Surgical treatment of hepatocellular cancer: Expert consensus conference

In this summary statement from the proceedings of the Consensus Conference on Multidisciplinary Treatment of Hepatocellular Carcinoma (HCC),1 the authors describe concisely and thoroughly the efficacy of multiple potentially curative treatment options for HCC. Furthermore, the authors have emphasized several areas of controversy in the field that remain open to discussion. The major question that this review addresses is ‘What is the optimal treatment and/or sequence of treatments for patients with early T stage disease?’ The data and references presented in this manuscript highlight the fact that patients with early stage HCC may be candidates for curative therapy with one of several modalities including liver transplantation, liver resection, and possibly radiofrequency ablation. No one modality fits all patient scenarios; multidisciplinary teams of surgeons, oncologists, hepatologists, and radiologists armed with a thorough understanding of the literature and these consensus guidelines are best suited to assess each individual case and assign the optimal treatment plan. The discussion of these three modalities in particular should always be made in the context of the epidemiology of the disease. It is exceedingly rare for patients to present with HCC outside of the setting of cirrhosis. Certainly, those patients who do present with precirrhotic HCC are frequently candidates for liver resection based on their functional hepatic reserve. Although it is common to see HCC patients with compensated cirrhosis (Child-Turcotte-Pugh Class A and low Model for End Stage Liver Disease (MELD) score), the majority of patients presenting with HCC have more decompensated liver disease with portal hypertension, eliminating resection and ablation from the treatment armamentarium. At the same time, not all patients with ‘transplantable’ stage HCC are eligible for liver transplantation, due to medical, financial, or social concerns.2 In the setting of cirrhosis and HCC, the risks of resection and radiofrequency ablation need to be carefully weighed against that of transplantation. For United Network for Organ Sharing (UNOS) T1 tumors (one lesion up to 2 cm) in patients with pre-cirrhotic or well compensated cirrhosis with minimal portal hypertension, there are likely equivalent patient survivals with liver transplantation, surgical resection, and radiofrequency ablation (RFA). As these patients are not advantaged on the liver transplant waitlist and the availability of cadaveric allografts is low for this patient group, it remains advisable that well compensated cirrhotic patients with early T-stage disease pursue non-transplant curative modalities. In contrast, patients with UNOS T2 stage HCC (1 lesion less than 5 cm or 2–3 lesions with none larger than 3 cm) are advantaged on the UNOS liver transplant list. Depending on UNOS region and blood type, these patients may receive liver transplantation with a short wait list time (less than six months of wait time). Using current neoadjuvant treatment protocols (mainly transarterial chemoembolization and/or RFA, but now also systemic therapies) it is very rare to see a waitlist drop out from progression of HCC in a patient with UNOS T2 disease and a short wait time. Given these dynamics, this group of patients is expected to receive a greater benefit from liver transplantation than from other modalities. These arguments emphasize that the decision on which curative therapy is best suited for a given early T stage HCC patient depends on four critical factors: the underlying liver function/portal hypertension, the availability of/patient candidacy for liver transplantation, the tolerance for early complications with non-transplant modalities, and the focality of the tumor. For example, a well compensated cirrhotic patient (minimal portal hypertension and MELD < 10) with a small, solitary, peripheral HCC lesion, evaluated in a competitive UNOS region with a long anticipated wait time, should be considered for resection. In contrast, a MELD 18 cirrhotic patient with two HCC lesions, listed at a transplant center with a short anticipated waitlist time is better approached with transplantation. With regard to the specific comparison of outcomes between liver transplant/resection and RFA, several important points should be emphasized. Independent of HCC treatment modality, the overwhelming majority of outcomes analyses indicate that survival in patients with HCC is most closely associated with the presence or absence of microvascular invasion.3–5 Both liver transplantation and resection have the benefit of providing a pathology specimen to obtain this critically important prognostic information. In contrast, RFA and other destructive modalities remove the possibility of obtaining this information for the clinician and the patient. In addition, there is compelling evidence that local recurrence after RFA in lesions larger than 2–3 cm is significant.6,7 Together, these data suggest that, in patients who are candidates for extirpative modalities, resection and transplantation have prognostic information advantages and a track record that exceeds that of RFA. Another area of controversy addressed in this summary is the impact that down staging may have on patient eligibility for curative therapies in this disease. This discussion warrants several comments. First, there is increasing evidence that response to neoadjuvant therapy is a predictor of favorable HCC biology, and therefore of success with subsequent curative treatments.8–10 Second, while the authors' summary describes multiple novel modalities and multimodality treatment strategies that may facilitate down staging of HCC, distinction should be made between established modalities (thermal ablation, chemoembolization, and ethanol injection) and unproven techniques (electroporation, nanoparticles, systemic chemotherapy, and bland arterial embolization). Third, the early data on equivalent outcomes achieved in patients down staged from T3 to T2 and subsequently treated with transplantation or resection are compelling, but needs further study and validation. Finally, this summary underscores the uncharted space open to basic and clinical investigation in this field. Identification of an ideal set of neoadjuvant therapies to use as ‘bridge therapies’ during wait times for liver transplantation or as down-staging therapies for patients with advanced T-stage disease remains elusive. In current practice, most patients who are eligible to receive curative therapy for HCC are receiving more than one form of therapy, be it local-regional and/or systemic. As we move forward the most important challenge to be faced in effectively treating this set of patients is identification of molecular profiles that can predict the combination of therapies that will have the most efficacy with the least amount of toxicity.