Resection Of Liver Metastases Research Articles

A prospective multicentre trial on survival after Microwave Ablation VErsus Resection for Resectable Colorectal liver metastases (MAVERRIC)

AimThis multi-centre prospective cohort study aimed to investigate non-inferiority in patients’ overall survival when treating potentially resectable colorectal cancer liver metastasis (CRLM) with stereotactic microwave ablation (SMWA) as opposed to hepatic resection (HR). MethodsPatients with no more than 5 CRLM no larger than 30 mm, deemed eligible for both SMWA and hepatic resection at the local multidisciplinary team meetings, were deliberately treated with SMWA (study group). The contemporary control group consisted of patients with no more than 5 CRLM, none larger than 30 mm, treated with HR, extracted from a prospectively maintained nationwide Swedish database. After propensity-score matching, 3-year overall survival (OS) was compared as the primary outcome using Kaplan-Meier and Cox regression analyses. ResultsAll patients in the study group (n = 98) were matched to 158 patients from the control group (mean standardised difference in baseline covariates = 0.077). OS rates at 3 years were 78% (Confidence interval [CI] 68–85%) after SMWA versus 76% (CI 69–82%) after HR (stratified Log-rank test p = 0.861). Estimated 5-year OS rates were 56% (CI 45–66%) versus 58% (CI 50–66%). The adjusted hazard ratio for treatment type was 1.020 (CI 0.689–1.510). Overall and major complications were lower after SMWA (percentage decrease 67% and 80%, p < 0.01). Hepatic retreatments were more frequent after SMWA (percentage increase 78%, p < 0.01). ConclusionSMWA is a valid curative-intent treatment alternative to surgical resection for small resectable CRLM. It represents an attractive option in terms of treatment-related morbidity with potentially wider options regarding hepatic retreatments over the future course of disease.

Surgery for colorectal liver metastases: Anatomic and non-anatomic approach

Liver resection is potentially curative for patients with colorectal liver metastasis, but an advanced understanding of tumor biology and improved adjuvant therapies have facilitated an ongoing evolution of metastatic resection, even in the setting of a significant metastatic disease burden. As indications for surgery have expanded, preferred techniques and timing have been debated. This commentary reviews the merits of anatomic versus non-anatomic approaches to colorectal liver metastasis resection, considering oncologic outcomes, overall survival, and conflicting theories in the pathophysiology of the metastatic liver spread.

Abstract 5715: Circulating tumor DNA in colorectal cancer patients with resectable liver metastases: Preliminary results of the MIRACLE study

Abstract Introduction: Recurrence risk after curative surgery for colorectal liver metastases (CRLM) remains high, underlining the need for novel prognostic markers. Liquid biopsies provide promising biomarkers to detect minimal residual disease (MRD) after local treatment. The aim of this study was to determine and compare the characteristics of cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) in liquid biopsies taken before and after surgical treatment of CRLM. Materials &amp; Methods: Patients with isolated CRLM were recruited before undergoing potentially curative hepatic resection. Only patients who did not receive per-operative chemotherapy were selected. Peripheral blood samples were collected in CellSave preservative tubes at four different time points and processed into plasma within 96 hours after withdrawal. Subsequently, cfDNA was isolated from 4mL plasma, in which the total cfDNA concentration was measured. Mutations characterizing ctDNA were determined before surgery by next generation sequencing (NGS) using a colon-specific targeted panel (Oncomine Colon cfDNA assay, 14 genes). Samples were sequenced at &amp;gt;20.000 average reads depth and variants were called mutations when the variant allele frequency was above their predefined limit of detection. Longitudinal blood samples of ctDNA-positive patients were evaluated by digital PCR (dPCR) using mutation-specific assays, in which samples were considered ctDNA positive when &amp;gt;5 mutant copies were detected. Results: Blood samples of 231 patients were collected one day before surgery (T0), and were repeated one day (T1), one week (T2), and three weeks (T3) after surgery. The cfDNA yields per mL plasma were higher at T1 and T2 (median 93 ng and 64 ng, respectively) compared to T0 (6 ng, p&amp;lt;0.001) and T3 (12 ng, p&amp;lt;0.001). NGS at T0 was performed for 196 patients and detected ctDNA in 129 patients (66%). Mutations had a median allele frequency of 6.3% (ranging from 0.28 to 86.4%), and were observed in 12 genes, predominantly in TP53 (n=69), KRAS (n=57), APC (n=40), and PIK3CA (n=23). dPCR analyses were performed for 87 patients out of the 129 patients with ctDNA at T0, and confirmed TP53, KRAS, PIK3CA, and BRAF mutations in 75 patients, with average ctDNA loads of 9%, 8%, 18% and 4% for these genes. Longitudinal dPCR analyses were performed in 58 patients of whom subsequent post-surgical samples were available, and revealed that ctDNA was detectable in 22 patients (40%) at T1/T2, and in 21 patients (36%) at T3. Nine patients (16%) had detectable ctDNA at both T1/T2 and T3. Average mutation loads were 0.97% at T1/T2 and 1.79% at T3 (p=0.36). Discussion/Conclusion: ctDNA is a potential biomarker to detect MRD after curative treatment for CRLM. Our results demonstrate that out of all patients with detectable ctDNA at baseline (before surgery), ctDNA is still present in 36% of patients three weeks after resection. Citation Format: Lissa Wullaert, Maurice P. Jansen, Jaco Kraan, Jan M. van Rees, Corine M. Beaufort, Yannick M. Meyer, Boris Galjart, Pieter M. Nierop, Florian E. Buisman, Diederik J. Höppener, Erik P. van der Stok, Gianmarco Motta, Dirk J. Grünhagen, Henk M. Verheul, Stefan Sleijfer, Saskia M. Wilting, Cornelis Verhoef, John W. Martens. Circulating tumor DNA in colorectal cancer patients with resectable liver metastases: Preliminary results of the MIRACLE study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5715.

Open Parenchymal Sparing Posterosuperior Liver Tumor Resection for Colorectal Liver Metastasis With Proximity to Hepatic Veins.

Liver resection for stage 4 colorectal cancer with liver metastasis is the standard of care, in combination with systemic chemotherapy. R-0 complete resection for colorectal liver metastasis is a curative-intent operation, which is considered the only chance for cure in this disease. The location and proximity of the tumor to major intrahepatic vessels such as hepatic and portal vein determine technical difficulty. Tumors located in the posterosuperior segments of the liver (segments 7 and 8) are technically challenging to resect using a minimally invasive fashion; therefore, conventional open resection is still the technique of choice today. In this video, we demonstrated our approach of an open parenchymal-sparing posterosuperior liver resection for a colorectal liver metastasis.

Neoadjuvant chemotherapy does not increase risk for anastomotic leak for simultaneous resection of primary colon cancer with synchronous liver metastasis: A NSQIP-colectomy analysis.

In patients with colon cancer with synchronous liver metastasis, treatment algorithms are complex and often require multidisciplinary evaluation. Neoadjuvant therapy is frequently utilized, but there is an unclear relationship with postoperative outcomes in patients with simultaneous resection. This is a retrospective cohort study from the National Surgical Quality Improvement Program and Targeted Colectomy databases. All patients with stage IV colon cancer undergoing simultaneous colectomy with synchronous liver metastasis resection or ablation between 2015 and 2019 were identified and categorized into subgroups based on receipt of neoadjuvant chemotherapy. Multivariable logistic regression was utilized to assess for risk factors of anastomotic leaks and serious postoperative complications. We identified 1006 patients who underwent simultaneous colectomy and liver operations. Of those, 418 (41.6%) received neoadjuvant chemotherapy within 90 days of surgery, while 588 (58.4%) had simultaneous upfront surgery. On multivariable logistic regression, neoadjuvant therapy was not associated with postoperative anastomotic leaks (odds ratio [OR]:1.30; p = 0.39) or serious complications (OR: 1.04; p = 0.82). Neoadjuvant therapy does not increase postoperative complications in simultaneous colon and liver resections. These results may alleviate concerns regarding postoperative morbidity in the decision-making process of administering neoadjuvant therapy.

Metastasis-Directed Local Therapy of Hepatic Oligometastasis from Colorectal Cancer and Future Perspective in Radiation Therapy.

Introduction of the concept for oligometastasis led to wide application of metastasis-directed local ablative therapies for metastatic colorectal cancer (CRC). By application of the metastasis-directed local ablative therapies including surgical resection, radiofrequency ablation (RFA), and stereotactic ablative body radiotherapy (SABR), the survival outcomes of patients with metastatic CRC have improved. The liver is the most common distant metastatic site in CRC patients, and recently various metastasis-directed local therapies for hepatic oligometastasis from CRC (HOCRC) are widely used. Surgical resection is the first line of metastatic-directed local therapy for HOCRC, but its eligibility is very limited. Alternatively, RFA can be applied to patients who are ineligible for surgical resection of liver metastasis. However, there are some limitations such as inferior local control (LC) compared with surgical resection and technical feasibility based on location, size, and visibility on ultrasonography of the liver metastasis. Recent advances in radiation therapy technology have led to an increase in the use of SABR for liver tumors. SABR is considered complementary to RFA for patients with HOCRC who are ineligible for RFA. Furthermore, SABR can potentially result in better LC for liver metastases > 2-3 cm compared with RFA. In this article, the previous studies regarding curative metastasis-directed local therapies for HOCRC based on the radiation oncologist's and surgeon's perspective are reviewed and discussed. In addition, future perspectives regarding SABR in the treatment of HOCRC are suggested.

The Impact of KRAS Status on the Required Surgical Margin Width for Colorectal Liver Metastasis Resection

Local recurrence after colorectal liver metastasis (CRLM) resection severely affects survival; however, the required surgical margin width remains controversial. This study investigated the impact of KRAS status on surgical margin width and local recurrence rate (LRR) post-CRLM resection. Overall, 146 resected CRLMs with KRAS status (wild-type KRAS (wtKRAS): 98, KRAS mutant (mKRAS): 48) were included. The LRR for each group, R1 (margin positive) and R0 (margin negative), was analyzed by KRAS status. R0 was further stratified into Ra (margin ≥ 5 mm) and Rb (margin < 5 mm). Patients with local recurrence had significantly worse 5-year overall survival than those without local recurrence (p = 0.0036). The mKRAS LRR was significantly higher than wtKRAS LRR (p = 0.0145). R1 resection resulted in significantly higher LRRs than R0 resection for both wtKRAS and mKRAS (p = 0.0068 and p = 0.0204, respectively), and while no significant difference was observed in the Ra and Rb LRR with wtKRAS, the Rb LRR with mKRAS (33.3%) was significantly higher than Ra LRR (5.9%) (p = 0.0289). Thus, R0 resection is sufficient for CRLM with wtKRAS; however, CRLM with mKRAS requires resection with a margin of at least 5 mm to prevent local recurrence.

Real-world treatment and outcomes of patients with metastatic BRAF mutant colorectal cancer.

BRAF mutation occurs in 5%-10% of metastatic colorectal cancers (mCRCs). Patients with BRAF mutant mCRC exhibit a specific metastatic pattern and poor prognosis. Survival outcomes are heterogeneous in cases of mCRC with a BRAF mutation. The optimal first-line therapy is still controversial. We retrospectively reviewed the medical records of patients with mCRC between June 2010 and December 2021. Clinicopathologic characteristics, treatment and BRAF mutation testing results were collected. Patients with a BRAF mutation were included. Kaplan-Meier methods and log-rank tests were used to analyze and compare survival. Cox proportional hazards regression was used to establish the predictive nomogram model. Of the 4475 mCRC, 261 have a BRAF mutation, including 240 V600E and 21 non-V600E mutants. The median overall survival (OS) was 18.2months in the BRAF V600E mutant group versus 38.0months in the non-V600E mutant group (p=0.022). ECOG score, tumor differentiation, liver metastasis, bone metastasis and primary tumor resection were independent prognostic factors for the OS of BRAF V600E mutant mCRC. A nomogram model was established using these factors. The median OS was 39.3m, 18.2m and 10.7m for the low-risk, intermediate-risk and high-risk groups defined by this model, respectively (p < 0.0001). Patients who received first-line triplet chemotherapy ± bevacizumab had comparable progression free survival (PFS) and OS compared with those treated with doublets ± bevacizumab. BRAF V600E mutant mCRCs exhibit unfavorable and heterogeneous prognosis. The first-line intensive chemotherapy did not confer a marked impact on the PFS and OS.

Conditional Survival After Hepatectomy for Colorectal Liver Metastasis: Results from the Colorectal Liver Operative Metastasis International Collaborative (COLOMIC).

Complete resection of colorectal liver metastasis (CLM) improves long-term survival in colorectal cancer. However, there is limited recent data on conditional survival (CS) as postoperative survival milestones are achieved post-hepatectomy. A retrospective analysis was performed on the penta-institutional Colorectal Liver Operative Metastasis International Collaborative (COLOMIC), with 906 consecutive CLM hepatectomy cases. CS was calculated using Bayes' theorem and Kaplan-Meier analysis. Additional CS analyses were performed on additional clinicopathologic risk factors, including colon cancer laterality, KRAS mutation status, and extrahepatic disease. The 5-year CS was 40.6%, 45.3%, 52.8%, and 65.3% at 0, 1, 2, and 3 years postoperatively, with significant improvements each year (p < 0.005). CS was not significantly different between right-sided and left-sided colorectal cancers by 3 years postoperatively. Patients with KRAS mutations had worse CS at all timepoints (p < 0.001). Extrahepatic disease was a poor prognostic factor for OS and CS (p < 0.001). However, CS for patients with KRAS mutations or extrahepatic disease improved significantly as 2-year, postoperative survival was achieved (p < 0.05). Five-year CS after hepatectomy for CLM improved with each passing year of survival postoperatively. Although extrahepatic disease and KRAS mutations are poor prognostic factors for OS, these populations still had improved CS after 2 years postoperatively.

Abstract P6-14-06: Histopathological and immune characterization of liver metastases from patients with breast cancer

Abstract Background: Liver metastases (LM) are ultimately present in ~50% of all patients with metastatic breast cancer (BC). Metastatic seeding to the liver relies on the interaction between cancer cells and the host microenvironment, resulting into two main histopathological growth patterns (HGPs): the replacement HGP (metastasis mimics the liver architecture and exploits liver vasculature) and the desmoplastic HGP (presence of a fibrotic rim separating the hepatocytes from the tumor cells). While the prognostic value of these HGPs is established for colorectal cancer, with the desmoplastic HGP being associated with better prognosis, investigation is needed for BC. It has also been reported that patients with LM have a poorer response to immune checkpoints inhibitors. A systematic evaluation of the HGP and LM-associated immune infiltrates (stromal tumor infiltrating lymphocytes, sTIL) is currently lacking. In this study, we aimed at: (i) investigating HGPs and sTIL in LM from patients with BC, and, (ii) evaluating the association of these HGPs and sTIL with standard variables and outcome. Patients and methods: The study currently includes clinical data and samples from: 1) a retrospective cohort of 122 patients from 7 hospitals with surgically resected LMs (represented by 548 hematoxylin and eosin (H&amp;E)-sections), further referred to as ‘surgical cohort’ and, 2) LMs from 2 institutional post-mortem tissue donation studies for a total of 23 patients (97 H&amp;E-sections). All available H&amp;E-sections were used to assess HGP and sTIL. HGPs were scored according to a standardized method (PMIDs: 35650276) and categorized per patient as pure-replacement (rHGP, i.e. 100% of the tumor-liver interface is replacement) or any-desmoplastic (dHGP, i.e. at least 1% of the tumor-liver interface is desmoplastic). sTIL are expressed as the percentage of stromal area covered by mononuclear immune cells at the metastasis-liver interface. Associations were assessed using Fisher exact and Wilcoxon tests. Univariable and multivariable Cox regression analyses stratified by center were used to evaluate the role of HGP on progression-free (PFS) and overall survival (OS). Results: In the surgical cohort, 54 (44%) of patients displayed a rHGP and 68 (56%) a dHGP. Intra-patient, meaning inter-slide, heterogeneity of the HGP was observed in 24/122 (20%) of the patients suggesting that scoring multiple slides is needed for accurate assessment of the HGPs. We did not find any statistically significant association between HGP and clinico-pathological data. Higher sTIL were associated with dHGP (p=.003), as well as with a higher histological grade (p= .087), estrogen receptor-positivity (p=0.062) and ductal histology (p= .08) of the primary tumor. rHGP was associated with worse PFS and OS, both at the univariable and multivariable level (Table). In the post-mortem cohort, we observed a higher frequency of rHGP patients (19/23 patients, 83 %) and significantly lower levels of sTIL in the rHGP patients as compared to the rHGP patients from the surgical cohort (p= .009). Conclusion: This study represents the largest study evaluating HGPs and immune infiltrates of LMs from patients with BC. Approximately half of the surgically resected LMs have a dHGP, which is associated with higher sTIL and a better prognosis. The results from the LMs from the post-mortem cohort suggest that a more advanced stage of the disease is associated with an increase in rHGP and with a more immunosuppressed environment. Table 1: Univariable and multivariable analyses Citation Format: Sophia Leduc, Maxim De Schepper, Peter Vermeulen, Giuseppe Floris, Elia Biganzoli, Vincent Donckier, Ali Bohlok, Marco Gerling, François Richard, Marion Maetens, Joris Jaekers, Baki Topal, Emily Latacz, Karen Van Baelen, Tatjana Geukens, Ha Linh Nguyen, Luc Dirix, Denis Larsimont, Sophie Van Kerckhove, Rui Caetano Oliveira, Janina Kulka, Valerio Lucidi, Yannick Meyer, Cornelis Verhoef, Eva Santos, Ferenc Salamon, Lilla Madaras, A. Marcell Szasz, Székely Borbála, Kristòf Dede, Jennie Engstrand, Carlos Fernandez Moro, Christine Desmedt. Histopathological and immune characterization of liver metastases from patients with breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-06.

Circulating Tumor DNA as a Prognostic Factor in Patients With Resectable Hepatic Metastases of Uveal Melanoma.

We report here the results of a prospective study of circulating tumor DNA (ctDNA) detection in patients undergoing uveal melanoma (UM) liver metastases resection (NCT02849145). In UM patients, the liver is the most common and often only site of metastases. Local treatments of liver metastases, such as surgical resection, have a likely benefit in selected patients. Upon enrollment, metastatic UM patients eligible for curative liver surgery had plasma samples collected before and after surgery. GNAQ / GNA11 mutations were identified in archived tumor tissue and used to quantify ctDNA by droplet digital polymerase chain reaction which was then associated with the patient's surgical outcomes. Forty-seven patients were included. Liver surgery was associated with a major increase of cell-free circulating DNA levels, with a peak 2 days after surgery (∼20-fold). Among 40 evaluable patients, 14 (35%) had detectable ctDNA before surgery, with a median allelic frequency of 1.1%. These patients experienced statistically shorter relapse-free survival (RFS) versus patients with no detectable ctDNA before surgery (median RFS: 5.5 vs 12.2 months; hazard ratio=2.23, 95% CI: 1.06-4.69, P =0.04), and had a numerically shorter overall survival (OS) (median OS: 27.0 vs 42.3 months). ctDNA positivity at postsurgery time points was also associated with RFS and OS. This study is the first to report ctDNA detection rate and prognostic impact in UM patients eligible for surgical resection of their liver metastases. If confirmed by further studies in this setting, this noninvasive biomarker could inform treatment decisions in UM patients with liver metastases.

Association of Variation in US County-Level Rates of Liver Surgical Resection for Colorectal Liver Metastasis With Poverty Rates in 2010

Among patients with colorectal liver metastasis (CRLM) who are eligible for curative-intent liver surgical resection, only half undergo liver metastasectomy. It is currently unclear how rates of liver metastasectomy vary geographically in the US. Geographic differences in county-level socioeconomic characteristics may, in part, explain variability in the receipt of liver metastasectomy for CRLM. To describe county-level variation in the receipt of liver metastasectomy for CRLM in the US and its association with poverty rates. This ecological, cross-sectional, and county-level analysis was conducted using data from the Surveillance, Epidemiology, and End Results Research Plus database. The study included the county-level proportion of patients who had colorectal adenocarcinoma diagnosed between January 1, 2010, and December 31, 2018, underwent primary surgical resection, and had liver metastasis without extrahepatic metastasis. The county-level proportion of patients with stage I colorectal cancer (CRC) was used as a comparator. Data analysis was performed on March 2, 2022. County-level poverty in 2010 obtained from the US Census (proportion of county population below the federal poverty level). The primary outcome was county-level odds of liver metastasectomy for CRLM. The comparator outcome was county-level odds of surgical resection for stage I CRC. Multivariable binomial logistic regression accounting for clustering of outcomes within a county via an overdispersion parameter was used to estimate the county-level odds of receiving a liver metastasectomy for CRLM associated with a 10% increase in poverty rate. In the 194 US counties included in this study, there were 11 348 patients. At the county level, the majority of the population was male (mean [SD], 56.9% [10.2%]), White (71.9% [20.0%]), and aged between 50 and 64 (38.1% [11.0%]) or 65 and 79 (33.6% [11.4%]) years. The adjusted odds of undergoing a liver metastasectomy was lower in counties with higher poverty in 2010 (per 10% increase; odds ratio, 0.82 [95% CI, 0.69-0.96]; P = .02). County-level poverty was not associated with receipt of surgery for stage I CRC. Despite the difference in rates of surgery (mean county-level rates were 0.24 for liver metastasectomy for CRLM and 0.75 for surgery for stage I CRC), the variance at the county-level for these 2 surgical procedures was similar (F370, 193 = 0.81; P = .08). The findings of this study suggest that higher poverty was associated with lower receipt of liver metastasectomy among US patients with CRLM. Surgery for a more common and less complex cancer comparator (ie, stage I CRC) was not observed to be associated with county-level poverty rates. However, county-level variation in surgical rates was similar for CRLM and stage I CRC. These findings further suggest that access to surgical care for complex gastrointestinal cancers such as CRLM may be partially influenced by where patients live.

Survival improvement for patients with metastatic colorectal cancer over twenty years

Over the past two decades of successive clinical trials in metastatic colorectal cancer (CRC), the median overall survival of both control and experimental arms has steadily improved. However, the incremental change in survival for metastatic CRC patients not treated on trial has not yet been quantified. We performed a retrospective review of 1420 patients with de novo metastatic CRC who received their primary treatment at the University of Texas M.D. Anderson Cancer Center (UTMDACC) from 2004 through 2019. Median OS was roughly stable for patients diagnosed between 2004 and 2012 (22.6 months) but since has steadily improved for those diagnosed in 2013 to 2015 (28.8 months), and 2016 to 2019 (32.4 months). Likewise, 5-year survival rate has increased from 15.7% for patients diagnosed from 2004 to 2006 to 26% for those diagnosed from 2013 to 2015. Notably, survival improved for patients with BRAFV600E mutant as well as microsatellite unstable (MSI-H) tumors. Multivariate regression analysis identified surgical resection of liver metastasis (HR = 0.26, 95% CI, 0.19–0.37), use of immunotherapy (HR = 0.44, 95% CI, 0.29–0.67) and use of third line chemotherapy (regorafenib or trifluridine/tipiracil, HR = 0.74, 95% CI, 0.58–0.95), but not year of diagnosis (HR = 0.99, 95% CI, 0.98–1), as associated with better survival, suggesting that increased use of these therapies are the drivers of the observed improvement in survival.

Outcomes and Patient Selection in Laparoscopic vs. Open Liver Resection for HCC and Colorectal Cancer Liver Metastasis.

Hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) are the two most common malignant tumors that require liver resection. While liver transplantation is the best treatment for HCC, organ shortages and high costs limit the availability of this option for many patients and make resection the mainstay of treatment. For patients with CRLM, surgical resection with negative margins is the only potentially curative option. Over the last two decades, laparoscopic liver resection (LLR) has been increasingly adopted for the resection of a variety of tumors and was found to have similar long-term outcomes compared to open liver resection (OLR) while offering the benefits of improved short-term outcomes. In this review, we discuss the current literature on the outcomes of LLR vs. OLR for patients with HCC and CRLM. Although the use of LLR for HCC and CRLM is increasing, it is not appropriate for all patients. We describe an approach to selecting patients best-suited for LLR. The four common difficulty-scoring systems for LLR are summarized. Additionally, we review the current evidence behind the emerging robotically assisted liver resection technology.

Clinical and survival characteristics of patients with BRAF-mutated metastatic colorectal cancer (mCRC) who receive metastases surgery in a Spanish cohort.

66 Background: Patients with mCRC harboring BRAF mutation have worse prognosis and poor outcomes. However, those who have resectable metastatic disease and undergo surgery may have better outcomes compared to those who do not. Differences in clinical characteristics are not well known and may be critical to identify patients with better prognosis. Methods: We performed a retrospective analysis of 299 patients with mCRC in a tumor registry from 2015 to 2021. We compared the clinical characteristics and survival trends of both cohorts (BRAF mutated and BRAF wild type). Furthermore, we analyzed clinical and survival features of 23 patients with BRAF mutated mCRC who received metastases resection. Results: We identified 34 patients with BRAF mutation (11.37%). Several characteristics were significantly more frequent in this group: age &lt;65 years (n = 24, OR 1.38, p = 0.03), female sex (n = 24, OR 1.74, p = 0.008), primary tumor in the right colon (n = 15, OR 1.93, p = 0.003), peritoneal carcinomatosis (n = 18, OR 2.29, p = 0.007) and increased CA19.9 levels at diagnosis (n = 18, OR 1.79, p = 0.003). They received more peritoneal surgery (n = 12, OR 4.27, p = 0.000) and less liver metastases resection (n = 7, OR 0.51, p = 0.011). Median PFS in the first line of treatment was shorter in patients with BRAF mutation (9.5 vs 12.6 months; HR 1.69; IC 95%: 1.16 – 2.45; p = 0.006); however, we did not found differences in OS. Within the 23 patients with BRAF mutated mCRC who underwent surgery (67,64%), we found significant differences compared with those without metastases surgery: primary tumor resection (n = 21, OR 2.51, p = 0.0017) and having a single metastatic location (n = 18, OR 2.04, p = 0.01). Other features were more frequent in patients who underwent surgery but did not reach statistical significance: right colon location (63.6% vs 37.5%), metachronic disease (47.8% vs 18.2%), normal CEA (50% vs 25%) and CA19.9 (45% vs 12%) at diagnosis, and receiving 3 or more lines of systemic treatment (57% vs 22%). Median PFS after metastasectomy was 14.9 months, but we found no differences between both groups. Conclusions: In our cohort, BRAF mutated mCRC patients were more frequently younger, women, had right-sided primary tumors, higher rates of peritoneal metastases and abnormal CA19.9 levels at diagnosis, including worse outcomes in terms of PFS. On the other hand, resection of the primary tumor and single metastatic location were associated with higher probability of having metastases surgery, although in this study no subsequent survival benefit was found, probably due to the small number of BRAF mutated patients analyzed.

Extended criteria liver resection: Can noncurative intent resection of colorectal liver metastasis improve survival?

164 Background: From initially believed to be a palliative diagnosis, CRLM management has ranged from nonoperative, resection of only solitary lesions, resection only if 1 cm margin could be obtained, to major hepatectomies with liver regenerative procedures. With a greater understanding of the disease and advances in systemic therapy, clinicians have been able to continuously push the envelope in both resection and local therapies to improve overall survival in patients with CRLM. The constant evolution of management for CRLM raises the question – would patients benefit from a non-curative intent resection by decreasing overall tumor burden? Is there a role for debulking of disease as an extended criterion to improve median survival? Methods: A retrospective study was conducted by identifying patients who consented to participate in the liver disease biobank research program. Consented patients with CRLM evaluated for a two-stage hepatectomy (TSH) between 2012-2020 were identified. Patients were divided into three groups: those that successfully completed TSH, those that underwent the first stage only of the TSH (surgical debulking + best chemotherapy +/- local ablative therapy), and those that were not resected (best chemotherapy +/- local ablative therapy). Patients that underwent successful completion of TSH were excluded from analysis. Kaplan Meier survival curves and log-rank test were performed to assess the median survival between the surgical debulking + best chemotherapy +/- local ablative therapy and best chemotherapy +/- local ablative therapy groups. Results: Of the 114 patients identified, 47 patients underwent successful completion of TSH, 35 patients underwent the first stage only of the TSH, and 32 patients were eventually deemed unresectable. Reasons for unresectability included intraoperative findings (n = 14), progression of disease on best chemotherapy (n = 8), unresectable extrahepatic disease, local recurrence of primary, or unfit for surgery. Patients who underwent first stage of the TSH and those that were not resected both received best chemotherapy with/without local ablative therapies. 32 of the 35 patients in the surgical debulking + best chemotherapy +/- local ablative therapy group and 27 of 32 patients in the best chemotherapy +/- local ablative therapy group presented with synchronous disease. Tumor volume resected ranged from 5% - 95%. Median survial of the surgical debulking + best chemotherapy +/- local ablative therapy group was 31 months vs 20 months in the best chemotherapy +/- local ablative therapy group (p = 0.029). Conclusions: Patients undergoing incomplete resection of CRLM demonstrated a survival benefit compared to patients who did not undergo any surgical resection. This suggests there may be a potential systemic benefit to reducing overall tumor burden. This preliminary study provides the framework to further explore the systemic effects of surgical debulking of CRLM to improve median survival as an extended criterion for non-curative intent liver resection.

Effect of dynamic circulating tumor DNA minimal residual disease detection on recurrence surveillance and second resection rate after curative intent resection of colorectal liver metastasis: A prospective cohort study.

242 Background: Recurrence rates after curative intent resection of colorectal cancer liver metastases (CRLM) are nearly 50%. Standard of care surveillance includes intensive computed tomographic (CT) imaging and CEA measurements. However, recurrence detection often happens too late to resume a second resection. Previous studies have shown that circulating tumor DNA (ctDNA) detection, as a biomarker of minimal residual disease (MRD), is a robust prognostic factor for patients with colorectal cancers. Here, we performed a prospective study to explore the potential use for improving postoperative CRLM surveillance by dynamic ctDNA detection and its impact on the second resection of recurrent patients. Methods: Enrolled patients received curative intent resection of CRLM and were confirmed at the status of no evidence of disease (NED) by CT about one month after surgery. All patients received stand-of-care postoperative surveillance and serial plasma samples were collected, including presurgical and postsurgical samples (4-6 weeks after surgery) and every 3rd month until relapse or up to 24 months after resection. A personalized tumor-informed assay (Signatera/HuaJianwei bespoke multiplex-PCR NGS) was used to quantify ctDNA in plasma samples. Results: A total of 318 plasma samples from 60 patients recruited from July 2020 to July 2021 were included in our analysis. Twenty-five (41.6%) patients received neoadjuvant chemotherapy, and 46 patients (76.7%) received adjuvant chemotherapy after surgery. The median follow-up time was 18.0 months (range, 7.5 to 25.3 months). ctDNA was detectable in 58/60 (96.7%) patients before surgery, in 35/60 (58.3%) patients after surgery, and in 23/58 (39.7%) patients at the end of treatment (EOT). Patients with ctDNA/MRD positive status post-surgery or EOT experienced a significant shorter recurrence-free survival (RFS) than patients with negative ctDNA/MRD [hazard ratio (HR) 4.2; P &lt; 0.001 and HR 9.8; P &lt; 0.001]. The recurrence rate in MRD-positive patients (aka. positive predictive value, PPV) was 91.4% (32/35) at post-surgery and 91.3% (21/23) at EOT, respectively. In 93.0% of postoperative MRD-positive patients, ctDNA detected early relapse with a lead time up to 9.0 months (median 3.4 months) compared with standard radiological imaging. Among 40 patients with recurrence, the total secondary resection rate was 52.5% (21/40) with 40% (21/40) cases reached secondary NED. While among 24 recurrent cases with only liver metastases, the secondary resection rate was 66.7% (16/24) with 58.3% (14/24) cases reached secondary NED. Conclusions: Postoperative ctDNA status is strongly associated with shorter RFS. Serial ctDNA monitoring assists early detection of relapse, and therefore, improves patient outcomes by secondary resection. Clinical trial information: ChiCTR2000035677 .

Distinct role of tumor-infiltrating lymphocytes between synchronous and metachronous colorectal cancer.

Tumor-infiltrating lymphocytes (TILs) may influence the prognosis of colorectal liver metastasis (CRLM). We assessed the prognostic value of evaluating TILs in the primary and metastatic sites of synchronous CRLM as well as metachronous CRLM. We examined 90 patients who underwent curative primary and liver metastasis resection for colorectal cancer. CD8+ TILs (cytotoxic T cells) or CD45RO+ TILs (memory T cells) in both primary and metastatic sites were simultaneously evaluated by immunohistochemistry. Fifty-one patients had synchronous CRLM, and 39 patients had metachronous CRLM. In synchronous cases, the overall survival (OS) was significantly worse in patients with low CD8+ or CD45RO+ TILs in a metastatic site than in those with high CD8+ or CD45RO+ TILs (P = 0.017 and P = 0.005, respectively). Multivariate analysis showed that age ≥ 65years (P = 0.043), maximum tumor size ≥ 30mm (P = 0.003), primary N2-3 (P = 0.019), and low CD8+ TILs in metastatic site (P = 0.046) were independent poor prognostic factors. In contrast, in metachronous cases, OS was significantly worse in patients with low CD45RO+ TILs in a primary site than in those with high CD45RO+ TILs (P = 0.021). CD45RO+ TILs in a primary site (P = 0.044) were determined to be independent prognostic factor on multivariate analysis. The immune microenvironment between synchronous and metachronous CRLM might be different, and these differences may affect its prognosis.

Long-term oncological outcomes for HALS/Hybrid vs pure laparoscopic approach in colorectal liver metastases: a propensity score matched analysis.

Studies comparing hand-assisted laparoscopic (HALS)/Hybrid and pure laparoscopic (PLS) resection for colorectal cancer liver metastasis have focused on short-term results, while long-term oncological outcomes remain understudied. We established a multi-institutional retrospective cohort study from four centers with experience in minimally invasive surgery between 2004 and 2020. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Other endpoints analyzed were intraoperative and postoperative outcomes. Propensity score matching (PSM) was used to minimize baseline differences. A total of 219 HALS/Hybrid (57.8%) and 160 PLS (42.2%) patients were included. After PSM, 155 patients remained in each group. Operative time (182 vs. 248min, p = 0.012), use of intraoperative ablation (12.3 vs. 4.5%, p = 0.024), positive resection margin (4.5 vs 13.2%, p = 0.012), and pringle time (21 vs. 37min, p = 0.001) were higher in PLS group. DFS at 1, 3, 5, and 7years in HALS/Hybrid and PLS groups were 65.4%, 39.3%, 37.5%, and 36.3% vs. 64.9%, 38.0%, 33.1%, and 33.1%, respectively (p = 0.84). OS at 1, 3, 5, and 7years in HALS/Hybrid and PLS groups were 94.5%, 71.4%, 54.3%, and 46.0% vs. 96.0%, 68.5%, 51.2%, and 41.2%, respectively (p = 0.73). Our study suggests no differences in long-term oncologic outcomes between the two techniques. We discovered that longer total operative, pringle time, higher rates of intraoperative ablation, and positive resection margins were associated with PLS. These differences in favor of HALS/Hybrid could be due to a shorter learning curve and a greater ability to control hemorrhage.

Survival nomograms for simultaneous resection of primary and hepatic lesions without neoadjuvant chemotherapy in patients with resectable colorectal liver metastasis.

No well-performing nomogram has been developed specifically to predict individual-patient cancer-specific survival (CSS) and overall survival (OS) among patients with resectable colorectal liver metastasis (CRLM) who undergo simultaneous resection of primary and hepatic lesions without neoadjuvant chemotherapy (NAC). We aim to investigate the prognosis of patients with resectable CRLM undergoing simultaneous resection of primary and hepatic lesions without NAC. Data of patients with CRLM in the Surveillance, Epidemiology and End Results Program (cohort, n = 225) were collected as the training set, and data of patients with CRLM treated at the National Cancer Center (cohort, n = 180) were collected as the validation set. The prognostic value of the clinicopathological parameters in the training cohort was assessed using Kaplan‒Meier curves and univariate and multivariate Cox proportional hazards models, and OS and CSS nomograms integrated with the prognostic variables were constructed. Calibration analyses, receiver operating characteristic (ROC) curves, and decision curve analyses (DCAs) were then performed to evaluate the performance of the nomograms. There was no collinearity among the collected variables. Three factors were associated with OS and CSS: the pretreatment carcinoembryonic antigen (CEA) concentration, pathologic N (pN) stage, and adjuvant chemotherapy (each p < 0.05). OSand CSS nomograms were constructed using these three parameters. The calibration plots revealed favorable agreement between the predicted and observed outcomes. The areas under the ROC curves were approximately 0.7. The DCA plots revealed that both nomograms had satisfactory clinical benefits. The ROC curves and DCAs also confirmed that the nomogram surpassed the tumor, node, and metastasis staging system. The herein-described nomograms containing the pretreatment CEA concentration, pN stage, and adjuvant chemotherapy may be effective models for predicting postoperative survival in patients with CRLM.