Patients in the radiotherapy plus surgery arm were re-evaluated at 4 weeks following RT, and surgery was performed within 5 days of assessment if there were no contraindications. Those randomized directly to hepatectomy received surgery within 5 days. OS was the primary endpoint of the trial. 

Baseline characteristics were mostly well matched between the 2 arms. The mean age was 52.8 years in the neoadjuvant arm and 50.5 in the surgery arm. A majority of patients had Child-Pugh grade A status (97%) and an alpha-fetoprotein level ≥20 (74%). Seventy-percent of patients received a major hepatectomy between the 2 arms, and 30% received a minor surgery. 

Th overall response rate to neoadjuvant radiotherapy was 20.7%, consisting of all partial remissions. An additional 58 patients had stable disease (70.7%) and 7 patients (8.5%) had progressive disease. In the responding patients, portal vein tumor thrombus was downstage from type III to type II or from II to I in 12 patients. Nine patients developed contraindications to surgery after receiving radiotherapy and instead received nonsurgical treatments.

Median follow-up was 15.2 months (range, 10.5-21.5) in the neoadjuvant radiotherapy arm and 10.8 months (range, 6.8-15.6) in the surgery-alone arm. HCC recurrence occurred in 66 patients in the neoadjuvant arm and in 75 patients in the surgery arm.

At 12 months, the rate of OS was 75.2% in the neoadjuvant radiotherapy arm and was 27.4% at 24 months. In the surgery-alone arm, the rate of OS was 43.1% at 12 months and 9.4% at 24 months. Disease-free survival (DFS) rates were 33.0% and 14.9% in the neoadjuvant and surgery arms, respectively, at 1 year, and were 13.3% and 3.3% at 2 years (P= .009).

Radiotherapy significantly increased the OS and DFS rates in patients with both type II and type III portal vein tumor thrombus. Neoadjuvant treatment also significantly decreased the risk of HCC-related mortality (HR, 0.35; 95% CI, 0.23-0.54;P<.001) and HCC recurrence (HR, 0.45; 95% CI, 0.31-0.64;P<.001) compared with surgery alone.

Immunohistochemistry staining for interleukin-6 (IL-6) was performed in patients who underwent neoadjuvant radiotherapy to test for associations between the levels of IL-6 and radioresistance. Baseline serum IL-6 levels were significantly higher in patients who had progression of disease after radiotherapy compared with those who achieved a response or stable disease (P= .047). In HCC tissue samples, the IL-6 levels were also significantly higher in the non-responders than the responders and those who achieved stable disease (P= .018).

&ldquo;The ability to identify biomarkers to predict the responses to radiotherapy is of critical importance to select patients for neoadjuvant radiotherapy,&rdquo; the study authors wrote. &ldquo;Our results indicate that IL-6 overexpression in serum or tumor tissues is related to radioresistance. More fundamental and clinical studies are needed to verify this hypothesis.&rdquo;

Grade 1/2 surgery-related complications were more common in the surgery-alone arm than in patients who received neoadjuvant therapy (23 vs 16;P= .380). There were 4 grade 3/4 complications in the neoadjuvant radiotherapy arm, including intra-abdominal hemorrhage in 2 patients, and liver failure and pulmonary infection in 1 patient each. One case of grade 3/4 liver failure was observed in the surgery-alone arm. There was 1 case of grade 5 liver failure reported in each arm as well as 1 case of grade 5 portal vein thrombosis in the surgery-alone arm.

References

1. 1) Wei X, Jiang Y, Zhang X, et al. Neoadjuvant Three-Dimensional Conformal Radiotherapy for Resectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Randomized, Open-Label, Multicenter Controlled Study [published online July 8, 2019].J Clin Oncol. doi: 10.1200/JCO.18.02184.
2. 2) Li N, Feng S, Xue J, et al. Hepatocellular carcinoma with main portal vein tumor thrombus: a comparative study comparing hepatectomy with or without neoadjuvant radiotherapy. HPB (Oxford). 2016;18(6):549-556. doi: 10.1016/j.hpb.2016.04.003.