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EDITORIALS |
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Correspondence: Address correspondence to: Eddie K. Abdalla, MD, Assistant Professor of Surgery, Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, PO Box 301402, 1515 Holcombe Boulevard, Houston, Texas 77230-1402; Fax: 713-745-1921; E-mail: eabdalla{at}mdanderson.org
In this issue of Annals of Surgical Oncology, Wu et al.1 present an initial experience with extracorporeal high intensity focused ultrasound (HIFU) for treatment of patients with cirrhosis and unresectable hepatocellular carcinoma (HCC). Fifty-five patients with predominantly large HCC (only 2/55 had tumors <5 cm) who were considered unresectable (only 4 were considered resectable but refused surgery) were studied; 38% were treated with HIFU because of "failure" of transarterial chemoembolization (TACE). Complications were minor and uncommon, and the 18-month survival rate was 35%. This analysis highlights two areas worthy of further discussion: treatment selection for all patients with large HCC, and advances and limitations of locoregional therapies for unresectable HCC.
Morphologic criteria such as tumor size do not accurately predict outcome following surgical treatment of HCC. Despite the association between tumor size and vascular invasion, (one of the strongest determinants of survival), the International Union Against Cancer (UICC) / 6th Edition American Joint Committee on Cancer (AJCC) staging for liver cancer confirms that median survival exceeds 5 years following resection of large solitary tumors (5–10 cm and even >10 cm) without vascular invasion (T1 tumors). This staging system was validated and this specific finding confirmed by Poon et al. in Chinese patients with HCC in a background of Hepatitis B,2 which is pertinent to the study population in the present report.
With regard to patients with large tumors, transplantation, TACE and local tumor ablation are usually contraindicated based on existing criteria,3–5 which leaves hepatic resection as the sole treatment shown to provide long-term survival for selected patients in this group.6–9 Lee et al. reported 1-, 3-, and 5-year disease-free survival rates of 42%, 30%, and 28%,7 and Zhou et al. described a 26% 5-year survival rate for patients with tumors equal to or greater than 10 cm; over 17% of patients were alive at 10-years of follow-up in their report.9
Because underlying liver disease compromises post-hepatectomy liver function, many patients with technically resectable tumors may not be candidates for safe major hepatic resection. Patients with Child-Pugh A cirrhosis and no portal hypertension may benefit from preoperative portal vein embolization in order to reduce the complications associated with inadequate function of the post-resection liver remnant10 and the risk of death from liver failure.11,12 Despite such advances in preoperative preparation, even when combined with technical advances in surgery, anesthesia and postoperative care, the majority of patients that present with large HCC are not candidates for potentially curative therapy due to tumor-related factors such as major vascular invasion or to liver factors such as extensive underlying fibrosis.
Interpretation of outcome data from tumor ablation studies is difficult for reasons described above—morphologic criteria alone do not accurately predict prognosis for HCC. The natural history of patients with untreated HCC varies widely, with median survival which can range from less than 6 months to 20 months, and estimated tumor doubling time which can range from 1 month to 19 months.13 Further, no rigorous evidence exists to suggest that local tumor ablation provides recurrence-free or overall survival equivalent to hepatic resection for any hepatic tumor (including the most studied technique of ablation, RFA)14,15 whereas RFA has been shown to be associated with inferior disease-free and overall survival compared to resection in patients with cirrhosis and resectable HCC.15 RFA is usually limited to treatment of tumors smaller than 4–6 cm because of the nearly uniform recurrence (persistence) of tumor after attempted ablation of large tumors.16,17 For these reasons, ablative treatments are limited to patients with truly unresectable HCC and those who will not tolerate surgery because of underlying medical co-morbidities.
Local recurrence or persistence following local ablation may relate not only to limitations of the ablation technique (or to limited accuracy of real-time monitoring of the procedure) but also to the biology of HCC which is known to spread along portal tracts and to produce satellite lesions not visible on imaging. The entire cirrhotic liver is felt to be a "field of cancerization" which can lead to occurrence of new HCCs.18 This concept is supported by the examination of disease-free survival after surgical treatment of HCC. Transplantation, which removes the tumor and the entire "field at-risk," provides the longest disease free survival for treatment of highly selected patients with early stage HCC.19,20 Portal-oriented/anatomic resection, which removes the tumor and the regional "field at-risk," provides the next best disease-free survival,3 followed by wedge resection, which removes only the tumor and a margin of liver. In contrast, ablation is in many ways the opposite of transplantation—not only is the maximum volume of "liver at-risk" left in place, the tumor itself is left in-situ and ablated, rather than being removed.
The treatment of choice for HCC is resection or transplantation. The treatment of choice for large HCC remains resection. When resection is not possible, HIFU may represent a therapeutic option that overcomes some of the problems of under-treatment associated with TACE and other ablative treatments. In particular, HIFU may be a promising approach to unresectable HCC, including large HCC, but further supportive evidence from outcome studies is needed. Selection of the best treatment for individual patients is best achieved following multidisciplinary review in centers with experience treating the complex combination of primary liver cancer and underlying liver disease.
Received for publication September 20, 2004. Accepted for publication October 18, 2004.
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