Five independent factors were associated with mortality within 1 year in HCC patients undergoing HR with curative intent: Child-Pugh B/C, multinodularity, MAVI, ARF, and ISGLS PHLF criteria.
Cirrhotic patients have increased perioperative general risk for both elective and emergency surgical procedures [15, 16]. Our study showed that Child-Pugh stage B/C patients have a five-fold risk of 1-year mortality. Due to high perioperative risk, patients with Child-Pugh class C are not candidates for HR, and we included one patient with Child-Pugh class C. Cirrhosis is also associated with poor oncologic outcomes. A study by Kojiro Taura et al. [17] reported a 5-year survival rate of 81%, 54%, and 28% in non-cirrhotic, Child-Pugh class A, and Child-Pugh class B following HR, respectively. This is attributed to either a recurrence or development of metasynchronous HCC in cirrhotic liver. Few studies have evaluated the short-term prognosis of cirrhosis on post-hepatectomy patients. Chopinet et al. [18] reported acceptable short-term mortality and morbidity in cirrhotic patients (up to Child-Pugh class B, 7 points) and suggested that HR can be considered if patients have normal indocyanine green test and no portal hypertension. TACE, while conventionally considered a palliative procedure, has shown to improve survival outcomes and improve quality of life in patients with unresectable HCC [7]. Saviano et al. [8] reported no statistical difference in a 3-year overall survival in cirrhotic patients who underwent TACE–RFA combination versus HR in the presence of large solitary tumors. In a recent meta-analysis comparing TACE–RFA combination versus surgery, Gui et al. have concluded that TACE–RFA combination has similar long-term oncologic outcomes with the benefit of lower morbidity compared with surgery [7]. Child-Pugh class B/C patients should be carefully evaluated and preoperatively optimized to reduce the risk of PHLF and mortality, ensuring that HR remains safe [18], while considering TACE–RFA combination as an alternative therapy. TACE should be re-classified as a ‘curative adjunct’ rather than palliative in its intent.
Our study, consistent with a study by Moriguchi et al. [19], showed that multifocal HCC is a risk factor associated with 1-year mortality. The European Association for the Study of the Liver (EASL) recommended LT instead of HR as a first-line treatment for multinodular tumors [20]. They showed that the 5-year survival of LT in early HCC was comparable to those without malignancy (70%), and recurrence rates were less than 25%. However, due to the scarcity of donor organs, HR is still the first-line surgical management in patients with HCC. Based on our results, surgery may not be an ideal option for patients with Child-Pugh class B/C and multinodular HCC. Recently, some studies have shown good surgical outcomes in select patients with multinodular tumors and well-preserved liver function. Cheung et al. [21] compared HR with combined resection and ablation in multinodular HCC. They showed that the combined therapy had longer median survival (53 vs. 44.5 months). Knowing the number of tumors would allow the surgeon to discuss and offer treatment that includes a combination of ablation, chemoembolization, and surgery that is individualized to each patient. Patients with multinodular HCC should be carefully monitored for recurrence and offered enrolment into clinical trials. We did not study the pattern of 1-year mortality and hence unable to comment if this was associated with early HCC recurrence.
Our study showed that MAVI was associated with a five-fold risk for 1-year mortality and this is consistent with other reports [22]. MAVI of the hepatic or portal vein is part of the natural progression of HCC and is associated with a high recurrence rate even when treated with LT. Previously, portal vein thrombosis was considered a contraindication for LT, but techniques like thromboendovenectomy have emerged and redefined the role of LT and HR in patients with portal vein thrombosis [23]. Both portal and hepatic vein thrombosis are known to induce hepatic hypertrophy, which has the benefit in increasing the FLR, and hence MAVI is not an absolute contraindication of HR. In patients with MAVI, the median survival is less than 1-year, and BCLC recommends palliative Sorafenib treatment [24]. Further stratification based on MAVI location has shown that tumor with hepatic vein or vena cava invasion had a meager median survival of less than 5 months, with postoperative mortality of 28% [25]. This led to Mount Sinai Medical Centre no longer offering HR in patients with MAVI, as this result is worse than medical treatment or no therapy at all. Based on our experience and available literature, we would caution against HR in patients with MAVI and multifocal HCC as 1-year mortality risk is high, and the patient may enjoy survival advantage from TACE–RFA combination therapy [7]. Hepatic venous invasion and portal venous invasion may have a different biologic basis and need to be considered separately. A recent study by Levi Sandri et al. [26] achieved a recurrence-free survival of 39.1 months in four BCLC stage C patients with portal vein thrombosis by doing yttrium-90 radio-embolization before LT. Our study did not compare the outcome between location-stratified or perioperatively and intraoperatively known MAVI. Nevertheless, if MAVI is known on preoperative imaging, the patient should be counseled so that they can make informed decisions.
PHLF occurs in 4–19% of patients undergoing HR and is a severe complication that impacts mortality [27]. The variation in incidence arises due to the lack of a standardized definition. As part of postoperative factors, our study looked at three well-established definitions of PHLF. This variability of the definition is demonstrated in our study, where PHLF incidence was 3.7%, 4.3%, and 15.3% for PHLF1, 2, and 3, respectively. Only PHLF3 was statistically significant in the multivariate analysis of postoperative factors. In a study reporting 807 patients, Rahbari et al. [14] reported ISGLS criteria predicted mortality (HR 13.80; 95% CI 4.27–44.61, p < 0.01). Validation of PHLF3 as a postoperative 1-year mortality predictor is essential. PHLF is best prevented by optimization of preoperative factors [27] and incorporating strategies like portal vein embolization, two-staged hepatectomy, and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) [28] to ensure satisfactory FLR. Integrating active monitoring of INR and bilirubin on postoperative day five can allow for early recognition of PHLF3, stratification of severity, and initiation of supportive organ therapy, and improving survival risk.
Postoperative ARF is a risk factor associated with 1-year mortality, which is consistent with a study by Saner et al. [29], that reported 73% of patients with post-hepatectomy ARF requiring dialysis died. In our study, 85% of ARF patients died, and seven patients (4.3%) experienced ARF. Lim et al. [30] suggested adequate volume expansion, use of diuretics or vasoactive drugs, and earlier postoperative renal replacement therapy for higher-risk patients.
Limitations of our study are retrospective, single-center study over a decade, and small sample size. Due to small sample and low event rate for mortality, the multivariate analysis showed wide confidence intervals. This impacts the precision of our study results. As there was only one patient with Child-Pugh class C, we have combined the data of Child-Pugh classes B and C. We did not categorize complications according to Clavien-Dindo classification and have reported each complication separately. We did not collect data related to the cause of mortality and if this was related or associated with the recurrence of HCC. We caution against generalizing the results as clinical profile, surgical technique, and technology and perioperative management would differ.
