Unresectable hepatocellular carcinoma: the need for an individualized multidisciplinary approach.
The incidence of hepatocellular carcinoma (HCC) varies substantially from country to country; cirrhosis from any cause is associated with an increased risk of HCC. It has been estimated that the incidence of HCC may exceed 20% in patients with more than a 5-year history of cirrhosis. 1 Selection of an appropriate treatment of HCC must be based on the patient's Child-Turchotte-Pugh score and the radiographic estimate of tumor growth using the tumor, node, and metastasis staging. Potentially curative surgical interventions range from segmental resection to total hepatectomy with orthotopic liver transplant and should always be considered as possible first-line therapy for the treatment of HCC. Nonsurgical ablative procedures are generally reserved for patients with unresectable tumor or those patients who are awaiting transplant. These therapies include percutaneous ethanol injection (PEI), radiofrequency thermal ablation (RFA), cryoablation therapy, and transarterial chemoembolization (TACE). CURATIVE SURGICAL TREATMENT OPTIONS Patients with Child's A cirrhosis with a Child-Turcotte-Pugh score of 5 to 6 (Tables 1 and 2) 14,15 and evidence of a HCC first should be considered for primary surgical resection, which may also include either adjuvant or neoadjuvant therapy. In contrast, patients with Child's B or C cirrhosis with a Child-Turcotte-Pugh score of 7 or more and evidence of a solitary HCC 5 cm or less or three or fewer lesions with no single tumor more than 3 cm should be considered for cadaveric orthotopic liver transplantation (OLT) or living related liver transplant. 2 These specific selection criteria were derived from a collective review of several large retrospective studies in which tumor-free patient survival time after OLT was stratified by tumor size. 3 Seventy percent of the patients that satisfy these selection criteria are disease-free for 5 years after transplant. 4 However, more extensive tumors often demonstrate an early and aggressive recurrence and represent a prohibitive risk after OLT. Therapies like PEI, RFA, or TACE are frequently used while the patients await transplantation to prevent further tumor growth. Given the current shortage of cadaveric organs, waiting times are commonly extending for 1 to 2 years. Unfortunately, this statistic highlights the fact that one in five patients with HCC who await OLT have progressive tumors and, therefore, may no longer be transplant candidates. 5TABLE 1: Current TNM staging for HCC. American Liver Tumor Study Group Modified Tumor-Node-Metastasis (TNM) Staging ClassificationTABLE 2: Child-Turcotte-Pugh scoring system to assess severity of liver diseaseYuen et al. 6 screened a cohort of patients with cirrhosis for HCC using alpha-fetoprotein and hepatic ultrasonography. They found that up to 61% of patients who had tumors initially satisfied United Network for Organ Sharing criteria for living related liver transplant or OLT. Yet, it has been estimated that, ultimately, only half of such patients are transplant candidates. 7 Thus, although screening cirrhotic populations may maximize early HCC identification, up to 70% of patients with cirrhosis and HCC are not candidates for surgical resection. NONSURGICAL TREATMENT OPTIONS Trevisani et al. 8 reviewed the literature on TACE for the treatment of HCC in a recent issue of the Journal. They very aptly noted that this area suffers from a lack of randomized controlled trials and standardization of patient populations, making evidence-based treatment decisions impossible. Overall, Trevisani and colleagues suggested that TACE be considered the gold standard therapy for patients with unresectable HCC. Although it is true that TACE perhaps has one of the longest track records in the treatment of unresectable HCC, we wish to remind the reader there are several other promising modalities documented in the literature and to advocate a more individualized approach to the treatment of patients with unresectable HCC. These treatments are reviewed below. PERCUTANEOUS ETHANOL INJECTION Percutaneous ethanol injection involves the introduction of a needle into a tumor mass under ultrasound or computed tomography guidance. Then, absolute (97.5%) ethanol is injected to induce coagulative necrosis of the cancer cells. In general, the amount of ethanol needed correlates directly with the cubic volume of mass. Calculations should include the addition of a 1-cm rim of normal tissue. Multiple treatment sessions and needle passes are often required to achieve complete tumor necrosis. The limitations of this therapy include the need for adequate visualization of the tumor, the need for identification of a safe tract for needle passage, and the fact that it can be used only for tumors encapsulated within surrounding liver tissue to prevent collateral damage to adjacent organs from ethanol leak. Several studies have compared PEI to surgical therapy and have found comparable results for lesions smaller than 3 cm. 9 The likelihood of inducing complete necrosis in tumors larger than 3 cm or in multinodular tumors is greatly reduced; hence, PEI is not advocated for tumors larger than 3 cm. The early morbidity of this treatment is limited to fever, reversible hepatic dysfunction, and rare needle tract bleeding complications. Late morbidity may occur from potential seeding of tumor cells along the multiple needle tracks needed for ablation. The mortality related to this procedure is negligible. The greatest advantage of this technique is its technical simplicity. Even in parts of the world where medical resources are scarce, PEI is feasible in trained hands. RADIOFREQUENCY ABLATION Radiofrequency thermal ablation is perhaps the newest and most promising therapy for unresectable HCC and is a rapidly evolving technology. The technique involves the percutaneous, laparoscopic, or open introduction of a specialized radiofrequency needle into the center of the tumor mass using ultrasound or computed tomography guidance. Once in place, hook-shaped electrodes are deployed from the needle, through which thermal energy is generated by microwave induction. Using this technique, a spherical mass of tissue of a defined size can be destroyed by raising local temperatures to more than 100°C for 3 minutes. Because coagulated tissues become more echodense by ultrasound, a rough estimate of the zone of tissue necrosis can be measured at the time of treatment. Specialized needles are now available that can achieve an up to 6-cm sphere of coagulative necrosis. Radiofrequency thermal ablation has several potential advantages over PEI. Using a single pass (or sometimes several passes) of an RFA needle, a large lesion can be selectively destroyed. The needle track itself can also be ablated, preventing seeding or shedding of tumor cells or track hemorrhage. Multiple tumors can also ablated at a single session. However, similar to PEI, there are limitations to this technique that concern safe needle tract passage, and the requirement for ultrasound or computed tomography visualization still apply. Currently, a randomized prospective trial is underway that compares the efficacy of PEI to RFA for unresectable HCC. 10 CRYOABLATION Cryoablation therapy represents another variation on the theme of thermal ablation. This technique involves open or laparoscopic placement of a large cryoprobe into the tumor mass under ultrasound guidance. Then, liquid nitrogen is circulated through the probe, generating a spherical ball of frozen tissue that leads to cell death. The boundary between frozen and unfrozen tissue can be accurately followed, ensuring necrosis of the tumor with an acceptable margin of normal tissue. A limitation of cryoablation therapy is its technical complexity and the increased risk of complications. Cryoablation therapy is associated with a 10% to 15% rate of significant complications, including bleeding and liver fracture. 11 The current advantages of cryoablation therapy over RFA include a more reliable necrosis of tumors larger than 6 cm and the ability to very accurately determine the boundary of cell death. 12 However, newer RFA probes may soon obviate this advantage. TRANSARTERIAL CHEMOEMBOLIZATION The TACE technique is well described in the review by Trevisani et al. 8 However, it is worth highlighting patient selection and the importance of exclusion criteria and technical complications for this procedure. Although TACE is often used for the palliation of large tumors, significant survival benefits have not yet been consistently demonstrated. Transarterial chemoembolization requires angiographic placement of a hepatic arterial catheter and an injection of lipiodol conjugated with an anticancer drug, followed by arterial embolization. Most protocols advocate repeated treatments to ensure complete tumor necrosis. 12 At our own institution, PEI, RFA, and TACE are not viewed as rival therapies but as a spectrum of complementary treatments for unresectable HCC. Percutaneous ethanol injection is selected for small (less than 2 cm), single lesions. Radiofrequency thermal ablation is used for multiple lesions or tumors that are between 2 to 6 cm, although the upper limit is changing as improved RFA probes become available. Transarterial chemoembolization is generally reserved for tumors with a more diffuse lobular picture, poor radiographic visualization, lesions abutting or adjacent to sensitive structures including portal vein, inferior vena cava, and central bile ducts or for patients in whom general anesthesia is contraindicated. There are several small series that describe the combination of these modalities that plays to the strengths of each treatment to achieve maximal benefit for the patient. 13 Rarely, even partial response to RFA or TACE has been used to downstage a patient with a large HCC to an acceptable candidate for OLT or resectional surgery. It should be emphasized that the selection of a treatment modality must be individualized based on thorough informed patient consent, treatment availability, and local expertise. In summary, although Trevisani and colleagues recommend that TACE be considered the standard treatment for unresectable HCC, we advocate a more individualized approach, based on the limited data available. Unfortunately, despite nearly 2 decades of treatment protocols, the state-of-the-art is still no closer to significantly improving the 5-year survival rates for patients with inoperable HCC. However, we do completely agree with the call for properly designed, large multicenter randomized trials to develop optimal therapy or HCC, as well as the selective screening of at-risk individuals to detect HCC at a time when it can potentially be cured.
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