Unresectable Liver Metastases Research Articles

Experience with stereotactic r adiation therapy for liver oligometastases of colorectal cancer

Introduction: The problem of treating patients with unresectable liver metastases of colon cancer is currently far f rom being solved. One possible approach is the use of stereotactic body radiotherapy.The purpose of this study was to evaluate the immediate and long-term results of stereotactic radiotherapy in patients with colorectal cancer and oligometastatic liver metastases.Methods: This study was designed as a retro-prospective, open-label, controlled, non-randomized clinical trial. We assessed one-year local control, one-year overall survival, progression-free survival, and toxicity in 60 patients with oligometastatic liver disease from colorectal cancer who underwent stereotactic body radiotherapy, with median dose of 54 Gy.Results: The median follow-up was 20,1 months. One-year local control (LC) was 73,7 % (95 % CI = 62,7–86,6 %). Oneyear overall survival (OS) was 92,8 % (95 % CI = 86,3–99,9 %), one-year progression-free survival (PFS) was 31,3 % (95 % CI = 21,1–46,4 %) with a median of 8,1 months. Grade ≥ 3 toxicity was not noted. No cases of radiation-induced liver failure were observed. Radiation dose (HR = 0.88, 95 % CI = 0.81–0.95, p = 0.00087), metastasis size (HR = 1.51, 95 % CI = 1.07–2.12, p = 0.01858) and their number (HR = 1.8, 95 % CI = 1.01–3.22, p = 0.04669) are significant risk factors for LC. Metastasis size > 3 cm is a significant risk factor for LC (HR = 5.5, 95 % CI = 1.7–17.9, p = 0.005) and OS (HR = 3.8, 95 % CI = 1.3–11.7, p = 0.02).Conclusion: Stereotactic body radiotherapy is an effective and safe method of providing local control of oligometastatic liver metastases in colorectal cancer as part of a combined treatment approach. Further studies are required to individualize the indications for this treatment method.

Rescue percutaneous transhepatic portal vein embolization after failed associated liver partition and portal vein ligation for staged hepatectomy in a patient with multiple liver metastases of rectal cancer: a case report

BackgroundLiver metastasis is the most common form of distant spread of colorectal cancer. Despite oncological and surgical advances, only about 25% of patients are eligible to undergo resection. As the liver has a limited resectable volume, tumor reduction and remnant liver hypertrophy are of critical importance in treating initially unresectable colorectal cancer liver metastasis. Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) allows rapid liver hypertrophy within a short period and has been reported to be useful in recent years.Case presentationA 29-year-old woman complaining of bloody stool was referred to our hospital. She was diagnosed with rectal cancer (Rb) with simultaneous multiple liver and lung metastases. The patient was then initially commenced on chemotherapy and completed it with a satisfactory response. Right trisectionectomy was necessary to achieve hepatic clearance; however, the future liver remnant (FLR) volume was insufficient. Therefore, we decided to perform totally laparoscopic ALPPS to obtain enough FLR volume. However, the FLR increase was slow, and FLR did not attain the required volume for right trisectionectomy. Computed tomography showed that right portal venous blood flow was increased via developed collateral vessels around the portal vein. We attempted to induce further liver growth by blocking portal blood flow using additional percutaneous transhepatic portal vein embolization (PTPE), and a rapid increase in FLR was obtained. The patient underwent right trisectionectomy and partial resection of S2 with negative margins, and the patient was discharged without postoperative liver failure.ConclusionsResumption of the portal venous blood flow through collateral vessels after ALPPS may have interfered with the planned residual liver hypertrophy. Performing PTPE in addition to ALPPS increased the FLR volume, and radical hepatectomy was completed safely. Remnant portal venous blood flow following ALPPS is an important issue to be considered in surgical planning, and early additional portal vein embolization could be effective.

Abstract CT105: Initial results of a phase II study evaluating a chemokine-modulatory (CKM) regimen in patients with colorectal cancer metastatic to the liver

Abstract Background: Liver metastases develop in 20-50% of colorectal cancer (CRC) patients, being typically resistant to immune checkpoint inhibitors (ICIs) and having a poor prognosis. Our preliminary data showed synergy between IFNα and TLR3 ligands in selectively enhancing the intratumoral production of CD8+ T cell (CTL) attracting chemokines (but not Treg attractants) in ex vivo-treated CRC explants and preferential impact of this combination on liver-metastatic CRC tumor tissues (rather than surrounding liver tissues). Based on these data and previous reports showing the prognostic value of intratumoral CTLs in the CRC outcomes, we hypothesized that systemic infusion of the combination of IFNα2b with rintatolimod (selective TLR3 ligand for i.v. use) can reprogram local balance between the CTL- and regulatory T cell (Treg)-attracting chemokines and the resulting patterns of immune infiltrate in liver lesions. Methods: Recurrent/metastatic CRC patients with unresectable liver metastases amenable to biopsy were eligible. Patients had prior treatment (Rx) with fluoropyrimidine, irinotecan, oxaliplatin, and an anti-EGFR targeted therapy (if RAS wt), or contra-indication to such. Patients received IFNα2b IV (20 million units/m2 IV daily) and rintatolimod (200 mg IV daily) plus oral celecoxib (200 mg twice daily) on days 1, 2, 3, 8, 9, 10, 15, 16, and 17. Response assessment was done via liver biopsies (pre-Rx and on day 24 ± 4 days) and CT imaging (RECIST v1.1) on D46. The primary endpoint was the change in CD8+ T-cells before Rx, with that seen post-Rx (measured by quantitative RT-PCR as a ratio of CD8α to a housekeeping gene, HPRT). With a sample size of N=12 evaluable pts, the study design had a 90% power to detect a 0.77 standard deviation increase (pre- to post Rx) at a significance level of 0.1 (ClinicalTrials.gov Identifier: NCT03403634). Results: Nineteen patients with microsatellite stable (MSS) CRC were enrolled between Apr 2018 and Oct 2020, 15 were treated and 12 were evaluable for the primary endpoint. Most were male (75%, N=9) and Caucasian (92%, N=11). The median age at diagnosis was 65 years. Most had previously received three or more prior lines of therapy (58%, N=7). The study's primary endpoint was met, evidenced by increased CD8a expression post-treatment (p=0.046). An increase in ratios of CD8a/CD4 (p=0.03), CD8a/FOXP3 (p<0.01) and GZMB/FOXP3 (p<0.01) was observed. The expression of CTL-attracting chemokines CCL5 (p=0.08), CXCL9 (p=0.05), and CXCL10 (p=0.06) were increased, while expression of the Treg/MDSC attractant CXCL12 (p=0.07) was decreased post-Rx. Median OS was 10.5 (90% CI 2.2-15.2) months, and the median PFS was 1.5 (90% CI 1.4, 1.8) months. No objective response was seen. The treatment was well tolerated. Of all enrolled patients (N=19), adverse events were noted in 74% of patients, with the most common being fatigue (58%). Grade 3 or higher adverse events were rare (5%). Age, gender, line of treatment, RAS mutational status, and tumor location did not significantly impact CD8a change or PFS. Conclusion: Our study demonstrated that a combinatorial CKM regimen could re-program the immunosuppressive tumor microenvironment in MSS CRC patients with liver metastasis, raising the possibility that the CKM regimen can be used to enhance the effectiveness of ICIs in this group of patients. Citation Format: Sarbajit Mukherjee, Patrick M. Boland, Melissa Grimm, Ronald Slomba, Kristopher Attwood, Renuka Iyer, Pawel Kalinski. Initial results of a phase II study evaluating a chemokine-modulatory (CKM) regimen in patients with colorectal cancer metastatic to the liver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT105.

Conversion therapy with the intent to perform radical local treatment may not be suitable for patients with 10 or more liver metastases from colorectal cancer.

The number of colorectal cancer liver metastases (CRLMs) is usually considered a contradictory indicator to surgical resection. However, some patients with initially unresectable CRLMs can receive radical local treatment after conversion therapy. This study aimed to evaluate the effect of radical local treatment after conversion therapy and the prognosis of patients with more than 10 initially unresectable CRLMs. Data for a total of 229 patients with initially unresectable CRLMs were retrospectively reviewed between December 2012 and January 2020. Among these patients, 107 had ≥10 CRLMs, and 122 had <10 CRLMs. Overall survival (OS) and progression-free survival (PFS) were used to reflect the prognosis of different groups of patients. Conversion therapy was defined as an initially unresectable liver metastasis converted into an R0 resectable lesion after systemic chemotherapy. Radical local treatment included hepatectomy and radiofrequency ablation (RFA). Patients with ≥10 CRLMs had a lower conversion rate (42.7% vs. 56.6%, p=0.001). Baseline clinical N stage 1-2, ≥8 first-line chemotherapy courses, and stable disease (SD) according to the Response Evaluation Criteria in Solid Tumours (RECIST) were independent factors predictive of conversion failure. Primary tumour location in the right colon, RECIST response of SD, and the absence of targeted therapy were independent factors predictive of unfavourable OS. The survival curves revealed that the OS of patients with or without conversion could be distinguished only among patients with <10 CRLMs (89.9% [95% CI, 82.5%-98.0%] vs. 58.9% [95% CI, 45.2%-76.7%], p < 0.001); this cut-off point could also distinguish patients with a successful conversion outcome according to OS (89.9% [95% CI, 82.5-98.0%] vs. 58.2% [95% CI, 42.2-80.4%], p=0.008). For CRLMs ≥ 10, patients with a successful conversion outcome cannot be distinguished from those without successful conversion outcome according to OS. Thus, conversion therapy with the intent to perform radical local treatment may not be suitable for patients with 10 or more liver metastases from colorectal cancer.

Kirsten rat sarcoma (KRAS) oncogene mutation predicts magnitude of response and outcomes in hepatic arterial infusion pump therapy of unresectable colorectal liver metastases.

The Kirsten rat sarcoma (KRAS) mutation predicts negative outcomes following resection of colorectal liver metastases (CRLM) and adjuvant hepatic arterial infusion (HAI) pump chemotherapy. Less is known on the effects of KRAS mutation on tumor response in patients with unresectable CRLM undergoing HAI chemotherapy with floxuridine. This is a retrospective cohort study investigating the effects of KRAS mutation on tumor response in patients with unresectable CRLM treated with HAI chemotherapy. Primary endpoint was objective response rate (ORR), secondary endpoints included overall tumor response and conversion to resectability. Twenty-five patients with unresectable liver metastases from colorectal cancer were treated with HAI chemotherapy between 2017-2019. Median number of liver lesions was 12 (range, 1-59) and almost all (n=24) had prior chemotherapy before starting HAI therapy. Median number of cycles administered via HAI pump was 6 (range, 3-12). Overall decrease in liver tumor burden was 63.5% (median; range, -257-100%) with an ORR of 20/25 (80%) and 10 (40%) patients converting to resectable status. Eleven (44%) patients had KRAS positive tumors. When compared to wild-type, KRAS positive tumors had less overall percent decrease (58% vs. 70%; P=0.04) and ORR (7/11 vs. 13/13; P=0.03). Fewer patients with KRAS positive tumors converted to resectable status during HAI therapy (2/11 vs. 8/13; P=0.05). At a median follow-up of 14.6 months (range, 4.0-36.6 months), overall survival is 45% among KRAS-positive and 77% for wild type patients. KRAS mutational status in patients with unresectable liver metastases from colorectal cancer predicts worse response to HAI chemotherapy compared to wild type.

Anlotinib plus chemotherapy as first-line therapy for gastrointestinal tumor patients with unresectable liver metastasis: A multicenter, multicohort clinical trial (ALTER-G-001).

TPS229 Background: Liver metastases (LMs) are usually found in gastrointestinal tumors, such as colorectal cancer (mCRC), esophageal squamous cell carcinoma (ESCC) and gastric cancer. Currently, there is no formal option for such patients (pts) due to the different pathological characteristics, and more effective treatment regimens are needed. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor targeting VEGFR1/2/3, FGFR1-4, PDGFRα/β and c-Kit, which effectively blocks tumor neovascularization and growth. Previous phase II clinical trials suggested that anlotinib plus chemotherapy as first-line therapy were well tolerated and showed clinical anti-tumor activity in mCRC and ESCC. It was demonstrated an objective response rate (ORR) of 76.7%, a disease control rate (DCR) of 93.3% and a median progression-free survival (mPFS) of 11.4 months in RAS/BRAF wild-type unresectable mCRC pts using anlotinib plus CAPEOX (ALTER-C002 trial, NCT04080843). Additionally, preliminary encouraging ORR (78.3%), DCR (93.5%) and mPFS (8.38 months) was observed in advanced ESCC pts treated with anlotinib plus cisplatin and paclitaxel (ALTER-E002 trial, NCT04063683). Based on these results, this multicohort, multicenter phase II ALTER-G-001 trial was launched to evaluate efficacy and safety of anlotinib plus chemotherapy as first-line therapy in gastrointestinal tumor pts with unresectable LMs. Methods: Previously untreated and histologically or cytologically confirmed gastrointestinal tumor pts with unresectable LMs were eligible, who will be divided into 3 cohorts, including mCRC (n = 45), ESCC (n = 31) and others (n = 25). Pts must be aged 18-75 years, with an ECOG PS of 0/1, adequate organ function, and at least one measurable LMs lesion according to RECIST v1.1. HER2-positive gastric adenocarcinoma, and pts with a high risk of bleeding, perforation or fistulas will be excluded. During first 6 cycles (3 weeks per cycle) of inducing treatment, mCRC pts will receive anlotinib (12mg, po, qd, d1-d14), oxaliplatin (130 mg/m2, iv, d1) and capecitabine (850 mg/m2, po, bid, d1-d14). ESCC pts will be treated with anlotinib, cisplatin (60-750 mg/m2, i.v., d1/d1-3) along with paclitaxel (135 mg/m2, i.v., d1) or docetaxel (75 mg/m2, i.v., d1). And pts in others cohort will receive anlotinib plus standard first-line chemotherapy. Then, pts without PD and LMs resection, will receive anlotinib and metronomic capecitabine (500mg, po. bid, d1-21, q3w) until PD or unacceptable toxicity. Primary endpoint is investigator-assessed ORR (RECIST 1.1). Secondary endpoints include duration of response (DoR), PFS, overall survival, DCR, radical resection rate for LMs and safety (NCI-CTCAE v5.0). Research sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: ChiCTR2100050872.

Chemotherapy as the first therapeutic option in patients with stage IV colorectal cancer with non resecable synchronic liver metastasis.

Background: Systemic chemotherapy followed by surgery on the primary tumor may be a good treatment program in patients with colorectal cancer with synchronous and unresectable liver metastases. But the expected results are not well understood. The objective of this study is to analyze the results of this treatment.

Prognostic factors affecting the success of conversion chemotherapy in patients with unresectable liver metastases from initially colorectal cancer

Objective: To investigate the factors affecting the success of conversion therapy in patients with initially unresectable colorectal cancer liver metastases (CRLM) in order to provide evidence-based medical evidence for formulating individualized treatment strategies for patients. Methods: A retrospective case-control study was used in this study. Clinical data of 232 patients with initially unresectable CRLM receiving first-line systemic treatment in Sun Yat-sen University Cancer Center from January 2013 to January 2020 were collected, including 98 patients of successful conversion and 134 patients of failed conversion as control. Conversion therapy scheme: 38 patients received FOLFOXIRI regimen chemotherapy (irinotecan, oxaliplatin, calcium folinate and fluorouracil), 152 patients received FOLFOX regimen (oxaliplatin, calcium folinate and fluorouracil), 19 patients received FOLRIRI regimen (irinotecan, calcium folinate and fluorouracil), 23 patients received systemic chemotherapy combined with fluorouridine hepatic artery infusion chemotherapy; 168 patients received targeted therapy, including 68 of bevacizumab and 100 of cetuximab. Logistics analysis was used to compare the factors affecting the success of conversion therapy. The Kaplan-Meier method was used to calculate progression-free survival (PFS), and the Log-rank test was used for survival comparison. Results: Among 232 patients, 98 patients had successful conversions and 134 patients had failed conversions with a successful conversion rate of 42.2%, meanwhile 30 patients underwent simple hepatectomy and 68 underwent hepatectomy combined with intraoperative radiofrequency ablation. After first-line chemotherapy, 111 patients (47.8%) were partial remission, 57 patients (24.6%) were stable disease, and 64 patients (27.6%) were progression disease. During the median follow-up of 18.8 (1.0-87.9) months, 148 patients were dead or with tumor progression. The median PFS time of patients with successful conversion was longer than that of patients with failed conversion (31.0 months vs. 9.9 months, P<0.001). Univariate analysis found that the bilobar distribution of liver tumors (P=0.003), elevated baseline carcinoembryonic antigen (CEA) levels (P=0.024), tumor invasion of the portal vein (P=0.001), number of metastatic tumor>8 (P<0.001), non-FOLFOXIRI (P=0.005), and no targeted therapy (P=0.038) were high risk factors for the failed conversion therapy. The results of multivariate logistics analysis indicated that the number of metastatic tumor >8 (OR=2.422, 95%CI: 1.291-4.544, P=0.006), portal vein invasion (OR=2.727, 95%CI: 1.237-4.170, P=0.008) were the independent risk factors for failed conversion therapy, while FOLFOXIRI regimen (OR=0.300, 95%CI: 0.135-0.666, P=0.003) and targeted drugs (OR=0.411, 95%CI: 0.209-0.809, P=0.010) were independent protective factors for successful conversion therapy. Conclusions: The number of metastatic tumor and portal vein invasion are key factors that affect the outcomes of conversion therapy for initially unresectable CRLM. If a patient can tolerate chemotherapy, a combination program of three-drug and targeted therapy is preferred for the active conversion therapy.

Small Particle DEBIRI TACE as Salvage Therapy in Patients with Liver Dominant Colorectal Cancer Metastasis: Retrospective Analysis of Safety and Outcomes.

The aim of this study was to examine the safety and efficacy of 40 µm and 75 µm calibrated irinotecan-eluting beads (DEBIRI-TACE) for the treatment of colorectal cancer metastases. We conducted a retrospective review of 36 patients with unresectable liver metastases from colorectal cancer who were treated with DEBIRI-TACE between 2017 to 2020. Patients who received at least one session of DEBIRI were included in our analysis. A total of 105 DEBIRI sessions were completed. 86% of patients (n = 31) underwent one round of treatment, 14% of patients (n = 5) underwent two distinct rounds of treatment. The majority of patients were discharged the next day (92%, n = 33 patients) with no 30-day post-DEBIRI mortality. Five high-grade adverse events occurred, including longer stay for pain management (n = 2), postembolization syndrome requiring readmission (n = 2), and liver abscess (n = 1). The average survival from diagnosis of metastatic disease was 33.3 months (range 11–95, median 28). Nine of 36 patients are still alive (December 2020) and have an average follow-up time of 36.8 months from T0 (range 12–63, median 39). Small particle DEBIRI is safe and well-tolerated in the salvage setting, with outcomes comparable to that of larger bead sizes.

Survival outcomes in unresectable metastatic rectal cancer patients after both primary site resection and chemoradiotherapy: a SEER-based observational study.

BackgroundThe liver is the most common site for rectal cancer metastasis, and liver resection combined with chemotherapy is the only treatment offering the possibility of long-term survival in patients with metastatic rectal cancer. However, a significant proportion of liver metastases cannot be surgically removed, and very limited data are available regarding the survival outcomes of these patients. This study aimed to investigate the survival pattern of rectal cancer patients with unresectable liver metastases after both chemoradiotherapy and primary tumor resection.MethodsA total of 51,178 rectal cancer patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database, of whom 448 had synchronous liver metastases and underwent both chemoradiotherapy and primary tumor resection. According to different treatment modalities, patients were divided into a hepatic resectable group and an unresectable group. The Kaplan-Meier method was used to estimate patient survival, and differences between the hepatic resectable and unresectable groups were compared using the log-rank test. Univariate and multivariate Cox regression models were used to analyze independent prognostic factors for unresectable tumors.ResultsAmong the 448 metastatic rectal cancer patients, 60.3% (270) had unresectable liver metastasis. The median survival period, 2-year overall survival (OS) rate, and 5-year OS rate of the unresectable group were 37.0 months, 68.5%, and 32.9%, respectively, compared with 56.0 months, 87.4%, and 48.0%, respectively, in the hepatic resectable group (P<0.001). Multivariate Cox regression analysis suggested that a poor or undifferentiated histological type was independently associated with poor CSS in patients with unresectable liver metastases (P=0.001).ConclusionsPrimary tumor resection combined with chemoradiotherapy might be able to yield a satisfactory survival outcome in unresectable metastatic rectal cancer patients. Resection of liver metastases remains the primary treatment for prolonging the OS and CSS time in stage IV patients.

Uloga stereotaksične radioterapije u lečenju metastaza u jetri kolorektalnog karcinoma

Colorectal cancer is third most common malignant disease and second leading cause of cancer-related deaths worldwide. In 2020, there were 5900 new cases in Serbia and around 3300 number of deaths related to this disease. Metastatic disease is most frequently located in liver. Surgery is first option if complete resection of liver metastases is achievable. Since liver metastases are resectable in 10 - 20% of cases, there is a possibility of implementation of other treatment modality. Alternative for surgery in local treatment of unresectable metastases are stereotactic body radiation therapy (SBRT), interstitial and intraluminal brachytherapy, transarterial chemoembolization, hepatic arterial infusion chemotherapy, selective internal radiation therapy with yttrium-90 resin microspheres, cryoablation, radiofrequency, chemical, and microwave ablation. Candidates for SBRT are patients with unresectable liver metastatic disease and patients with comorbidities which disable surgical treatment, with adequate function of uninvolved liver tissue. Respiration induced motion of target volume can be reduced by introduction of motion management strategies such as infrared markers, deep inspiration breath hold, abdominal compression, respiratory tracking and gating. CyberKnife, TomoTherapy machine and modified linear accelerators are used for delivering SBRT. These units allow us to deliver dose more precisely and to make dose escalation. Different regimes of fractionation are optional, from single fraction to hypo fractionation regimes, and doses are typically around 30 - 60 Gy in 3 fractions. Low toxicity rates in patients with liver metastases treated with SBRT are in relation with precise treatment planning, dose prescription and fractionation. Results of research suggest that delivery of large doses can provide high rate of local response, but on the other hand there is possibility of disease progression out of target volumes. With adequate selection of patients with unresectable liver metastases, the implementation of SBRT, especially in combination with effective systematic treatment modalities, can provide better local control with extension of survival.

Impact of Perihepatic Adhesions on Liver Regeneration during Two-Stage Hepatectomy for Unresectable Colorectal Liver Metastases: Results from the Sepra-C2T Prospective Trial

Introduction: Two-stage hepatectomy (TSH) is an effective treatment for unresectable colorectal liver metastasis (CLM). Insufficient hepatic growth may prevent from performing the second stage. Peri-hepatic adhesions are frequent after the first hepatectomy. Incidence and severity of adhesions can be prevented by anti-adhesion barriers. The objective of our study was to investigate the impact of post-operative peri-hepatic adhesions on liver regeneration in patients who underwent TSH for unresectable CLM.

Advances in liver transplantation for unresectable colon cancer liver metastasis.

It is estimated that 50% of patients with colorectal cancer will develop liver metastasis. Surgical resection significantly improves survival and provides a chance of cure for patients with colorectal cancer liver metastasis (CRLM). Increasing the resectability of primary unresectable liver metastasis provides more survival benefit for those patients. Considerable surgical innovations have been made to increase the resection rate and decrease the potential risk of hepatic failure postoperation. Liver transplantation (LT) has been explored as a potential curative treatment for unresectable CRLM. However, candidate selection criteria, chemotherapy strategies, refined immunity regimens and resolution for the shortage of grafts are lacking. This manuscript discusses views on surgical indication, peritransplantation anti-tumor and anti-immunity therapy and updated advances in LT for unresectable CRLM. A literature review of published articles and registered clinical trials in PubMed, Google Scholar, and Clinicaltrials.gov was performed to identify studies related to LT for CRLM. Some research topics were identified, including indications for LT for CRLM, oncological risk, antitumor regimens, graft loss, administration of anti-immunity drugs and solutions for graft deficiency. The main candidate selection criteria are good patient performance, good tumor biological behavior and chemosensitivity. Chemotherapy should be administered before transplantation but is not commonly administered posttransplantation for preventive purposes. Mammalian target of rapamycin regimens are recommended for their potential oncological benefit, although there are limited cases. In addition to extended criterion grafts, living donor grafts and small grafts combined with two-stage hepatectomy are efficient means to resolve organ deficiency. LT has been proven to be an effective treatment for selected patients with liver-only CRLM. Due to limited donor grafts, high cost and poorly clarified oncological risks, LT for unresectable CRLM should be strictly performed under a well-organized study plan in selected patients. Some vital factors, like LT indication and anti-tumor and anti-immune treatment, remain to be confirmed. Ongoing clinical trials are expected to delineate these topics.

Isolated chemohyperthermal perfusion of the liver with melphalan in the treatment of unresectable liver metastases with uveal melanoma

Uveal melanoma belongs to rare malignant neoplasms, and the biological peculiarity of this tumor determines the high rate of distant metastasis, which reaches 60 %. Most frequently, uveal melanoma metastases are localized in the liver and have an isolated character. At the same time, despite the achievements of modern drug therapy, the treatment results of this category of patients remain unsatisfactory. Among the regional methods of treatment of metastatic uveal melanoma, surgical treatment is considered to be the most effective. Median survival rate in the group of radically operated patients (R0) is 27 months. At present, in the vast majority of cases, surgical treatment is impossible because of multiple bilobar metastasis and advanced cancer process. Median life expectancy of patients with liver metastases is only 9 months. A promising method of regional treatment of inoperable metastatic uveal melanoma is isolated liver chemoperfusion. Multidisciplinary team of Radiology Scientific Research Center and Kostroma Oncologic Dispensary for the first time in Russia presents a clinical case of a patient with isolated inoperable uveal melanoma liver metastases using an innovative method - isolated high-dose chemo hyperthermic liver perfusion with melphalan. The article describes in detail the method of the procedure, estimates immediate (partial response in 1 month after the procedure) and long-term results of the method (stabilization of the condition against the background of immunotherapy in 9 months after surgery). Based on the presented clinical observation, isolated liver chemoperfusion with melphalan for this category of patients is reasonable. However, despite the encouraging immediate results, clinical experience needs to be accumulated in order to be further evaluated in clinical trials.

Indications for conversion hepatectomy for initially unresectable colorectal cancer with liver metastasis.

Selected patients with initially unresectable colorectal cancer (CRC) and liver metastases undergo conversion surgery after appropriate chemotherapy. The prognosis of these patients is good, with some even cured of the disease. This retrospective, single-institution study analyzes the clinical importance of patient characteristics on the outcomes of conversion hepatectomy. We evaluated 229 consecutive patients with initially unresectable CRC and liver metastasis, who underwent systemic chemotherapy. The patients were assigned to groups depending on conversion hepatectomy. Conversion hepatectomy was performed in 30 patients (13.1%). The proportion of patients with extrahepatic metastasis was significantly lower in the conversion group than in the unresectable group (30.0 vs. 66.8%; P < 0.01). The rate of left-sided primary colorectal tumors was significantly higher in the conversion group than in the unresectable group (96.7 vs. 65.8%; P < 0.01). Multivariate analyses identified that left-sided tumors, no extrahepatic metastasis, H1 or H2 grade CLM, and treatment with molecular-targeted agents were associated with conversion hepatectomy (odds ratios: 16.314, 4.216, 7.631, and 4.070; P < 0.01). Overall survival was significantly longer in the conversion group than in the unresectable group (MST: 50.0 versus 14.7months; P < 0.01). Left-sided primary tumors, absence of extrahepatic metastases, H1 or H2 grade, and use of molecular-targeted agents were associated with successful conversion hepatectomy; thus, patients with these characteristics may be candidates for conversion therapy.

Role of hepatic surgery in colorectal cancer multiple liver metastasis

Colorectal cancer liver metastasis can be categorized as initially resectable and initially unresectable liver metastasis. Patients with initially resectable colorectal cancer liver metastases may benefit from hepatic surgery significantly,while those with initially unresectable metastases also have an opportunity to be treated radically by liver surgery after conversion therapy,so as to have a prolonged survival time. It is crucial to choose the right time and right way of surgical intervention. The timing depends on determination of tumor resectability,controlling of pre-operative systemic therapy and evaluation of liver function after systemic treatment. The selection of right way contains the election between synchronous operation and staged operation, resection margin and using of technologies such as laparoscope and associating liver partition and portal vein ligation for staged hepatectomy. This paper aims to explore the optimal timing for operation and the approaches of surgical method based on the research progress worldwide for prolonging the survival time of patients with colorectal cancer multiple liver metastases.

Role of Resin Microsphere Y90 Dosimetry in Predicting Objective Tumor Response, Survival and Treatment Related Toxicity in Surgically Unresectable Colorectal Liver Metastasis: A Retrospective Single Institution Study.

Simple SummaryColorectal liver metastases are difficult to treat, with only a minority of patients eligible for surgical resection. Yttrium-90 selective internal radiation therapy is an alternative treatment currently used for patients who have progressed on chemotherapy. A technique called dosimetry allows clinicians to analyze how much radiation was delivered to target lesions post-treatment. The aim of this study is to evaluate the relationship of various dosimetric parameters with objective tumor response, overall survival, and treatment related toxicity with the potential goal of optimizing Yttrium-90 treatment in this patient population. Additionally, other potential predictors of survival outcomes, including clinical and demographic factors, were also evaluated. We found that delivering a mean tumor dose ≥100 Gy when using resin microspheres was significantly associated with objective tumor response and prolonged overall survival. In this study, no mean non-tumoral liver dose threshold was found to predict treatment related toxicity.Purpose: To Evaluate the correlation between tumor dosimetric parameters with objective tumor response (OR) and overall survival (OS) in patients with surgically unresectable colorectal liver metastasis (CRLM) undergoing resin-based Ytrrium-90 selective internal radiation therapy (Y90 SIRT). Materials and Methods: 45 consecutive patients with CRLM underwent resin-based Y90 SIRT in one or both hepatic lobes (66 treated lobes total). Dose volume histograms were created with MIM Sureplan® v.6.9 using post-treatment SPECT/CT. Dosimetry analyses were based on the cumulative volume of the five largest tumors in each treatment session and non-tumoral liver (NTL) dose. Receiver operating characteristic (ROC) curve was used to evaluate tumor dosimetric factors in predicting OR by Response Evaluation Criteria for Solid Tumors at 3 months post-Y90. Additionally, ROC curve was used to evaluate non-tumoral liver dose as a predictor of grade ≥ 3 liver toxicity and radioembolization induced liver disease (REILD) 3 months post Y90. To minimize for potential confounding demographic and clinical factors, univariate and multivariate analysis of survival with mean tumor dose as one of the factors were also performed. Kaplan-Meier estimation was used for OS analysis from initial Y90 SIRT. Results: 26 out of 45 patients had OR with a median OS of 17.2 months versus 6.8 months for patients without OR (p < 0.001). Mean tumor dose (TD) of the five largest tumors was the strongest predictor of OR with an area under the curve of 0.73 (p < 0.001). Minimum TD, and TD to 30%, 50%, and 70% of tumor volume also predicted OR (p’s < 0.05). Mean TD ≥ 100 Gy predicted a significantly prolonged median OS of 19 vs. 11 months for those receiving TD < 100 Gy (p = 0.016). On univariate analysis, mean TD < 100 Gy, presence of any genomic mutation, presence of MAPK pathway mutation, bilobar hepatic metastases and diffuse metastatic disease (>10 lesions per liver lobe) were found to be predictors of shorter median OS. On multivariate analysis, mean TD < 100 Gy, presence of any genomic mutation, and diffuse hepatic metastatic disease were found to be independent predictors of shorter OS. Overall, six (13.3%) patients developed grade ≥ 3 liver toxicity post Y90 of whom two (4.4%) patients developed REILD. No dose threshold predicting grade ≥ 3 liver toxicity or REILD was identified. Conclusions: Mean TD ≥ 100 Gy in patients with unresectable CRLM undergoing resin-based Y90 SIRT predicts OR and prolonged OS.

Perioperative Systemic Chemotherapy for Colorectal Liver Metastasis: Recent Updates.

Simple SummaryThe development of cytotoxic chemotherapy, targeted agents and immune check point inhibitors has improved survival outcomes and quality of life in patients diagnosed with metastatic colorectal cancer (CRC). Long-term survival and cure are possible in well-selected CRC patients with liver metastases (LM). The criteria for resectable LM and the eligibility of patients should be evaluated at the time of diagnosis or during the clinical course via a multidisciplinary team approach. The advantages of adjuvant chemotherapy after curative resection of LM are uncertain currently. Systemic preoperative chemotherapy may convert unresectable LM to a resectable type. However, the optimal combination of systemic drugs and treatment strategy has yet to be established. This article summarizes recent reports of perioperative systemic treatment for patients with colorectal liver metastases (CLM). This review provides an update for physicians involved in managing patients with CLM.The liver is the most common site of metastases for colorectal cancer. Complete resection in some patients with resectable liver metastases (LM) can lead to long-term survival and cure. Adjuvant systemic chemotherapy after complete resection of LM improves recurrence-free survival; however, the overall survival benefit is not clear. In selected patients, preoperative systemic treatment for metastatic colorectal cancer can convert unresectable to resectable cancer. This review will focus on patient selection, and integration of perioperative and postoperative systemic treatment to surgery in resectable and initially unresectable LM. Additionally, new drugs and biomarkers will be discussed.

Initiation of Chemosaturation With Percutaneous Hepatic Perfusion Program in Interventional Radiology Department.

ObjectivesChemosaturation with percutaneous hepatic perfusion (PHP) is a relatively new minimally-invasive liver-directed therapy, which aims to deliver high-dose chemotherapy into the liver with low systemic side effects. Initial studies showed promising results, especially in the treatment of metastatic uveal melanoma. But unfamiliarity of the interventional radiologists prevents its widespread implantation in clinical routine. This study aimed to outline how to initiate a PHP program and report initial results.MethodsWe retrospectively reviewed all patients who underwent chemosaturation with PHP in our institution between March 2016 and February 2017 and their follow-up results till October 2018. Patient demographics, procedural characteristics, clinical and imaging results, and complications were evaluated. Additionally, modifications regarding infrastructure and procedure techniques were described.ResultsA total of three patients (two females and one male) with a mean age of 59 underwent six PHP procedures. The primary disease was colorectal carcinoma in one patient and uveal melanoma in two patients. The technical success rate was 100% and the mean melphalan dose was 190.8 mg. No procedural death was observed. Patients were hospitalized for a mean of 3.3 days after procedures. Grade 3 and 4 complications were seen after 50% and 33.3% of procedures, respectively. Two patients showed partial response and the other patient showed stable disease after procedures. Mean hepatic progression-free survival was 10.8 months. Overall survival from the first procedure was 14.8 months in our cohort.ConclusionOur results show that chemosaturation with PHP offers a promising minimally invasive treatment option in patients with unresectable liver metastases. The technical challenges of PHP can be easily handled by an experienced interventional radiology (IR) team. It is a relatively safe procedure and its toxicities are usually hematological and can be manageable with close surveillance and appropriate medical therapies.

Impact of primary tumor resection on the survival of patients with unresectable colon cancer liver metastasis at different colonic subsites: a propensity score matching analysis

Objective To investigate the effect of primary tumor resection (PTR) on the prognosis of patients with unresectable colon cancer liver metastasis (UCCLM) at seven colonic subsites using the Surveillance, Epidemiology, and End Results (SEER) database. Methods Propensity score matching (PSM) was performed to balance selection bias using all available variables that could be of potential relevance. After matching, the groups were redefined in a 1:1 ratio using the nearest method. Cancer-specific survival (CSS) was compared among the patients of PTR and non-PTR groups. Cox regression models were used to identify the prognostic factors for CSS. Results CSS was significantly different between all groups. Cox regression analysis showed that PTR was an independent prognostic factor for all groups. After PSM, PTR significantly prolonged CSS for all groups. Subgroup analysis showed that PTR did not improve the prognosis of N2 stage patients in the cecum, ascending colon, and descending colon groups; T1 + T2 stage patients in the hepatic flexure group; and patients with a tumor size ≤5 cm in the splenic flexure group. Segmental colectomy could prolong CSS of patients in the cecum, ascending colon, transverse colon, splenic flexure, and sigmoid colon groups, while extended colectomy could prolong CSS of patients in the hepatic flexure and descending colon groups. Conclusion At different colonic subsites, UCCLM patients had different CSS. PTR could improve their prognosis, however, N stage, T stage, and tumor size are important reference indicators. In addition to patients in the hepatic flexure and descending colon groups, we suggested that patients in other groups should choose segmental colectomy.