Health Economic Evaluation of Patients With Colorectal Liver Metastases Randomized to ALPPS or TSH: Analysis From the LIGRO Trial.

Objective: This is a preplanned, health economic evaluation from the LIGRO trial. One hundred patients with colorectal liver metastases (CRLM) and standardized future liver remnant <30% were randomized to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or two-staged hepatectomy (TSH). Summary Background Data: TSH, is an established method in advanced CRLM. ALPPS has emerged providing improved resection rate and survival. The health care costs and health outcomes, combining health-related quality of life (HRQoL) and survival into quality-adjusted life years (QALYs), of ALPPS and TSH have not previously been evaluated and compared. Methods: Costs and QALYs were compared from treatment start up to 2 years. Costs are estimated from resource use, including all surgical interventions, length of stay after interventions, diagnostic procedures and chemotherapy, and applying Swedish unit costs. QALYs were estimated by combining survival and HRQoL data, the latter being assessed with EQ-5D 3L. Estimated costs and QALYs for each treatment strategy were combined into an incremental cost-effectiveness ratio (ICER). Nonparametric bootstrapping was used to assess the joint distribution of incremental costs and QALYs. Results: The mean cost difference between ALPPS and TSH was 12,662€, [95% confidence interval (CI): -10,728-36,051; P = 0.283]. Corresponding mean difference in life years and QALYs was 0.1296 (95% CI: -0.12-0.38; P = 0.314) and 0.1285 (95% CI: -0.11-0.36; P = 0.28), respectively. The ICER was 93,186 and 92,414 for QALYs and life years as outcomes, respectively. Conclusions: Based on the 2-year data, the cost-effectiveness of ALPPS is uncertain. Further research, exploring cost and health outcomes beyond 2 years is needed.

Portal vein embolization with N-butyl-cyanoacrylate improves liver hypertrophy compared to microparticles - A Swedish multicenter cohort study.

Background: An adequate future liver remnant (FLR) is fundamental for major liver resections. To achieve sufficient FLR, portal vein embolization (PVE) may be used. The most effective material for PVE has yet to be determined. The aim of this study was to investigate the differences in FLR growth between n-butyl-cyanoacrylate glue (NBCA) and microparticles. Material/methodsa: retrospective study was performed at three Swedish hepatobiliary centers and included patients who underwent PVE 2013-2021. Electronic medical records were reviewed, and procedure-related data were collected. Data were analyzed with respect to embolizing material. Results: A total of 265 patients were included: 160 in the NBCA group and 105 in the microparticle group. The NBCA group had a higher degree of hypertrophy (12.1 vs. 9.4 % points, p = 0.003) and a higher resection rate (68 vs. 59 %, p = 0.01) than the microparticle group. Procedure-related data all indicated the superiority of NBCA. No difference in inducing hypertrophy was observed when comparing patients who received chemotherapy before PVE with those who received chemotherapy before and after PVE within the NBCA group. Discussion/conclusion: This retrospective multicenter study supports the superiority of NBCA compared to microparticles in the setting of PVE. Chemotherapy after PVE does not seem to negatively affect hypertrophy.

The Resection Rate of Synchronously Detected Liver and Lung Metastasis from Colorectal Cancer Is Low-A National Registry-Based Study.

Population-based data on the incidence and surgical treatment of patients with colorectal cancer (CRC) and synchronous liver and lung metastases are lacking as are real-life data on the frequency of metastasectomy for both sites and outcomes in this setting. This is a nationwide population-based study of all patients having liver and lung metastases diagnosed within 6 months of CRC between 2008 and 2016 in Sweden identified through the merging of data from the National Quality Registries on CRC, liver and thoracic surgery and the National Patient Registry. Among 60,734 patients diagnosed with CRC, 1923 (3.2%) had synchronous liver and lung metastases, of which 44 patients had complete metastasectomy. Surgery of liver and lung metastases yielded a 5-year OS of 74% (95% CI 57-85%) compared to 29% (95% CI 19-40%) if liver metastases were resected but not the lung metastases and 2.6% (95% CI 1.5-4%) if non-resected, p < 0.001. Complete resection rates ranged from 0.7% to 3.8% between the six healthcare regions of Sweden, p = 0.007. Synchronous liver and lung CRC metastases are rare, and a minority undergo the resection of both metastatic sites but with excellent survival. The reasons for differences in regional treatment approaches and the potential of increased resection rates should be studied further.

Impact of post-hepatectomy liver failure on morbidity and short- and long-term survival after major hepatectomy.

BACKGROUND: Post-hepatectomy liver failure (PHLF) is one of the most serious postoperative complications after hepatectomy. The aim of this study was to assess the impact of the International Study Group of Liver Surgery (ISGLS) definition of PHLF on morbidity and short- and long-term survival after major hepatectomy. METHODS: This was a retrospective review of all patients who underwent major hepatectomy (three or more liver segments) for various liver tumours between 2010 and 2018 at two Swedish tertiary centres for hepatopancreatobiliary surgery. Descriptive statistics, regression models, and survival analyses were used. RESULTS: A total of 799 patients underwent major hepatectomy, of which 218 patients (27 per cent) developed ISGLS-defined PHLF, including 115 patients (14 per cent) with ISGLS grade A, 76 patients (10 per cent) with grade B, and 27 patients (3 per cent) with grade C. The presence of cirrhosis, perihilar cholangiocarcinoma, and gallbladder cancer, right-sided hemihepatectomy and trisectionectomy all significantly increased the risk of clinically relevant PHLF (grades B and C). Clinically relevant PHLF increased the risk of 90-day mortality and was associated with impaired long-term survival. ISGLS grade A had more major postoperative complications compared with no PHLF but failed to be an independent predictor of both 90-day mortality and long-term survival. The impact of PHLF grade B/C on long-term survival was no longer present in patients surviving the first 90 days after surgery. CONCLUSIONS: The presently used ISGLS definition for PHLF should be reconsidered regarding mortality as only PHLF grade B/C was associated with a negative impact on short-term survival; however, even ISGLS grade A had clinical implications.

Complications and chemotherapy have little impact on postoperative quality of life after pancreaticoduodenectomy - a cohort study.

BACKGROUND: With the poor prognosis of pancreatic cancer and the high rate of postoperative complications after pancreaticoduodenectomy, it is important to evaluate how the operation affects patients' quality of life. METHODS: This single-centre study included all patients undergoing pancreaticoduodenectomy from 2006 to 2016. Quality of life was measured with two questionnaires preoperatively, and at 6 and 12 months postoperatively. Comparisons between groups were made using a linear mixed models analysis. RESULTS: Of 279 patients planned for pancreaticoduodenectomy, 245 underwent the operation. The postoperative response rates were all 80% or more. Differences were found in one domain between the early and late time periods and three domains between patients receiving and not receiving adjuvant chemotherapy. No significant differences were found between patients with and without severe postoperative complications. However, the demographic variables of age group, sex, preoperative diabetes and smoking all exerted a significant impact on postoperative quality of life. CONCLUSION: While little or no impact was shown for the factors of postoperative complications, time period and adjuvant chemotherapy, demographic data, such as age, sex, preoperative diabetes and smoking, had considerable impacts on postoperative quality of life after pancreaticoduodenectomy.

Treatment intention and outcome in patients with simultaneously diagnosed liver and lung metastases from colorectal cancer.

BACKGROUND: The aim was to assess the likelihood of patients with simultaneously diagnosed liver and lung metastases (SLLM) from colorectal cancer (CRC) to receive the curative treatment decided upon multidisciplinary team meeting (MDT) and to elaborate on the reasons for treatment intention failure and survival outcomes depending on final treatment strategy. METHOD: The study included a retrospective review of all patients discussed at the MDT at a single centre between 2010 and 2018 to identify all patients presenting with SLLM from CRC. Treatment intention, actual treatment outcome and reasons for treatment failure was documented. Descriptive and survival statistics were applied. RESULTS: Of the 160 patients who had SLLM, resection of all metastatic sites was deemed possible in 107 patients (67%) of whom 39 patients (36%) finalized the curative treatment plan. The most common reason for noncompliance with management recommendations was disease progression or recurrence. Complete resection resulted in longer survival compared to patients who did not undergo resection of all metastatic sites with median survival of 63 and 27 months, respectively (p < 0.001). CONCLUSION: A low proportion of patients completed the initially intended curative resections. Simultaneous resection of liver/lung metastases and primary tumour might increase the proportion of fulfilled hepatopulmonary resections.

How should liver hypertrophy be stimulated? A comparison of upfront associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and portal vein embolization (PVE) with rescue possibility.

BACKGROUND: The role of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in comparison to portal vein embolization (PVE) is debated. The aim of this study was to compare successful resection rates (RR) with upfront ALPPS vs. PVE with rescue ALPPS on demand and to compare the hypertrophy of the liver between ALPPS and PVE plus subsequent rescue ALPPS. METHODS: A retrospective analysis of all patients treated with PVE for colorectal liver metastasis (CRLM) or ALPPS (any diagnosis, rescue ALPPS included) at five Scandinavian university hospitals during the years 2013-2016 was conducted. A Chi-square test and a Mann-Whitney U test were used to assess the difference between the groups. A successful RR was defined as liver resection without a 90-day mortality. RESULTS: A total of 189 patients were included. Successful RR was in 84.5% of the patients with ALPPS upfront and in 73.3% of the patients with PVE and rescue ALPPS on demand (P=0.080). The hypertrophy of the future liver remnants (FLRs) with ALPPS upfront was 71% (48-97%) compared to 96% (82-113%) after PVE and rescue ALPPS (P=0.010). CONCLUSIONS: Upfront ALPPS offers a somewhat higher successful RR than PVE with rescue ALPPS on demand. The sequential combination of PVE and ALPPS leads to a higher overall degree of hypertrophy than upfront ALPPS.

Malignancy in elective cholecystectomy due to gallbladder polyps or thickened gallbladder wall: a single-centre experience.

INTRODUCTION: Gallbladder cancer is a rare but aggressive malignancy. Surgical resection is recommended for gallbladder polyps ≥10 mm. For gallbladder wall thickening, resection is recommended if malignancy cannot be excluded. The incidence of gallbladder malignancy after cholecystectomy with indications of polyps or wall thickening in the Swedish population is not known. MATERIAL/METHODS: A retrospective study was performed at Linköping University Hospital and included patients who underwent cholecystectomy 2010 - 2018. All cholecystectomies performed due to gallbladder polyps or gallbladder wall thickening without other preoperative malignant signs were identified. Preoperative radiological examinations were re-analysed by a single radiologist. Medical records and histopathology reports were analysed. RESULTS: In all, 102 patients were included, of whom 65 were diagnosed with gallbladder polyps and 37 with gallbladder wall thickening. In each group, one patient (1.5% and 2.7% in each group) had gallbladder malignancy ≥ pT1b.Two (3.1%) and three (8.1%) patients with gallbladder malignancy < T1b were identified in each group. DISCUSSION/CONCLUSION: This study indicates that the incidence of malignancy is low without other malignant signs beyond gallbladder polyps and/or gallbladder wall thickening. We propose that these patients should be discussed at a multidisciplinary tumour board. If the polyp is 10-15 mm or if the gallbladder wall is thickened but no other malignant signs are observed, cholecystectomy can be safely performed by an experienced general surgeon at a general surgery unit. If the histopathology indicates ≥ pT1b, the patient should be referred immediately to a hepatobiliary centre for liver and lymph node resection.

ALPPS Improves Survival Compared With TSH in Patients Affected of CRLM: Survival Analysis From the Randomized Controlled Trial LIGRO.

OBJECTIVE: To evaluate the oncological outcome for patients with colorectal liver metastases (CRLM) randomized to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or 2-stage hepatectomy (TSH). BACKGROUND: TSH with portal vein occlusion is an established method for patients with CRLM and a low volume of the future liver remnant (FLR). ALPPS is a less established method. The oncological outcome of these methods has not been previously compared in a randomized controlled trial. METHODS: One hundred patients with CRLM and standardized FLR (sFLR) <30% were included and randomized to resection by ALPPS or TSH, with the option of rescue ALPPS in the TSH group, if the criteria for volume increase was not met. The first radiological follow-up was performed approximately 4 weeks postoperatively and then after 4, 8, 12, 18, and 24 months. At all the follow-ups, the remaining/recurrent tumor was noted. After the first follow-up, chemotherapy was administered, if indicated. RESULTS: The resection rate, according to the intention-to-treat principle, was 92% (44 patients) for patients randomized to ALPPS compared with 80% (39 patients) for patients randomized to TSH (P = 0.091), including rescue ALPPS. At the first postoperative follow-up, 37 patients randomized to ALPPS were assessed as tumor free in the liver, and also 28 patients randomized to TSH (P = 0.028). The estimated median survival for patients randomized to ALPPS was 46 months compared with 26 months for patients randomized to TSH (P = 0.028). CONCLUSIONS: ALPPS seems to improve survival in patients with CRLM and sFLR <30% compared with TSH.

Preoperative Biliary Drainage Does Not Independently Reduce Survival After Pancreaticoduodenectomy Among Patients With Pancreatic Ductal Adenocarcinoma: A National Registry Study.

Objective: This study aimed to explore a possible relationship between preoperative biliary drainage (PBD) and overall survival in a national cohort of Swedish patients who underwent pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). Background: PBD has been shown to increase postoperative complications after PD, but its use is steadily increasing. There are a few small studies that have indicated that PBD might in itself negatively affect overall survival after PD. Methods: Patients from the Swedish National Registry for tumors in the pancreatic and periampullary region diagnosed from 2010 to 2019 who underwent PD for PDAC were included. Kaplan-Meier curves, log-rank tests and Cox proportional hazards analyses were performed to investigate survival. Results: Out of 15,818 patients in the registry, 3113 had undergone PD, of whom 1471 had a histopathological diagnosis of PDAC. Patients who had undergone PBD had significantly worse survival, but the effect of PBD disappeared in the multivariable analysis when elevated bilirubin at any time was included. Conclusions: PBD does not independently influence survival after PD for PDAC, but this study implies that even a nominally increased preoperative bilirubin level might impair long-term survival.

Liver resection is beneficial for patients with colorectal liver metastases and extrahepatic disease.

BACKGROUND: Liver metastases are the most common cause of death for patients with colorectal cancer and affect up to half of the patients. Liver resection is an established method that can potentially be curative. For patients with extrahepatic disease (EHD), the role of liver surgery is less established. METHODS: This is a retrospective study based on data from the national quality registry SweLiv. Data were obtained between 2009 and 2015. SweLiv is a validated registry and has been in use since 2009, with coverage above 95%. Patients with liver metastases and EHD were analyzed and cross-checked against the national death cause registry for survival analysis. RESULTS: During the study period, 2,174 patients underwent surgery for colorectal liver metastases (CRLM), and 277 patients with EHD were treated with resection or ablation. The estimated median survival time for the entire cohort from liver resection/ablation was 40 months (95% CI, 32-47). The survival time for patients treated with liver resection was 45 months compared to 26 months for patients treated with ablation (95% CI 38-53, 18-33, P=0.001). A subgroup analysis of resected patients revealed that the group with pulmonary metastases had a significantly longer estimated median survival (50 months; 95% CI, 39-60) than the group with lymph node metastases (32 months; 95% CI, 7-58) or peritoneal carcinomatosis (28 months; 95% CI, 14-41) (P=0.022 and 0.012, respectively). Other negative prognostic factors were major liver resection and nonradical liver resection. CONCLUSIONS: For patients with liver metastases and limited EHD, liver resection results in prolonged survival compared to what can be expected from chemotherapy alone.

Segment 4 occlusion in portal vein embolization increase future liver remnant hypertrophy - A Scandinavian cohort study.

BACKGROUND: The additional value of including segment 4 (S4) portal branches in right portal vein embolization (rPVE) is debated. The aim of the study was to explore this in a large multicenter cohort. MATERIAL AND METHODS: A retrospective cohort study consisting of all patients subjected to rPVE from August 2012 to May 2017 at six Scandinavian university hospitals. PVE technique was essentially the same in all centers, except for the selection of main embolizing agent (particles or glue). All centers used coils or particles to embolize S4 branches. A subgroup analysis was performed after excluding patients with parts of or whole S4 included in the future liver remnant (FLR). RESULTS: 232 patients were included in the study, of which 36 received embolization of the portal branches to S4 in addition to rPVE. The two groups (rPVE vs rPVE + S4) were similar (gender, age, co-morbidity, diagnosis, neoadjuvant chemotherapy, bilirubin levels prior to PVE and embolizing material), except for diabetes mellitus which was more frequent in the rPVE + S4 group (p = 0.02). Pre-PVE FLR was smaller in the S4 group (333 vs 380 ml, p = 0.01). rPVE + S4 resulted in a greater percentage increase of the FLR size compared to rPVE alone (47 vs 38%, p = 0.02). A subgroup analysis, excluding all patients with S4 included in the FLR, was done. There was no longer a difference in pre-PVE FLR between groups (333 vs 325 ml, p = 0.9), but still a greater percentage increase and also absolute increase of the FLR in the rPVE + S4 group (48 vs 38% and 155 vs 112 ml, p = 0.01 and 0.02). CONCLUSION: In this large multicenter cohort study, additional embolization of S4 did demonstrate superior growth of the FLR compared to standard right PVE.

Future Liver Remnant (FLR) Increase in Patients with Colorectal Liver Metastases Is Highest the First Week After Portal Vein Occlusion : FLR Increase in Patients with CRLM Is Highest the First Week After PVO.

BACKGROUND: Portal vein occlusion (PVO) is an established method to increase the volume of the future liver remnant (FLR). The main reasons for not proceeding to radical hepatectomy are lack of volume increase and tumor progression due to a wait-time interval of up to 8 weeks. The hypothesis was that the increase in FLR volume is not linear and is largest during the first weeks. METHODS: Patients with colorectal liver metastases (CRLM) and standardized future liver remnant (sFLR) < 30% treated with PVO were prospectively included. All patients had at least one CT evaluation before radical hepatectomy. RESULTS: Forty-eight patients were included. During the first week after PVO, the kinetic growth rate (KGR) was 5.4 (± 4), compared to 1.5 (± 2) between the first and second CT (p < 0.05). For patients reaching adequate FLR and therefore treated with radical hepatectomy, the KGR was 7 (± 4) the first week, compared to 4.3 (± 2) for patients who failed to reach a sufficient volume (p = 0.4). During the interval between the first and second CT, the KGR was 2.2 (± 2), respectively (± 0.1) (p = 0.017). DISCUSSION: The increase in liver volume after PVO is largest during the first week. As KGR decreases over time, it is important to shorten the interval between PVO and the first volume evaluation; this may aid in decision-making and reduce unnecessary waiting time.

Neoadjuvant chemotherapy does not affect future liver remnant growth and outcomes of associating liver partition and portal vein ligation for staged hepatectomy.

BACKGROUND: The only potentially curative treatment for patients with colorectal liver metastases is hepatectomy. Associating liver partition and portal vein ligation for staged hepatectomy has emerged as a method of treatment for patients with inadequate future liver remnant. One concern about associating liver partition and portal vein ligation for staged hepatectomy is that preoperative chemotherapy may negatively affect the volume increase of the future liver remnant and outcomes. METHODS: This study from the International Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy Registry (NCT01924741) includes 442 patients with colorectal liver metastases registered from 2012-2016. Future liver remnant hypertrophy (absolute increase, percent increase, and kinetic growth rate) and clinical outcome were analyzed retrospectively in relation to type and amount of chemotherapy. The analyzed groups included patients with no chemotherapy, 1 regimen of chemotherapy, >1 regimen, and a group that received monoclonal antibodies in addition to chemotherapy. RESULTS: Ninety percent of the patients received neoadjuvant oncologic therapy including 42% with 1 regimen of chemotherapy, 44% with monoclonal antibodies, and 4% with >1 regimen. Future liver remnant increased between 74-92% with the largest increase in the group with 1 regimen of chemotherapy. The increase in milliliters was between 241 mL (>1 regimen) and 306 mL (1 regimen). Kinetic growth rate was between 14-18% per week and was greatest for the group with 1 regimen of chemotherapy. No statistical significance was found between the groups with any of the measurements of future liver remnant hypertrophy. CONCLUSION: Neoadjuvant chemotherapy, including monoclonal antibodies, does not negatively affect future liver remnant growth. Patients with colorectal liver metastases who might be potential candidates for associating liver partition and portal vein ligation for staged hepatectomy should be considered for neoadjuvant chemotherapy.

Scandinavian multicenter study on the safety and feasibility of the associating liver partition and portal vein ligation for staged hepatectomy procedure.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has emerged as an additional tool to increase the size of the future liver remnant (FLR) in the settings of advanced tumor burden in the liver. Initial reports have indicated high feasibility but also high mortality and morbidity. The aim of this study was to assess the initial experience with ALPPS in Scandinavia regarding feasibility, morbidity, and mortality. MATERIALS AND METHODS: We conducted a retrospective analysis of all patients who underwent ALPPS since its introduction at 3 Scandinavian hepatobiliary centers. RESULTS: Thirty-six patients were identified, 21 male and 15 female. Median age was 67 years (22-83). Colorectal liver metastases (n = 25) were the most common indication for ALPPS followed by hepatocellular carcinoma (n = 4), cholangiocarcinoma (n = 4), and other (n = 3). Median growth of the FLR between the operations was 67% (-17 to 238) in 6 (5-13) days. All patients completed the second operation, and 71% of the resections were R0. Although the total percentage of patients with complication(s) was 92%, only 4 patients (11%) had a grade 3b complication according to the Clavien-Dindo classification, and no other severe complications were noted. There was no in-hospital mortality, but 1 (2.8%) patient died within 90 days of operation. CONCLUSION: ALPPS is a highly feasible method to stimulate FLR growth in patients with colorectal liver metastases as well as primary hepatobiliary malignancies. The treatment can be carried out with relative safety.

Role of associating liver partition and portal vein ligation for staged hepatectomy in colorectal liver metastases: a review.

Colorectal cancer is the third most common cancer in the Western world. Approximately half of patients will develop liver metastases, which is the most common cause of death. The only potentially curative treatment is surgical resection. However, many patients retain a to small future liver remnant (FLR) to allow for resection directly. There are therefore strategies to decrease the tumor with neoadjuvant chemotherapy and to increase the FLR. An accepted strategy to increase the FLR is portal vein occlusion (PVO). A concern with this strategy is that a large proportion of patients will never be operated because of progression during the interval between PVO and resection. ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) is a new procedure with a high resection rate. A concern with this approach is the rather high frequency of complications and high mortality, compared to PVO. In this review, it is shown that with ALPPS the resection rate was 97.1% for CRLM and the mortality rate for all diagnoses was 9.6%. The mortality rate was likely lower for patients with CRLM, but some data were lacking in the reports. Due to the novelty of ALPPS, the indications and technique are not yet established but there are arguments for ALPPS in the context of CRLM and a small FLR.