Recurrent Colorectal Liver Metastases Research Articles

Renin-Angiotensin Inhibitor, Captopril, Attenuates Growth of Patient-Derived Colorectal Liver Metastasis Organoids.

The recurrence of colorectal liver metastasis (CRLM) following liver resection is common; approximately 40% of patients will experience tumor recurrence post-surgery. Renin-angiotensin inhibitors (RASis) have been shown to attenuate the growth and progression of CRLM in pre-clinical models following liver resection. This study examined the efficacy of the RASi captopril on patient-derived colorectal liver metastasis organoids. Patient-derived organoids (PDOs) were established using fresh samples of colorectal liver metastasis from appropriately consented patients undergoing liver resection. To mimic the regenerating liver post-CRLM liver resection, PDOs were cultured under hepatocyte regeneration conditions in vitro. CRLM PDOs were established from three patients' parent tissue. CRLM PDOs and parent tissue expressed markers of colorectal cancer, CDX2 and CK20, consistently. Furthermore, CRLM PDOs treated with captopril showed a dose dependent reduction in their expansion in vitro. In conclusion, CRLM PDOs recapitulate in vivo disease and displayed a dose-dependent response to treatment with captopril. RASis may be an additional viable treatment for patients with CRLM.

Predictive nomograms of repeat intrahepatic recurrence and overall survival after radiofrequency ablation of recurrent colorectal liver metastases

Objectives This study was conducted to develop nomograms for predicting repeat intrahepatic recurrence (rIHR) and overall survival (OS), after radiofrequency ablation (RFA), treatment in patients with recurrent colorectal liver metastases (CLMs) after hepatectomy based on clinicopathologic features. Methods A total of 160 consecutive patients with recurrent CLMs after hepatectomy who were treated with ultrasound-guided percutaneous RFA from 2012 to 2022 were retrospectively included. Patients were randomly divided into a training cohort and a validation cohort, with a ratio of 8:2. Potential prognostic factors associated with rIHR and OS, after RFA, were identified by using the competing-risks and Cox proportional hazard models, respectively, and were used to construct the nomogram. The nomogram was evaluated by Harrell’s C-index and a calibration curve. Results The 1-, 2-, and 3-year rIHR rates after RFA were 58.8%, 70.2%, and 74.2%, respectively. The 1-, 3- and 5-year OS rates were 96.3%, 60.4%, and 38.5%, respectively. In the multivariate analysis, mutant RAS, interval from hepatectomy to intrahepatic recurrence ≤ 12 months, CEA level >5 ng/ml, and ablation margin <5 mm were the independent predictive factors for rIHR. Mutant RAS, largest CLM at hepatectomy >3 cm, CEA level >5 ng/ml, and extrahepatic disease were independent predictors of poor OS. Two nomograms for rIHR and OS were constructed using the respective significant variables. In both cohorts, the nomogram demonstrated good discrimination and calibration. Conclusions The established nomograms can predict individual risk of rIHR and OS after RFA for recurrent CLMs and contribute to improving individualized management.

Redo surgery for recurrent colorectal liver metastasis: does the robot extend the boundaries of minimally invasive surgery?

Redo surgery for recurrent colorectal liver metastasis: does the robot extend the boundaries of minimally invasive surgery?

CT-based radiomics analysis to predict local progression of recurrent colorectal liver metastases after microwave ablation

The objective of this study is to establish and validate a radiomics nomogram for prediction of local tumor progression (LTP) after microwave ablation (MWA) for recurrent colorectal liver metastases (CRLM) after hepatic resection. We included 318 consecutive recurrent CRLM patients (216 of training while 102 of validation cohort) with contrast-enhanced computerized tomography images treated with MWA between January 2014 and October 2018. Support vector machine-generated radiomics signature was incorporated together with clinical information to establish a radiomics nomogram. Our constructed radiomics signature including 15 features (first-order intensity statistics features, shape and size-based features, gray level size zone/dependence matrix features) performed well in assessing LTP for both cohorts. With regard to its predictive performance, its C-index was 0.912, compared to the clinical or radiomics models only (c-statistic 0.89 and 0.75, respectively) in the training cohort. In the validation cohort, the radiomics nomogram had better performance (area under the curve = 0.89) compared to the radiomics and clinical models (0.85 and 0.69). According to decision curve analysis, our as-constructed radiomics nomogram showed high clinical utility. As revealed by survival analysis, LTP showed worse progression-free survival (3-year progression-free survival 42.6% vs 78.4%, P &lt; .01). High-risk patients identified using this radiomics signature exhibited worse LTP compared with low-risk patients (3-year LTP 80.2% vs 48.6%, P &lt; .01). A radiomics-based nomogram of pre-ablation computerized tomography imaging may be the precious biomarker model for predicting LTP and personalized risk stratification for recurrent CRLM after hepatic resection treated by MWA.

MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial

Guidelines are inconclusive on whether contrast-enhanced MRI using gadoxetic acid and diffusion-weighted imaging should be added routinely to CT in the investigation of patients with colorectal liver metastases who are scheduled for curative liver resection or thermal ablation, or both. Although contrast-enhanced MRI is reportedly superior than contrast-enhanced CT in the detection and characterisation of colorectal liver metastases, its effect on clinical patient management is unknown. We aimed to assess the clinical effect of an additional liver contrast-enhanced MRI on local treatment plan in patients with colorectal liver metastases amenable to local treatment, based on contrast-enhanced CT. We did an international, multicentre, prospective, incremental diagnostic accuracy trial in 14 liver surgery centres in the Netherlands, Belgium, Norway, and Italy. Participants were aged 18 years or older with histological proof of colorectal cancer, a WHO performance status score of 0-4, and primary or recurrent colorectal liver metastases, who were scheduled for local therapy based on contrast-enhanced CT. All patients had contrast-enhanced CT and liver contrast-enhanced MRI including diffusion-weighted imaging and gadoxetic acid as a contrast agent before undergoing local therapy. The primary outcome was change in the local clinical treatment plan (decided by the individual clinics) on the basis of liver contrast-enhanced MRI findings, analysed in the intention-to-image population. The minimal clinically important difference in the proportion of patients who would have change in their local treatment plan due to an additional liver contrast-enhanced MRI was 10%. This study is closed and registered in the Netherlands Trial Register, NL8039. Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26-36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5-24·0]). Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging. The Dutch Cancer Society and Bayer AG - Pharmaceuticals.

Recurrent Colorectal Liver Metastases: Upfront Local Treatment versus Neoadjuvant Systemic Therapy Followed by Local Treatment (COLLISION RELAPSE): Study Protocol of a Phase III Prospective Randomized Controlled Trial

PurposeThe objective of the COLLISION RELAPSE trial is to prove or disprove superiority of neoadjuvant systemic therapy followed by repeat local treatment (either thermal ablation and/or surgical resection), compared to repeat local treatment alone, in patients with at least one recurrent locally treatable CRLM within one year and no extrahepatic disease.MethodsA total of 360 patients will be included in this phase III, multicentre randomized controlled trial. The primary endpoint is overall survival. Secondary endpoints are distant progression-free survival, local tumour progression-free survival analysed per patient and per tumour, systemic therapy-related toxicity, procedural morbidity and mortality, length of hospital stay, pain assessment and quality of life, cost-effectiveness ratio and quality-adjusted life years.DiscussionIf the addition of neoadjuvant systemic therapy to repeat local treatment of CRLM proves to be superior compared to repeat local treatment alone, this may lead to a prolonged life expectancy and increased disease-free survival at the cost of possible systemic therapy-related side effects.Level of EvidenceLevel 1, phase III randomized controlled trial.Trial RegistrationNCT05861505. May 17, 2023.Graphical

112P Optimal classification and treatment strategy based on technical and oncological futures in recurrence of colorectal liver metastases

112P Optimal classification and treatment strategy based on technical and oncological futures in recurrence of colorectal liver metastases

Value of prognostic scoring systems in the era of multimodal therapy for recurrent colorectal liver metastases

BackgroundVarious predictive scoring systems have been developed to estimate outcomes of patients undergoing surgery for colorectal liver metastases (CRLM). However, data regarding their effectiveness in recurrent CRLM (recCRLM) are very limited. MethodsPatients who underwent repeat hepatectomy for recCRLM at the University Hospital RWTH Aachen, Germany from 2010 to 2021 were included. Nine predictive scoring systems (Fong's, Nordlinger, Nagashima, RAS mutation, Tumor Burden, GAME, CERR, and Glasgow Prognostic score, Basingstoke Index) were evaluated by likelihood ratio (LR) χ2, linear trend (LT) χ2 and Akaike Information Criterion (AIC) for their predictive value regarding overall survival (OS) and recurrence free survival (RFS). ResultsAmong 150 patients, median RFS was 9 (2–124) months with a 5-year RFS rate of 10%. Median OS was 39 (4–131) months with a 5-year OS rate of 32%. For RFS and OS, the Nagashima score showed the best prognostic ability (LT χ2 3.00, LR χ2 9.39, AIC 266.66 and LT χ2 2.91, LR χ2 20.91, 290.36). DiscussionThe Nagashima score showed the best prognostic stratification to predict recurrence as well as survival, and therefore might be considered when evaluating patients with recCRLM for repeat hepatectomy.

Locoregional treatment for colorectal liver metastases aiming for precision medicine.

In patients with colorectal liver metastases (CLM), surgery is potentially curative. The use of novel surgical techniques and complementary percutaneous ablation allows for curative-intent treatment even in marginally resectable cases. Resection is used as part of a multidisciplinary approach, which for nearly all patients will include perioperative chemotherapy. Small CLM can be treated with parenchymal-sparing hepatectomy (PSH) and/or ablation. For small CLM, PSH results in better survival and higher rates of resectability of recurrent CLM than non-PSH. For patients with extensive bilateral distribution of CLM, two-stage hepatectomy or fast-track two-stage hepatectomy is effective. Our increasing knowledge of genetic alterations allows us to use them as prognostic factors alongside traditional risk factors (e.g. tumor diameter and tumor number) to select patients with CLM for resection and guide surveillance after resection. Alteration in RAS family genes (hereafter referred to as "RAS alteration") is an important negative prognostic factor, as are alterations in the TP53, SMAD4, FBXW7, and BRAF genes. However, APC alteration appears to improve prognosis. RAS alteration, increased number and diameter of CLM, and primary lymph node metastasis are well-known risk factors for recurrence after CLM resection. In patients free of recurrence 2 y after CLM resection, only RAS alteration is associated with recurrence. Thus, surveillance intensity can be stratified by RAS alteration status after 2 y. Novel diagnostic instruments and tools, such as circulating tumor DNA, may lead to further evolution of patient selection, prognostication, and treatment algorithms for CLM.

The impact of recurrence timing and tumor burden score on overall survival among patients undergoing repeat hepatectomy for colorectal liver metastases.

Approximately 15% of patients experience a resectable intrahepatic recurrence after an index curative-intent hepatectomy for colorectal liver metastases (CRLM). We sought to investigate the impact of recurrence timing and tumor burden score (TBS) at the time of recurrence on overall survival among patients undergoing repeat hepatectomy. Patients with CRLM who experienced recurrent intrahepatic disease after initial hepatectomy between 2000 and 2020 were identified from an international multi-institutional database. The impact of time-TBS, defined as TBS divided by the time interval of recurrence, was assessed relative to overall survival. Among 220 patients, the median age was 60.9 years (interquartile range [IQR]: 53.0-69.0), and 144 (65.5%) patients were male. Most patients experienced multiple recurrences (n = 120, 54.5%) within 12 months after the initial hepatectomy (n = 139, 63.2%). The median tumor size of the recurrent CRLM was 2.2 cm (IQR: 1.5-3.0 cm) with a median TBS of 3.5 (2.3-4.9) at the time of recurrence. Overall, 121 (55.0%) patients underwent repeat hepatectomy, whereas 99 (45.0%) individuals were treated with systemic chemotherapy or other nonsurgical treatments; repeat hepatectomy was associated with better postrecurrence survival (PRS) (p < 0.001). Three-year PRS incrementally worsened (low time-TBS:71.7%, 95% confidence interval [CI], 57.9-88.8 vs. medium: 63.6%, 95%CI, 47.7-84.8 vs. high: 49.2%, 95%CI, 31.1-77.7, p = 0.02) as time-TBS values increased. Each unit increase in time-TBS score was independently associated with a 41% higher possibility of death (hazard ratio: 1.41; 95% CI, 1.04-1.90, p = 0.03). Time-TBS was associated with long-term outcomes after repeat hepatectomy for recurrent CRLM. Time-TBS may be an easy tool to help select patients who may benefit the most from repeat hepatic resection of recurrent CRLM.

Hepatectomy is associated with improved oncologic outcomes in recurrent colorectal liver metastases: A propensity-matched analysis

BackgroundFollowing resection of colorectal liver metastasis, most patients have disease recurrence, most commonly intrahepatic. Although the role of resection in colorectal liver metastasis is well-established, there have been limited investigations assessing the benefit of repeat hepatic resection compared with systemic treatment alone for intrahepatic recurrence. MethodsA retrospective single-institution cohort study of patients with recurrent colorectal liver metastasis following curative-intent hepatectomy was performed from 2003 to 2019. The oncologic outcomes, including post-recurrence overall survival, were evaluated using Kaplan-Meier and Cox proportional hazards modeling. Patients undergoing repeat hepatic resection were propensity-matched with patients receiving systemic treatment alone based on relevant clinicopathologic variables. ResultsThere were 338 patients treated with hepatic resection for colorectal liver metastasis over the study period. Liver recurrence was observed in 147 (43%) patients at a median time of 10 months from prior resection, with a median post-recurrence overall survival of 29 months. There were 37 patients managed with repeat hepatic resection; 33 (89%) received perioperative chemotherapy. On propensity matching, there were no significant clinicopathologic differences between 37 patients having repeat hepatic resection and 37 patients treated with systemic treatment alone. Repeat hepatic resection was independently associated with improved 5-year post-recurrence overall survival compared with systemic treatment alone (median overall survival 41 vs 35 months, 5-year overall survival 19% vs 3%, P = .048). ConclusionDisease characteristics of patients with intrahepatic recurrence of colorectal liver metastasis, specifically the number of liver lesions and size of the largest lesion, are most predictive of survival and response to systemic therapy. Patients who recur with oligometastatic liver disease experience improved outcomes and derive benefit from curative-intent repeat hepatic resection with integrated perioperative systemic therapy.

ASO Visual Abstract: Glissonian Approach During Robotic Mesohepatectomy for Recurrent Colorectal Liver Metastasis.

ASO Visual Abstract: Glissonian Approach During Robotic Mesohepatectomy for Recurrent Colorectal Liver Metastasis.

Glissonian Approach During Robotic Mesohepatectomy for Recurrent Colorectal Liver Metastasis.

Glissonian Approach During Robotic Mesohepatectomy for Recurrent Colorectal Liver Metastasis.

Limited Effect of Perioperative Systemic Therapy in Patients Selected for Repeat Local Treatment of Recurrent Colorectal Cancer Liver Metastases.

The aim of this study was to determine the potential benefit of perioperative systemic therapy on overall and progression-free survival after repeat local treatment in patients suffering from recurrent colorectal cancer liver metastasis (CRLM). The optimal treatment strategy in patients with recurrent CRLM needs to be clarified, in particular for those suffering from early recurrence of CRLM. In this multicenter observational cohort study, consecutive patients diagnosed with recurrent CRLM between 2009 and 2019 were retrospectively identified in 4 academic liver surgery centers. Disease-free interval after initial local treatment of CRLM was categorized into recurrence within 6, between 6 and 12, and after 12 months. Perioperative systemic therapy consisted of induction, (neo)adjuvant, or combined regimens. Overall and progression-free survival after repeat local treatment of CRLM were analyzed by multivariable Cox regression analyses, resulting in adjusted hazard ratios (aHRs). Out of 303 patients included for analysis, 90 patients received perioperative systemic therapy for recurrent CRLM. Favorable overall (aHR, 0.45; 95% confidence interval [CI], 0.26-0.75) and progression-free (aHR, 0.53; 95% CI, 0.35-0.78) survival were observed in patients with a disease-free interval of more than 12 months. No significant difference in overall and progression-free survival was observed in patients receiving perioperative systemic therapy at repeat local treatment of CRLM, stratified for disease-free interval, previous exposure to chemotherapy, and RAS mutation status. No benefit of perioperative systemic therapy was observed in overall and progression-free survival after repeat local treatment of recurrent CRLM.

Thermal Ablation Compared to Partial Hepatectomy for Recurrent Colorectal Liver Metastases: An Amsterdam Colorectal Liver Met Registry (AmCORE) Based Study

Background: Between 64 and 85% of patients with colorectal liver metastases (CRLM) develop distant intrahepatic recurrence after curative intent local treatment. The current standard of care for new CRLM is repeat local treatment, comprising partial hepatectomy and thermal ablation. Although relatively safe and feasible, repeat partial hepatectomy can be challenging due to adhesions and due to the reduced liver volume after surgery. This AmCORE based study assessed safety, efficacy and survival outcomes of repeat thermal ablation as compared to repeat partial hepatectomy in patients with recurrent CRLM.

Long Term Follow up Strategy for CRLM Following Liver Resection

Introduction: Liver resection for colorectal liver metastasis (CRLM) can be achieved with curative intent in 10 – 20% of these cases, and 5 year survival is approaching 50%. There is evidence that those patients who survive beyond 10 years are effectively cured of their disease. Currently there are no consensus guidelines regarding long term follow up for patients who have undergone liver resection for CRLM. Methods: We retrospectively analysed all patient undergoing at least one repeat liver resection for recurrent CRLM at our instution since 1997. We assessed time between resections as a marker of time to recurrence. Results: In total 279 patients underwent at least 2 liver resections for recurrent CRLM. Some patients went on to have third and fourth resections for recurrent CRLM. In total 279 patients underwent 348 resections. Median time to recurrence between resections was; 15.5 months (n=279) to second recurrence, 15.7 months to third recurrence (n=59), and 20.7 months to 4threcurrence (n=10). Overall 96.6 of patients recurred within 5 years. There were 12 (3.4%) patients who recurred after 5 years. Conclusion: This study demonstrates that the majority of recurrent CRLM occurs within the first 5 years following liver resection. There are a small proportion of patients that recur after 5 years that still have a potential benefit from surgery. We recommend that follow up for patients undergoing liver resection for CRLM should be for 10 years in selected patients, in particular those that are fit enough for consideration of further surgery

KRAS Mutation at Codon 12 Predicts Clinical Outcome in Repeat Hepatic Resection for Recurrent Colorectal Liver Metastases

Introduction: Repeat hepatic resection for recurrent colorectal liver metastasis (CRLM) has been shown to be associated with improved overall survival. Our aim was to elucidate the prognostic role of KRAS mutational status in predicting outcome in patients with CRLM undergoing repeat surgical resection after liver recurrence.

Ten Year Survival after Repeat Local Treatment for Colorectal Liver Metastases: A Multicenter Analysis

Introduction: Ten year overall survival (OS) after resection of colorectal liver metastases (CRLM) is reached in about 25% of patients. However, the majority of CRLM patients develop recurrent disease within the liver, for which repeat local treatment (i.e., resection and/or ablation) is frequently performed. This study investigated the probability of ten year OS after local treatment for recurrent CRLM.

Clinical Added Value of MRI to CT in Patients Scheduled for Local Therapy of Colorectal Liver Metastases (CAMINO): An International Multicenter Prospective Diagnostic Accuracy Study

Background: Computed Tomography(CT) is the standard imaging method in the diagnostic workup of patients with colorectal liver metastases(CRLM). Compared to CT, magnetic resonance imaging (MRI) is superior in detection and characterization of CRLM but its effect on patient management is unknown. The aim of this study is to evaluate whether MRI has sufficient clinical added value to be routinely added to CT in staging CRLM. Methods: An international multicenter prospective incremental diagnostic accuracy study in consecutive patients with primary or recurrent CRLM scheduled for curative liver resection or thermal ablation based on CT, recruited in centers across the Netherlands, Belgium, Norway, and Italy. All patients had CT and diffusion-weighted and gadoxetic-acid enhanced MRI prior to local therapy. Primary outcome is the proportion of clinically significant CRLM (CS-CRLM) detected by MRI, but not visible on CT, leading to a change in local treatment plan. The minimum incremental diagnostic accuracy of MRI for CS-CRLM was set at 10% of patients. Results: Patient recruitment was completed in July 2021 with 299 patients included from 15 centers. Data collection is currently ongoing and will be completed in January 2022 with the 6 months follow-up of the last patient included. Results will be available prior to IHBPA 2022. Conclusion: The CAMINO study will clarify the clinical added value of MRI to CT in patients with CRLM scheduled for local therapy. This study will provide evidence required for the implementation of MRI in the routine work-up of patients with primary and recurrent CRLM scheduled for local therapy.

Recurrent Colorectal Liver Metastases in the Liver Remnant After Major Liver Surgery\u2014IRE as a Salvage Local Treatment When Resection and Thermal Ablation are Unsuitable

PurposeTo examine the safety and short-term oncologic outcomes of computer-tomography-guided (CT-guided) irreversible electroporation (IRE) of recurrent, irresectable colorectal liver metastases (CRLM) after major hepatectomy deemed unsuitable for thermal ablation.Patients and MethodsTwenty-three patients undergoing CT-guided IRE of recurrent CRLM after major hepatectomy were included in this study. All tumors were located adjacent to sole remaining intrahepatic blood vessels and bile ducts, precluding thermal ablation. Patients underwent systematic clinical and imaging follow-up, including magnetic resonance imaging of the liver at 1-month and 3-month intervals thereafter. Time to local and intrahepatic tumor progression within 12 and 36 months and associated risk factors were assessed using Kaplan Meier and Cox regression analysis, respectively.ResultsComplete ablation with a safety margin of at least 0.5 cm was achieved in 22/23 (95.6%) patients. No vessel injury or thrombosis occurred. Five patients developed moderate biliary stenosis after a median of 4 weeks, without requiring treatment. Local tumor-progression-free rates within 12/36 months were 64%/57.4%, respectively. Intrahepatic-progression-free rate within 12/36 months was 36.4%/19.5%, respectively. Five (23%) patients were tumor-free at the end of follow-up. Multivariate Cox regression analysis did not show any association between local tumor-progression-free rates and patient age, target tumor size, primary tumor side or synchronicity of liver metastases.ConclusionIn this highly selected patient population with local recurrences of CRLM after major surgery, IRE was shown to be a safe salvage treatment option when thermal ablation is unsuitable.