Malignant liver tumours include a wide range of primary and secondary tumours. Although surgery remains the mainstay of curative treatment, modern therapies integrate a variety of neoadjuvant and adjuvant strategies and have achieved dramatic improvements in survival. Extensive tumour loads, which have traditionally been considered unresectable, are now amenable to curative treatment through systemic conversion chemotherapies followed by a variety of interventions such as augmentation of the healthy liver through portal vein occlusion, staged surgeries or ablation modalities. Liver transplantation is established in selected patients with hepatocellular carcinoma but is now emerging as a promising option in many other types of tumour such as perihilar cholangiocarcinomas, neuroendocrine or colorectal liver metastases. In this Review, we summarize the available therapies for the treatment of malignant liver tumours, with an emphasis on surgical and ablative approaches and how they align with other therapies such as modern anticancer drugs or radiotherapy. In addition, we describe three complex case studies of patients with malignant liver tumours. Finally, we discuss the outlook for future treatment, including personalized approaches based on molecular tumour subtyping, response to targeted drugs, novel biomarkers and precision surgery adapted to the specific tumour.

Modern therapeutic approaches for the treatment of malignant liver tumours

OBJECTIVE To longitudinally assess whether risk adjustment in Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) occurred over time and is associated with postoperative outcome. BACKGROUND ALPPS is a novel 2-stage hepatectomy enabling resection of extensive hepatic tumors. ALPPS has been criticized for its high mortality, which is reported beyond accepted standards in liver surgery. Therefore, adjustments in patient selection and technique have been performed but have not yet been studied over time in relation to outcome. METHODS ALPPS centers of the International ALPPS Registry having performed ≥10 cases over a period of ≥3 years were assessed for 90-day mortality and major interstage complications (≥3b) of the longitudinal study period from 2009 to 2015. The predicted prestage 1 and 2 mortality risks were calculated for each patient. In addition, questionnaires were sent to all centers exploring center-specific risk adjustment strategies. RESULTS Among 437 patients from 16 centers, a shift in indications toward colorectal liver metastases from 53% to 77% and a reverse trend in biliary tumors from 24% to 9% were observed. Over time, 90-day mortality decreased from initially 17% to 4% in 2015 (P = 0.002). Similarly, major interstage complications decreased from 10% to 3% (P = 0.011). The reduction of 90-day mortality was independently associated with a risk adjustment in patient selection (P < 0.001; OR: 1.62; 95% CI: 1.36-1.93) and using less invasive techniques in stage-1 surgery (P = 0.019; OR: 0.39; 95% CI: 0.18-0.86). A survey indicated risk adjustment of patient selection in all centers and ALPPS technique in the majority (80%) of centers. CONCLUSIONS Risk adjustment of patient selection and technique in ALPPS resulted in a continuous drop of early mortality and major postoperative morbidity, which has meanwhile reached standard outcome measures accepted for major liver surgery.

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Risk Adjustment in ALPPS Is Associated With a Dramatic Decrease in Early Mortality and Morbidity.

Introduction Resection of perihilar cholangiocarcinoma (PHC) entails high-risk surgery with postoperative mortality reported up to 18%, even in specialized centers. The aim of this study was to compare outcomes of PHC patients who underwent associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) to patients who underwent resection without ALPPS. Methods All patients who underwent ALPPS for PHC were identified from the international ALPPS registry and matched controls were selected from a standard resection cohort from two centers based on future remnant liver size. Outcomes included morbidity, mortality, and overall survival. Results ALPPS for PHC was associated with 48% (14/29) 90-day mortality. 90-day mortality was 13% in 257 patients who underwent major liver resection for PHC without ALPPS. The 29 ALPPS patients were matched to 29 patients resected without ALPPS, with similar future liver remnant volume (P = 0.480). Mortality in the matched control group was 24% (P = 0.100) and median OS was 27 months, comparted to 6 months after ALPPS (P = 0.064). Discussion Outcomes of ALPPS for PHC appear inferior compared to standard extended resections in high-risk patients. Therefore, portal vein embolization should remain the preferred method to increase future remnant liver volume in patients with PHC. ALPPS is not recommended for PHC.

High mortality after ALPPS for perihilar cholangiocarcinoma: case-control analysis including the first series from the international ALPPS registry

Hepatobiliary scintigraphy to evaluate liver function in associating liver partition and portal vein ligation for staged hepatectomy: Liver volume overestimates liver function

The current associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) approach is represented by an aggressive first surgical procedure followed by a shorter and less aggressive second procedure. This paradigm has been associated with high morbidity and mortality. Inverting the aggressiveness of the surgical stages might be beneficial in order to facilitate patient recovery during interval period. We propose a new technical paradigm for the ALPPS approach. During the first stage, partial parenchymal transection combined with intraoperative portal vein embolization (PVE) was performed. Liver mobilization was kept at minimum while hilar plate or hilum dissection was strictly avoided. The completion surgery by means of the anterior approach was carried out once sufficient future liver remnant (FLR) hypertrophy and function were certified. We applied this technique in four patients (hepatocellular carcinoma in a cirrhotic liver = 1 and colorectal liver metastases = 3). The mean FLR hypertrophy was 62.6 % (range 49–79). All the four patients underwent the completion surgery with R0 margins, and neither one developed liver failure nor major complications. The technique proposed inverts the current ALPPS strategy, minimizing the first stage impact to promote rapid patient recovery and leaving the main surgical procedure for the second stage. The combination of evidence-based facts such as partial parenchymal transection, intraoperative PVE, and “non-touch” oncological rules was feasible and safe, allowing complete tumor resection in highly selected candidates with extensive liver disease.

Inverting the ALPPS paradigm by minimizing first stage impact: the Mini-ALPPS technique

Background Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) was recently developed to induce rapid hypertrophy and reduce post-hepatectomy liver failure in patients with insufficient remnant liver volume (RLV). However, mortality rates >12% have been reported. This study aimed to analyze the perioperative course of ALPPS and to identify factors associated with morbi-mortality. Methods Between April 2011 and September 2013, 62 patients operated in 9 Franco-Belgian hepatobiliary centres underwent ALPPS for colorectal metastases (N = 50) or primary tumors, following chemotherapy (N = 50) and/or portal vein embolization (PVE; N = 9). Results Most patients had right (N = 31) or right extended hepatectomy (N = 25) (median RLV/body weight ratio of 0.54% [0.21–0.77%]). RLV increased by 48.6% [−15.3 to 192%] 7.8 ± 4.5 days after stage1, but the hypertrophy decelerated beyond 7 days. Stage2 was cancelled in 3 patients (4.8%) for insufficient hypertrophy, portal vein thrombosis or death and delayed to ≥9 days in 32 (54.2%). Overall, 25 patients (40.3%) had major complication(s) and 8 (12.9%) died. Fourteen patients (22.6%) had post-stage1 complication of whom 5 (35.7%) died after stage2. Factors associated with major morbi-mortality were obesity, post-stage1 biliary fistula or ascites, and infected and/or bilious peritoneal fluid at stage2. The latter was the only predictor of Clavien ≥3 by multivariate analysis (OR: 4.9; 95% CI: 1.227–19.97; p = 0.025). PVE did not impact the morbi-mortality rates but prevented major cytolysis that was associated with poor outcome. Conclusions The inter-stages course was crucial in determining ALPPS outcome. The factors of high morbi-mortality rates associated with ALPPS are linked to the technique complexity.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Impact of the inter-stages course on morbi-mortality and implications for management

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Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Impact of the inter-stages course on morbi-mortality and implications for management