Many patients with primary hepatocellular carcinoma (HCC) have a single large tumor (>5 cm). Official guidelines (1,2) and large retrospective studies (3,4) assign these patients to different Barcelona Clinic Liver Cancer (BCLC) stages, leading to different treatment recommendations. Current BCLC guidelines recommend transarterial chemoembolization (TACE) for BCLC stage B patients (1,2). However, improvements in surgical technique and perioperative care at several large liver centers have made hepatic resection (HR) a first-line therapy for many patients in stage B as well as earlier and advanced stages (5-7).
In a recent issue of J Gastroenterol Hepatol, Jung and coworkers retrospectively analyzed 1,005 HCC patients to determine the optimal staging of patients with a single large HCC tumor, based on median survival time and overall survival. They found that patients with a single nodule >5 cm had worse prognosis than those in BCLC stage A, who had a single nodule >2 cm and ≤5 cm or 2−3 nodules ≤3 cm; and similar prognosis to those in BCLC stage B, who had 2 or 3 nodules >3 cm or >3 nodules (8). Those authors concluded that BCLC stage B is the best designation for patients with a single large tumor. We believe this conclusion should be treated with caution because it is inconsistent with the results of our study involving 927 patients without macrovascular invasion or tumor metastasis who underwent initial HR, in which we found patients with a single large tumor were with significantly better overall survival than those with two to three tumors with a maximum diameter >3 cm or those with more than three tumors of any diameter (all these patients were classified as BCLC stage B) (9).
In addition, potentially serious problems in how Jung et al. (8) designed and executed their study weaken its conclusions. Each of the three patient groups underwent heterogeneous treatments involving HR alone (20%), radiofrequency ablation with or without TACE (31%), or TACE alone (49%). Main factors influence patients survival includes not only tumor stage, but also treatment modality. Large original study (3) and systematic reviews (6,7) have associated HR with significantly greater overall survival than TACE for patients with BCLC stage A, B, and C HCC. Indeed, the authors’ own subgroup analyses based on treatment modality within each HCC group showed that HR was associated with significantly better overall survival than TACE alone in all three groups. Thus treatment modality is a known confounder in the authors’ comparisons based on tumor stage, yet they did not control for this by grouping patients by treatment and subsequently stratifying by HCC type.
Among patients who underwent HR alone in the study by Jung et al. (8), median survival time in those with a single nodule >5 cm (84.2 months, n=41) was slightly shorter than survival in those with stage B disease (110.7 months, n=27). This conflicts with the authors’ conclusion that stage B is the most accurate classification for patients with a single nodule >5 cm. In fact, median survival time among patients treated by HR did not differ significantly across all three HCC groups (8).
We congratulate Jung and coworkers for using evidence-based methods to resolve discrepancies among official treatment guidelines. Work from our own group suggests the need to revise recommended treatments for patients with stage B HCC by including HR as a potential treatment (3,6,9-11). Consistent with that work, and with numerous studies from other medical centers, Jung et al. (8) found that HR was associated with significantly better overall survival than radiofrequency ablation with or without TACE, or TACE alone. It may be that expanding the indications for HR in the BCLC staging scheme may be therapeutically more useful than attempting to determine an “optimal” BCLC stage for patients with single large tumors >5 cm.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- European Association for Study of Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. Eur J Cancer 2012;48:599-641. [PubMed]
- Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020-2. [PubMed]
- Zhong JH, Ke Y, Gong WF, et al. Hepatic resection associated with good survival for selected patients with intermediate and advanced-stage hepatocellular carcinoma. Ann Surg 2014;260:329-40. [PubMed]
- Torzilli G, Belghiti J, Kokudo N, et al. A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations?: an observational study of the HCC East-West study group. Ann Surg 2013;257:929-37. [PubMed]
- Zhong JH, Ke Y, Wang YY, et al. Liver resection for patients with hepatocellular carcinoma and macrovascular invasion, multiple tumours, or portal hypertension. Gut 2015;64:520-1. [PubMed]
- Zhong JH, Rodríguez AC, Ke Y, et al. Hepatic resection as a safe and effective treatment for hepatocellular carcinoma involving a single large tumor, multiple tumors, or macrovascular invasion. Medicine (Baltimore) 2015;94:e396. [PubMed]
- Qi X, Wang D, Su C, et al. Hepatic resection versus transarterial chemoembolization for the initial treatment of hepatocellular carcinoma: A systematic review and meta-analysis. Oncotarget 2015;6:18715-33. [PubMed]
- Jung YK, Jung CH, Seo YS, et al. BCLC stage B is a better designation for single large hepatocellular carcinoma than BCLC stage A. J Gastroenterol Hepatol 2015. [Epub ahead of print]. [PubMed]
- Zhong JH, You XM, Lu SD, et al. Historical Comparison of Overall Survival after Hepatic Resection for Patients With Large and/or Multinodular Hepatocellular Carcinoma. Medicine (Baltimore) 2015;94:e1426. [PubMed]
- Zhong JH, Xiang BD, Gong WF, et al. Comparison of long-term survival of patients with BCLC stage B hepatocellular carcinoma after liver resection or transarterial chemoembolization. PLoS One 2013;8:e68193. [PubMed]
- Zhong JH, Lu SD, Wang YY, et al. Intermediate-stage HCC--upfront resection can be feasible. Nat Rev Clin Oncol 2015.12. [PubMed]