Advanced Colorectal Liver Metastases Research Articles

Long-Term Follow-Up of Patients with Advanced Colorectal Liver Metastasis: A Survival Analysis from the Randomized Controlled Multicenter Trial LIGRO.

The objective of this study was to evaluate the long-term oncological outcomes of patients with colorectal liver metastasis (CRLM) randomized for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or 2-stage hepatectomy (TSH). For advanced CRLM, TSH or ALPPS may be needed for tumor freedom. The randomized, controlled, multicenter trial LIGRO showed an increased resection rate in patients who underwent ALPPS but no difference in morbidity or mortality. The 2-year survival analysis revealed better overall survival in the ALPPS group. Here, the long-term survival analysis from the LIGRO trial is reported. In the LIGRO trial, 100 patients were randomized to TSH or ALPPS, with the option of rescue ALPPS if insufficient growth was found after the initial step of TSH. Patients were enrolled between June 2014 and August 2016. Follow-up data for this study were collected between November 2022 and February 2023. In total, 16 patients were alive at the end of the follow-up period. The estimated median follow-up time was 93 months. Estimated median overall survival times were 45 months in the ALPPS group and 27 months in the TSH group (P = 0.057), with 5-year survival rates of 31% and 20%, respectively. Positive prognostic factors were liver tumor-free status at the first follow-up and rectal primary tumor. Negative prognostic factors were extrahepatic disease and increasing CLRM size. Liver tumor-free status is a predictor of long-term survival, along with extrahepatic disease, large CRLM size, and rectal primary tumor. Survival did not significantly differ between patients treated with ALPPS or TSH.

Long-term follow-up of patients with advanced colorectal liver metastasis: a survival analysis from the randomized controlled multicenter trial LIGRO

Long-term follow-up of patients with advanced colorectal liver metastasis: a survival analysis from the randomized controlled multicenter trial LIGRO

Objective Definition and Optimized Strategy for "Biologically Borderline Resectable" Colorectal Liver Metastases.

The prognostic benefit of preoperative chemotherapy leading to conversion surgery for unresectable colorectal liver metastases (CRLM) is well recognized, while that of neoadjuvant chemotherapy (NAC) compared with upfront surgery (UFS) for resectable CRLM is negligible. This study aims to assess the prognostic benefit and search for optimal indication of NAC for resectable advanced CRLM by establishing an objective definition of biologically borderline resectable (bBR) CRLM. A bicentric retrospective analysis of patients with CRLM undergoing curative-intent initial liver resection between 2007 and 2021 was performed. An original classification matrix was established, which reassessed technical resectability using virtual hepatectomy and oncological favorability using Beppu's nomogram. Patients with technically resectable but biologically unfavorable CRLM were classified into the bBR group. The propensityscorematchinganalysis using preoperatively available factors was performed to assess long-term outcomes of the bBR-UFS and bBR-NAC groups. Of 831 patients reviewed, 240 were categorized into the bBR group: bBR -UFS (n = 139) and bBR-NAC (n = 101). Ten (10%) in the bBR-NAC group (n = 101) experienced biological status change from unfavorable to favorable after NAC (BiologicalConversion) and showed significantly longer overall survival (hazard ratio 5.63, 95% confidence interval 1.37-23.1; P = 0.016) than the bBR-UFS group. However, after propensity score matching, no significant difference between the UFS and NAC groups (n = 67 for each) was found in long-term outcomes. NAC for bBR-CRLM did not enhance the prognostic impact of the following liver resection, except for a limited number of optimal candidates experiencing the BiologicalConversion.

Dynamic radiomics for predicting the efficacy of antiangiogenic therapy in colorectal liver metastases.

For patients with advanced colorectal liver metastases (CRLMs) receiving first-line anti-angiogenic therapy, an accurate, rapid and noninvasive indicator is urgently needed to predict its efficacy. In previous studies, dynamic radiomics predicted more accurately than conventional radiomics. Therefore, it is necessary to establish a dynamic radiomics efficacy prediction model for antiangiogenic therapy to provide more accurate guidance for clinical diagnosis and treatment decisions. In this study, we use dynamic radiomics feature extraction method that extracts static features using tomographic images of different sequences of the same patient and then quantifies them into new dynamic features for the prediction of treatmentefficacy. In this retrospective study, we collected 76 patients who were diagnosed with unresectable CRLM between June 2016 and June 2021 in the First Hospital of China Medical University. All patients received standard treatment regimen of bevacizumab combined with chemotherapy in the first-line treatment, and contrast-enhanced abdominal CT (CECT) scans were performed before treatment. Patients with multiple primary lesions as well as missing clinical or imaging information were excluded. Area Under Curve (AUC) and accuracy were used to evaluate model performance. Regions of interest (ROIs) were independently delineated by two radiologists to extract radiomics features. Three machine learning algorithms were used to construct two scores based on the best response and progression-free survival (PFS). For the task that predict the best response patients will achieve after treatment, by using ROC curve analysis, it can be seen that the relative change rate (RCR) feature performed best among all features and best in linear discriminantanalysis (AUC: 0.945 and accuracy: 0.855). In terms of predicting PFS, the Kaplan-Meier plots suggested that the score constructed using the RCR features could significantly distinguish patients with good response from those with poor response (Two-sided P<0.0001 for survival analysis). This study demonstrates that the application of dynamic radiomics features can better predict the efficacy of CRLM patients receiving antiangiogenic therapy compared with conventional radiomics features. It allows patients to have a more accurate assessment of the effect of medical treatment before receiving treatment, and this assessment method is noninvasive, rapid, and less expensive. Dynamic radiomics model provides stronger guidance for the selection of treatment options and precision medicine.

Individualized Selection Criteria Based on Tumor Burden in Future Remnant Liver for Staged Hepatectomy of Advanced CRLM: Conventional TSH or ALPPS.

Simple SummaryCurrently, two established staged hepatectomy techniques are used for curative resection of advanced colorectal liver metastasis (CRLM) as well as preventing inadequate future remnant liver (FRL). However, the selection of staged hepatectomy between the conventional two-stage hepatectomy (cTSH) and the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) remains under debate. Therefore, the present study proposed a selection criterion based on tumor burden related to the size and number of metastases within the FRL for decision making when utilizing staged hepatectomy for advanced CRLM. Accordingly, metastatic tumors within the FRL should not exceed three nodules and none of the nodules should measure larger than 3 cm for ALPPS. By contrast, cTSH would be considered in patients whose tumor burdens within the FRL beyond the aforementioned criteria. The individualized selection criteria appear to be promising and can be used to select a more effective staged hepatectomy approach for patients with advanced CRLM.Staged hepatectomy is a promising strategy for curative resection of advanced colorectal liver metastasis (CRLM) to prevent inadequate future remnant liver (FRL). However, the selection criteria for conventional two-stage hepatectomy (cTSH) and associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) remain unclear. This study aimed to propose a selection criterion for determining the optimal staged hepatectomy for patients with advanced CRLM. A selection criterion based on the degree of metastatic tumors within the FRL was established to determine staged hepatectomy approaches. Generally, ALPPS is recommended for patients with ≤3 metastatic nodules and whose nodules do not measure >3 cm in the FRL. cTSH is performed for patients whose tumor burden in FRL beyond the selection criteria. Data of 37 patients who underwent staged hepatectomy and curative intent of CRLM were analyzed. The clinical characteristics and outcomes of the two approaches were compared. Overall, cTSH and ALPPS were performed for 27 (73.0%) and 10 (27.0%) patients, respectively. Of those, 20 patients in the cTSH group and all patients in the ALPPS group had completed staged hepatectomy. The 1-, 3-, and 5-year survival rates were 91.6%, 62.4%, and 45.4% for all patients, respectively. The outcomes of patients who had successfully completed the staged hepatectomy were significantly better than those of other patients who failed to achieve staged hepatectomy. However, no significant difference was observed in the overall survival of patients who underwent staged hepatectomy between the two groups, but those in the ALPPS group had 100% survival at the end of this study. The individualized selection criteria based on tumor burden in the FRL that could balance the operative risk and oncologic outcome appear to be a promising strategy for achieving complete staged hepatectomy in patients with advanced CRLM.

Hepatic arterial infusion chemotherapy plus regorafenib in advanced colorectal cancer: a real-world retrospective study

BackgroundHepatic arterial infusion chemotherapy delivers the drug directly to the liver. We aim to explore the benefits and tolerability of Hepatic arterial infusion chemotherapy plus regorafenib in advanced colorectal liver metastasis refractory to standard systemic chemotherapy.MethodsThis study analyzed 47 patients treated with hepatic arterial infusion chemotherapy plus regorafenib after standard systemic oxaliplatin and/or irinotecan in combination with bevacizumab or cetuximab between Jan 2017 and Jun 2020. Regorafenib was given for only 3 weeks in a 4-week cycle.ResultsAmong 47 patients, 32 (68%) were males. The median age was 61 (29–75). With a median follow-up of 22.2 months (3.7–50.7 months). Before Hepatic arterial infusion chemotherapy administration in combination with regorafenib, 34 (72.3%) patients previously received ≥ 2 prior lines of systemic therapy and 37 (78.7%)patients previously received targeted biological treatment (anti-VEGF or anti-EGFR, or both). The initial doses of regorafenib were 40 mg/d (n = 1, 2.13%), 80 mg/d (n = 11, 23.43%), 120 mg/d (n = 2, 4.26%), and 160 mg/d (n = 23, 48.94%), while for 24.6% (n = 14) dose was unknown. Median Overall Survival was 22.2 months. Median Progression-Free Survival was 10.8 (95% CI: 9.0–13.7) months. Common Adverse Events were hand-foot skin reaction (12.77%), fatigue (6.38%), vomiting (6.38%), and decreased appetite (6.38%). Only 2 patients discontinued regorafenib due to Adverse Events.ConclusionsRegorafenib combined with Hepatic arterial infusion was effective and tolerable in patients with liver predominant metastasis of colorectal cancer. Hence, this therapy can be considered as an alternative for second- or subsequent lines of therapy in patients refractory to standard systemic chemotherapy.

Repeat Resection for Advanced Colorectal Liver Metastases-Does it have the Potential for Cure?

Although surgical resection is the only potential treatment for patients with colorectal liver metastases (CLM), the actual cure is rare in patients with advanced CLM. Repeat resection (RR) is the most effective treatment in patients with recurrence; however, whether patients with initially advanced CLM achieve cure throughout RR or experience repeated recurrence even after RR remains unclear. In this study, we analyzed whether patients with advanced CLM achieve cure after RR. Consecutive patients who underwent initial hepatectomy with curative intent for CLM from January 1999 to August 2007 were included. Patients who were alive at 10years from the initial hepatectomy without any evidence of recurrence were defined as cured. Cure rates were compared between patients with Fong's clinical risk score (CRS) of ≥ 3 and those with CRS of ≤ 2. A total of 257 patients were included and followed up. Among them, 93 (36.2%) patients achieved actual cure postoperatively. The cure rate of patients with a CRS of ≥ 3 was 32.4% (33/102), which was not different from that of patients with a CRS of ≤ 2 (38.7% [60/155]; p = 0.299), although former patients had higher recurrence rate after the initial hepatectomy than latter ones (85.3% vs. 72.3%; p = 0.014). The cure rates after the initial, second, and third resections were 23.0% (59/257), 30.0% (24/80), and 22.5% (7/31), respectively. In multivariate analysis, RR was determined as an independent favorable factor of achieving cure. RR had a potential to cure patients with advanced CLM, and one-third of them achieved cure.

Hepatic arterial infusion pump chemotherapy combined with systemic therapy for patients with advanced colorectal liver metastases: Outcomes in a newly established program.

Colorectal liver metastasis (CRLM) is a leading cause of morbidity and mortality in patients with colorectal cancer. Hepatic arterial infusion (HAI) chemotherapy has been demonstrated to improve survival in patients with resected CRLM and to facilitate conversion of technically unresectable disease. Between 2016 and 2018, n = 22 HAI pumps were placed for CRLM. All patients received systemic chemotherapy concurrently with HAI floxuridine/dexamethasone. Overallsurvival(OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method. HAI pumps were placed in seven patients with completely resected CRLM and 15 patients with unresectable disease. Twenty-one patients received HAI floxuridine with a median of 5 total HAI cycles (interquartile range: 4-7). Biliary sclerosis was the most common HAI-related complication (n = 5, 24%). Of the 13 patients treated to convert unresectable CRLM, 3 (23%) underwent hepatic resection with curative intent after a median of 7 HAI cycles (range: 4-10). For all HAI patients, the mean OS was 26.7 months from CRLM diagnosis, while the median PFS and hepatic PFS from pump placement were 9 and 13 months, respectively. Concomitant HAI and systemic therapy can be utilized at multidisciplinary programs for patients with advanced CRLM, both in the adjuvant setting and to facilitate conversion of unresectable disease.

Associating liver partition and portal vein ligation for staged hepatectomy ​for colorectal liver metastasis: a single-center experience

Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) is increasingly used for the treatment of primarily unresectable colorectal liver metastases (CRLM) because of the insufficient future liver remnant (FLR). The aim of this study was to share our experience with ALPPS for advanced CRLM and review the role of ALPPS in the management of patients with CRLM. Consecutive patients (n = 10) with CRLM who underwent ALPPS at our center between December 2014 and October 2021 were retrospectively studied. The median age of patients was 58 years (range 49–70 years). Five patients had metachronous CRLM and the other 5 patients had synchronous CRLM. Five patients had unilateral CRLM and the other 5 patients had bilateral CRLM. All patients previously underwent neoadjuvant chemotherapy. The FLR volume increased by 45.3% (35.8%–61.6%) over 14 days (range 7–21 days). The absolute and relative kinetic growth rates were 17.9 mL/day (range 7.5–32.1 mL/day) and 4.6%/day (range 2.3%–8.8%/day), respectively. Overall morbidity rates were 20% (2/10) and 40% (4/10) after ALPPS stage 1 and stage 2, respectively. The 30-day and 90-day mortality rates were 0% and 10%, respectively. R0 resection was achieved for all patients, and the median disease-free survival was 18.7 months. ALPPS is an effective treatment option for advanced CRLM. It enables rapid hypertrophy of the FLR and achieves a high R0 resection rate with an acceptable oncological outcome. However, ALPPS should be reserved for selected patients because of its relatively high morbidity and mortality.

Hepatectomy with Perioperative Chemotherapy for Multiple Colorectal Liver Metastases is the Available Option for Prolonged Survival.

Hepatic resection combined with perioperative chemotherapy is the standard of care for patients with multiple colorectal liver metastases (CLMs). However, the optimal surgical strategy for treating advanced CLMs remains unclear. The role of the two-stage hepatectomy (TSH) strategy in the management of multiple CLMs remains challenging. This study aimed to compare the outcomes of one-step hepatectomy (OSH)-treated and TSH-treated patients with multiple CLMs. This single-institution study included 742 consecutive patients who underwent initial liver resection for histologically confirmed CLMs. The study enrolled patients with 10 or more tumors (n = 106). Clinicopathologic characteristics and long-term outcomes were compared between patients who underwent OSH and those who underwent TSH for 10 or more CLMs. The study planned OSH for 67 patients (63%) and TSH for 39 patients (37%). One of the OSH-planned patients and two of the TSH-planned patients underwent a trial laparotomy because of non-curative factors. Five patients (13%) did not progress to the second stage of TSH. In the entire cohort, the cumulative 3-year overall survival rate was 58.4% for the patients who had 10 or more CLMs treated with OSH compared with 61.1% for the patients treated with TSH (P = 0.746). In the curative resection cohort, the cumulative 1-year recurrence-free survival rate was 18.2% for the patients treated with OSH and 17.9% for the patients treated with TSH (P = 0.640). Hepatectomy with perioperative chemotherapy for advanced CLMs with 10 or more tumors is feasible and effective. To prolong survival, TSH is a promising option when curative resection with OSH is impossible.

A multicenter phase II trial to assess the efficacy and safety of bevacizumab plus mFOLFOX6 as induction chemotherapy toward R0 surgical resection in advanced colorectal liver metastases with mutant-type KRAS: NEXTO-mt trial.

450 Background: The oncological benefit of bevacizumab plus mFOLFOX6 in advanced colorectal liver metastases (CRLMs) in terms of conversion to curative resection remains unknown. This multicenter phase II trial aimed to evaluate the efficacy and safety of bevacizumab plus mFOLFOX6 as induction chemotherapy for advanced CRLMs harboring mutant-type KRAS. Methods: Patients who had advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included in this study. The induction chemotherapy of bevacizumab plus mFOLFOX6 was administered and assessed for resectability every 4 cycles. If the unresectable CRLMs were converted to be resectable, liver resection was planned after a waiting period of 4–6 weeks and followed by postoperative chemotherapy up to 12 cycles. The primary endpoint was R0 resection rate. The secondary endpoints were safety, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). The trial was conducted following approval from the Institutional Ethics Review Board of all institutions and registered in the University Hospital Medical Information Network Clinical Trials Registry (registration number: UMIN000009530). Results: Between February 2013 and December 2017, 29 patients from six centers were enrolled in this trial. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality after liver resection occurred. During the median follow-up of 30.7 months (range, 7.2–82.6 months), the median OS for the 29 patients was 49.1 months. The 3-year PFS and OS rates were 7.4%, and 64.4%, respectively. The 3-year RFS rate was 10.0% in 20 patients who achieved R0 or R1 resections. Conclusions: Bevacizumab plus mFOLFOX6 achieved a high R0 resection rate with a favorable survival for patients with advanced CRLMs harboring mutant-type KRAS. Clinical trial information: UMIN000009530.

Two stage hepatectomy (TSH) or Associating liver partition and portal vein ligation for staged hepatectomy (ALLPS) for bilobar multiple colorectal liver metastasis

Of patients with colorectal cancer, 30% to 50% present with liver metastasis at the time of diagnosis or develop metastasis later. Hepatectomy is the primary curative treatment option for patients with colorectal liver metastases (CRLMs). Patients with bilateral, multiple CRLMs and a small estimated tumor free future liver remnant (FLR) present a treatment challenge. These patients may need a two-stage hepatectomy (TSH) in which portal venous ligation (PVL) or portal venous embolization (PVE) is included in the first stage to stimulate hypertrophy of the FLR before final resection. This method generates a 27% to 39% increase in FLR volume in 4 to 8 weeks. The risks in this method are tumor progression during the waiting period and insufficient hypertrophy, making resection impossible in 25% to 38% of the patients preparing to undergo TSH. To increase liver growth rate and volume, which renders more patients resectable in a shorter time, a novel concept of liver resection, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), was described in 2011. However, in the early study 68% of the patients experienced complications and the surgical mortality rate was 12%. A recent, the only multicenter randomized controlled trial (RCT) revealed that compared with the use of TSH, the use of ALPPS for patients with CRLM resulted in a higher resection rate (92%) without a higher 90-day mortality rate (8.3%), a higher rate of severe complication rate (43%) or a lower rate of negative surgical margins in the liver. A previous meta-analysis including 9 retrospective studies showed that TSH for CRLM exhibited lower perioperative morbidity and mortality rates than ALPPS, suggesting the superiority of TSH. On the other hand, in a recent meta-analysis in 2020 including 7 retrospective studies and 1 RCT, compared with TSH, ALPPS for advanced CRLM resulted in superior surgical efficacy with comparable perioperative mortality rate and short-term oncological outcomes, while this was at the cost of increased perioperative minor complications. From a clinical perspective, traditional TSH has been frequently regarded as a preferred treatment modality in earlier studies, and ALPPS was reserved as an alternative, typically after failed PVE or PVL. At present, this paradigm may have changed, as there is growing evidence indicating that the surgical benefits given by ALPPS are at least not inferior to those given by TSH according to recent studies. ALPPS may be feasible for bilobar multiple colorectal liver metastasis. Still, long-term outcomes remain to be elucidated and therefore the role of ALPPS regarding oncological outcome remains uncertain.

Health Economic Evaluation of Patients with Colorectal Liver Metastases Randomized to ALPPS or TSH - Analysis from the LIGRO Trial

Introduction: Two-staged hepatectomy (TSH), is an established method in advanced colorectal liver metastases (CRLM). Associating liver partition and portal vein ligation for staged hepatectomy (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: This is a pre-planned, health economic evaluation from the LIGRO trial. One hundred patients with CRLM and standardized FLR < 30 % were randomized to ALPPS or TSH. 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). Non-parametric bootstrapping was used to assess the joint distribution of incremental costs and QALYs. Results: The mean cost difference between ALPPS and TSH was 12662€, (95% CI -10728-36051, 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 93186 and 92414 for QALYs and life-years as outcomes, respectively. Conclusion: Based on the two-year data, the cost-effectiveness of ALPPS is uncertain. Further research, exploring cost and health outcomes beyond 2 year is needed.

Complete remission of multiple liver metastases with only partial response of the primary rectal cancer after neoadjuvant chemotherapy

BackgroundColorectal cancer is commonly diagnosed among the Japanese population, and various strategies in treating the colorectal liver metastasis have been introduced over the years. Here, we present a case of colorectal liver metastases in which we devised a multidisciplinary treatment plan for a better prognosis.Case presentationWe report a case of a 44-year-old female who developed rectal cancer with advanced synchronous liver metastases and was treated by a liver-first surgical approach following neoadjuvant chemotherapy. At diagnosis, there were 12 bilobular lesions in the liver, and the primary rectal cancer was asymptomatic and unprogressive. We adopted a liver-first strategy because the control of the liver metastases was considered the key prognostic factor. Furthermore, because the lesions were highly progressive, we planned neoadjuvant systemic chemotherapy first to provide an observational period to identify potential new metastatic lesions that were refractory to systemic chemotherapy or contraindicative for surgical resection. We administered two courses of S-1 + oxaliplatin (SOX)+ bevacizumab (BV) and an additional course of SOX without BV as neoadjuvant chemotherapy in preparation for surgery. This resulted in a prominent minimalization of colorectal liver metastases, and no other remote metastasis was observed. Then, surgical resection of the colorectal liver metastases was performed safely, and the pathological result revealed complete remission of all tumors by neoadjuvant chemotherapy. The primary tumor in the colon was successfully resected 2 months after the hepatectomy. Although the patient experienced a recurrence in two different sites in the lungs 10 months after resection of the primary rectal lesion, these metastases were successfully resected after diagnosis. The patient is alive with no signs of recurrence 3 years after the diagnosis of colorectal cancer with synchronous liver metastases.ConclusionsThe combination of a liver-first strategy and neoadjuvant chemotherapy is a possible treatment of choice to cure colorectal cancer with simultaneous advanced colorectal liver metastases.

Hepatic arterial infusion pump chemotherapy combined with systemic therapy for patients with advanced colorectal liver metastases: Outcomes in a newly established program

Presenter: Brett Walker MD | Oregon Health and Science University Background: Metastatic disease to the liver is a leading cause of morbidity and mortality in patients with colorectal cancer, with the majority of patients presenting with initially unresectable disease. Although hepatic resection offers the best chance of cure for colorectal liver metastases (CRLM), 40% of patients will develop intrahepatic recurrence not amenable to additional hepatic resection. Hepatic arterial infusion (HAI) chemotherapy with floxuridine has been demonstrated to improve survival in patients with resected CRLM and can be integrated with systemic therapy to convert patients with technically unresectable disease to a resectable status. Herein, we describe the experience of a recently established multidisciplinary hepatic arterial infusion program for the treatment of patients with advanced CRLM at an NCI Comprehensive Cancer Center. Methods: Between 2016 and 2018, n=22 consecutive patients had a HAI pump placed as part of their multidisciplinary treatment plan for advanced CRLM. All patients received systemic chemotherapy peri-operatively and concurrently with HAI. A multidisciplinary tumor board reviewed each HAI candidate before pump placement and throughout their therapy. Clinicopathologic data were collected and patient overall (OS) and progression-free (PFS) survival was assessed using the Kaplan-Meier method. Results: Over the 30-month period, 7 patients with resected CRLM and 15 patients with unresectable CRLM had an HAI pump operatively placed at a median of 6 months after diagnosis. The median age was 55 years (range: 32-67) and 59% (n=13) were women. The majority of patients had a high hepatic tumor burden (76% with >10 metastases) and received a median of 8 (range: 4-18) cycles of systemic chemotherapy, mostly commonly FOLFOX, prior to HAI pump placement (Table). Of the 12 patients with an intact primary cancer, 11 had simultaneous HAI pump placement with resection of their primary cancer. Only 1 patient experienced a major complication (Clavien-Dindo ≥ 3) within 30 days of their operation (small bowel obstruction from prior loop ileostomy procedure). 21 patients received at least one HAI cycle of floxuridine and had a median of 5 cycles (range: 1-10) before HAI therapy was discontinued or held after clearance of intrahepatic disease. In total, 32% (n=7) of patients developed pump related complications, with biliary sclerosis being the most common (n=5/21, 24%). Of the 13 patients treated to convert their initially unresectable disease, 3 patients (23%) underwent hepatic resection with curative intent after a median of 7 HAI cycles (range: 4-10) and achieved complete clearance of their hepatic disease. For all patients treated with HAI and systemic therapy, the median OS from diagnosis was 52 months (95%: IQR 43-64 months) and the median PFS from pump placement was 21 months (95%: IQR 17-31 months). Conclusion: HAI pump therapy with floxuridine can be used in combination with modern systemic chemotherapy for patients with advanced CRLM, both in the adjuvant setting and to facilitate conversion of unresectable disease in more than 20% of patients presenting with high liver disease burden. When implemented in a multidisciplinary program, HAI therapy is safe with low of peri-operative morbidity and promising outcomes in patients with limited treatment options.

An initial experience with Partial ALPPS vs palliative chemotherapy in advanced colorectal liver metastases

Background: Associating liver partition and portal vein ligation (ALPPS) is a novel 2-stage accelerated procedure to treat bilobar colorectal liver metastases with a curative intent. Partial ALPPS (p-ALPPS) is a modified technique whereby 50-80% liver is transected during stage 1. Data comparing survival outcome of p-ALPPS with palliative treatment is still limited. We aim to compare long-term survival of patients who underwent p-ALPPS with patients who received either palliative chemotherapy or best supportive care (BSC). Methods: We retrospectively reviewed 409 patients in our institution with colorectal liver metastases from January 2014 to December 2016. Patients with advanced colorectal liver metastases as defined by >6 metastases and/or > 6 involved segments were identified. These were grouped into 3 main categories: p-ALPPS, palliative chemotherapy and BSC. The median survival in each arm is calculated and compared. Results: 48 patients had advanced bilobar disease. 4 underwent p-ALPPs, 28 received palliative chemotherapy and 16 had BSC. In the p-ALPPS group, 3 have survived more than 365 days (range 366-457) and are still alive. However, 1 demised at 85 days due to chemotherapy related sepsis. Median survival for palliative chemotherapy and BSC are 315 and 97 days respectively. Conclusion: Early data suggests there is a role for p-ALPPS and palliative systemic chemotherapy compared to BSC alone. A more robust study of p-ALPPS outcomes is needed to draw meaningful comparison with palliative chemotherapy.

An initial experience with Partial ALPPS vs palliative chemotherapy in advanced Colorectal Liver Metastases

An initial experience with Partial ALPPS vs palliative chemotherapy in advanced Colorectal Liver Metastases

Parenchymal sparing surgery brings treatment of colorectal liver metastases into the precision medicine era

The treatment of advanced colorectal liver metastases (CRLMs) follows the biphasic pattern characteristic of oncological surgery. A phase of escalation—the therapeutic aggressiveness—is followed by a phase of de-escalation aimed at decreasing the morbidity, while preserving the gains in survival. From a maximum of three lesions, the rule no longer limits the number, provided the intervention does not cause lethal liver failure. Technically feasible non-anatomical resections, two-stage hepatectomies, portal vein obliteration and so forth, have pushed the boundaries of surgery far. However, the impact and the biology of metastatic processes have been long ignored.Parenchymal sparing surgery (PSS) is a de-escalation strategy that targets only metastasis by minimising the risk of stimulating tumour growth, while enabling iterative interventions. Reducing the loss of healthy parenchyma increases the tolerance of the liver to interval chemotherapy. Technically, PSS could use any type of hepatectomy, providing it is centred on the metastatic load alongside intraoperative ablation.The PSS concept sometimes wrongly comes across as a debate between minor versus major hepatectomies. Hence, we propose a clear definition, both quantitative and qualitative, of what PSS is and what it is not. Conversely, the degree of selectivity of PSS as a percentage of the volume of resected metastases versus the volume of total liver removed has not been stopped to date and should be the subject of prospective studies.Ultimately, the treatment of advanced CRLMs, of which PSS is a part, needs to be personalised by the multidisciplinary team by adapting its response to each new recurrence.

Impaired kinetic growth rate and increased posthepatectomy liver failure rates after ALPPS for colorectal liver metastasis

Introduction: Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) is a fairly new operative technique, which pushes the limits of resectability of liver tumors. It has especially become a valid treatment option for patients with advanced colorectal liver metastasis (CRLM). It has the potential to facilitate much faster hypertrophy of the future liver remnant (FLR), thereby increasing resectability of previously unresectable CRLM, yet posthepatectomy liver failure (PHLF) as well as impaired hypertrophy of the FLR may still pose a problem in this setting. Methods: To further investigate and understand these issues, we retrospectively analyzed all consecutive patients undergoing ALPPS for resection of CRLM between January 2013 and March 2017 in search for potential risk factors. Cases of posthepatectomy liver failure (PHLF) were graded according to the consensus of the International Study Group of Liver Surgery (ISGLS). The kinetic growth rate (KGR, ml/d) was calculated as mean volume increase per day between the two stages of the ALPPS procedure. Results: A total of 22 patients were included in the analysis. Seven patients (31.8%) developed PHLF (all grade B). Multivariate regression analysis showed a statistically significant association between preoperative chemotherapy involving EGFR inhibitors (cetuximab, panitumumab) and grade B PHLF (p< 0.01) as well as a reduced KGR (p< 0.05). Conclusions: Impaired liver regeneration following EGFR signaling inhibition has been shown in rodents, but not in the clinical setting as of yet. Pending further investigation of these phenomena, we suggest caution when considering ALPPS in this subgroup of patients.

ALPPS improves resectability compared to conventional two-stage hepatectomy in patients with advanced colorectal liver metastasis

The aim was to evaluate ALPPS could increase resection rates (RRs) compared with two stage hepatectomy (TSH) in a randomized controlled trial (RCT). Radical liver metastasis resection offers the only chance of a cure for patients with metastatic colorectal cancer. Patients with colorectal liver metastasis (CRLM) and an insufficient future liver remnant (FLR) volume are traditionally treated with chemotherapy with portal vein embolization or ligation followed by hepatectomy (TSH). This treatment sometimes fails. A prospective, multicenter RCT was conducted between June 2014 and August 2016. It included 97 patients with CRLM and a standardized FLR (sFLR) of < 30%. Primary outcome, resection rates (RRs) were measured as the percentages of patients completing both stages of the treatment. Secondary outcomes were complications, radicality and 90-day mortality measured from the final intervention. Baseline characteristics, besides body mass index, did not differ between the groups. The RR was 92% (C.I. 84-100%)(44/48) in the ALPPS arm compared to 57% (43-72%)(28/49) in the TSH arm (rate ratio 8.25 [95% CI 2.6-26.6]; P< 0.0001). No differences in complications (Clavien-Dindo ≥3a) (43% (19/44) vs. 43% (12/28) (1.01 [95% CI 0.4-2.6]; P=0.99), 90-day mortality (8.3% (4/48) vs. 6.1% (3/49) (1.39 [95% CI 0.3-6.6]; P=0.68) or R0 RRs (77% (34/44) vs. 57% (16/28) (2.55 [95% CI 0.9-7.1]; P=0.11)) were observed. Of the patients in the TSH arm that failed to reach a sFLR of 30%, 12 were successfully treated with ALPPS. ALPPS is superior to TSH in terms of RR, with comparable surgical margins, complications and short-term mortality.