• Chemotherapy response
• Colorectal liver metastasis
• Next-generation sequencing
• Treatment

• 82473383 National Natural Science Foundation of China
• CFH Beijing Capital's Funds for Health Improvement and Research
• No.2022-1-2151 Beijing Capital's Funds for Health Improvement and Research

• Colorectal cancer
• Extensive metastasis
• Oligometastasis
• Prediction model
• Risk factors

• Humans
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/surgery
• Male
• Female
• Neoplasm Metastasis
• Middle Aged
• Nomograms
• Risk Factors
• Aged
• Proportional Hazards Models
• Postoperative Period
• Prognosis

• Borderline resectable colorectal liver metastases
• Colorectal cancer
• Colorectal liver metastases
• Optimal treatment strategies
• Resectability in colorectal liver metastases

• Humans
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Liver Neoplasms/therapy
• Colorectal Neoplasms/pathology
• Hepatectomy/methods

• Metastatic colorectal cancer
• doublet chemotherapy
• epidermal growth factor receptor
• monoclonal antibody
• secondary surgery

• Chemotherapeutic regimens
• Colorectal cancer liver metastasis
• Multidisciplinary teams
• Neoadjuvant therapy
• Resectability criteria

• Humans
• Neoadjuvant Therapy
• Hepatectomy/adverse effects
• Colorectal Neoplasms/pathology
• Treatment Outcome
• Liver Neoplasms/drug therapy
• Liver Neoplasms/surgery

• Artificial Intelligence
• Cholangiocarcinoma
• Computed Tomography
• Deep Learning
• Diagnosis
• Hepatocellular carcinoma
• Liver metastases
• Machine Learning
• Magnetic resonance imaging
• Prognosis
• Radiomics
• Texture analysis

• Humans
• Radiomics
• Tomography, X-Ray Computed
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/pathology
• Radiography
• Magnetic Resonance Imaging

• Colorectal cancer liver metastases
• Nomogram
• Primary tumor resection
• Propensity score matching

• KJ2020A0171 University Natural Science Research Project of Anhui Province
• 2019KJ04 National Natural Science Foundation Training Program of The First Affiliated Hospital of Anhui Medical University

• colorectal liver metastases
• disease progression
• liver resection

• Colorectal liver metastases
• liver
• magnetic resonance diffusion
• pathology
• preoperative chemotherapy
• surgery

• Humans
• Colorectal Neoplasms/pathology
• Retrospective Studies
• Diffusion Magnetic Resonance Imaging/methods
• Prognosis
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/drug therapy
• Liver Neoplasms/surgery
• Treatment Outcome

• Adjuvant chemotherapy
• Colorectal cancer
• Hepatectomy
• Liver metastasis
• Second-line chemotherapy

The management of patients with liver metastases from colorectal cancer is still debated. Several therapeutic options and treatment strategies are available for an extremely heterogeneous clinical scenario. Adequate prediction of patients’ outcomes and of the effectiveness of chemotherapy and loco-regional treatments are crucial to reach a precision medicine approach. This has been an unmet need for a long time, but recent studies have opened new perspectives. New morphological biomarkers have been identified. The dynamic evaluation of the metastases across a time interval, with or without chemotherapy, provided a reliable assessment of the tumor biology. Genetics have been explored and, thanks to their strong association with prognosis, have the potential to drive treatment planning. The liver-tumor interface has been identified as one of the main determinants of tumor progression, and its components, in particular the immune infiltrate, are the focus of major research. Image mining and analyses provided new insights on tumor biology and are expected to have a relevant impact on clinical practice. Artificial intelligence is a further step forward. The present paper depicts the evolution of clinical decision-making for patients affected by colorectal liver metastases, facing modern biomarkers and innovative opportunities that will characterize the evolution of clinical research and practice in the next few years.

• Colorectal liver metastases
• Biomarkers
• Genetics
• Immune infiltrate
• Radiomics
• Artificial Intelligence

• Artificial Intelligence
• Biomarkers
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/therapy
• Humans
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/genetics
• Liver Neoplasms/therapy
• Precision Medicine/methods
• Utopias

• Colorectal Neoplasms/pathology
• Embolization, Therapeutic
• Hepatectomy
• Humans
• Liver
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Liver Transplantation
• Portal Vein/pathology

• Colorectal liver metastasis
• chemotherapy
• pathologic response
• predictive model

The liver-first approach in patients with synchronous colorectal liver metastases (CRLM) has gained wide consensus but its role is still to be clarified. We aimed to elucidate the outcome of the liver-first approach and to identify patients who benefit at most from this approach.

Patients with synchronous CRLM included in the LiverMetSurvey registry between 2000 and 2017 were considered. Three strategies were analyzed, i.e. liver-first approach, colorectal resection followed by liver resection (primary-first), and simultaneous resection, and three groups of patients were analyzed, i.e. solitary metastasis, multiple unilobar CRLM, and multiple bilobar CRLM. In each group, patients from the three strategy groups were matched by propensity score analysis.

Overall, 7360 patients were analyzed: 4415 primary-first, 552 liver-first, and 2393 simultaneous resections. Compared with the other groups, the liver-first group had more rectal tumors (58.0% vs. 31.2%) and higher hepatic tumor burden (more than three CRLMs: 34.8% vs. 24.0%; size > 50 mm: 35.6% vs. 22.8%; p < 0.001). In patients with solitary and multiple unilobar CRLM, survival was similar regardless of treatment strategy, whereas in patients with multiple bilobar metastases, the liver-first approach was an independent positive prognostic factor, both in unmatched patients (3-year survival 65.9% vs. primary-first 60.4%: hazard ratio [HR] 1.321, p = 0.031; vs. simultaneous resections 54.4%: HR 1.624, p < 0.001) and after propensity score matching (vs. primary-first: HR 1.667, p = 0.017; vs. simultaneous resections: HR 2.278, p = 0.003).

In patients with synchronous CRLM, the surgical strategy should be decided according to the hepatic tumor burden. In the presence of multiple bilobar CRLM, the liver-first approach is associated with longer survival than the alternative approaches and should be evaluated as standard.

The online version contains supplementary material available at 10.1245/s10434-021-10220-w.

• chemotherapy-associated liver injuries
• colorectal liver metastases
• diagnostic imaging
• liver surgery
• nodular regenerative hyperplasia
• radiomics
• sinusoidal dilatation
• steatohepatitis
• textural features
• virtual liver biopsy

• 2019-23822 Associazione Italiana per la Ricerca sul Cancro

• Colorectal liver metastases
• Percutaneous ablation
• Somatic gene mutations

• Biology
• Colorectal Neoplasms/surgery
• Colorectal Neoplasms/therapy
• Hepatectomy
• Humans
• Liver Neoplasms/surgery
• Liver Neoplasms/therapy
• Neoplasm Recurrence, Local
• Prognosis

Resection of colorectal cancer (CRC) metastases provides good survival but is probably underused in real-world practice.

A prospective Finnish nationwide study enrolled treatable metastatic CRC patients. The intervention was the assessment of resectability upfront and twice during first-line therapy by the multidisciplinary team (MDT) at Helsinki tertiary referral centre. The primary outcome was resection rates and survival.

In 2012–2018, 1086 patients were included. Median follow-up was 58 months. Multiple metastatic sites were present in 500 (46%) patients at baseline and in 820 (76%) during disease trajectory. In MDT assessments, 447 (41%) were classified as resectable, 310 (29%) upfront and 137 (18%) after conversion therapy. Six-hundred and ninety curative intent resections or local ablative therapies (LAT) were performed in 399 patients (89% of 447 resectable). Multiple metastasectomies for multisite or later developing metastases were performed in 148 (37%) patients. Overall, 414 liver, 112 lung, 57 peritoneal, and 107 other metastasectomies were performed. Median OS was 80·4 months in R0/1-resected (HR 0·15; CI_95% 0·12–0·19), 39·1 months in R2-resected/LAT (0·39; 0·29–0·53) patients, and 20·8 months in patients treated with “systemic therapy alone” (reference), with 5-year OS rates of 66%, 40%, and 6%, respectively.

Repeated centralized MDT assessment in real-world metastatic CRC patients generates high resectability (41%) and resection rates (37%) with impressive survival, even when multisite metastases are present or develop later.

The funders had no role in the study design, analysis, and interpretation of the data or writing of this report.

• Colorectal cancer
• Conversion
• Metastatic
• Multidisciplinary
• Multisite metastases
• Resectability
• Resection

The standard treatment of patients with hepatic and extrahepatic metastases from colorectal cancer is systemic chemotherapy. We assume that this therapy has the same effectiveness on all disease foci, independent of the involved organ. The effectiveness of chemotherapy is assessed by the pathological response rate: the higher the response rate, the higher the effectiveness of chemotherapy. In the present manuscript, we analyzed patients undergoing resection of hepatic and extrahepatic metastases from colorectal cancer after preoperative chemotherapy. We observed unexpected heterogeneity of the response to chemotherapy of distant metastases from colorectal cancer according to the involved organ. Peritoneal metastases had the highest pathological response rate, which was much higher than the hepatic metastases, while lung and lymph node metastases had extremely poor response rates. Such inhomogeneous effectiveness of systemic treatment in different organs open new perspectives in the treatment of colorectal cancer with distant metastases and oncological research.

Background: Systemic therapy is the standard treatment for patients with hepatic and extrahepatic colorectal metastases. It is assumed to have the same effectiveness on all disease foci, independent of the involved organ. The present study aims to compare the response rates of hepatic and extrahepatic metastases to systemic therapy. Methods: All consecutive patients undergoing simultaneous resection of hepatic and extrahepatic metastases from colorectal cancer after oxaliplatin- and/or irinotecan-based preoperative chemotherapy were analyzed. All specimens were reviewed. Pathological response to chemotherapy was classified according to tumor regression grade (TRG). Results: We analyzed 45 patients undergoing resection of 134 hepatic and 72 extrahepatic metastases. Lung and lymph node metastases had lower response rates to chemotherapy than liver metastases (TRG 4–5 95% and 100% vs. 67%, p = 0.008, and p = 0.006). Peritoneal metastases had a higher pathological response rate than liver metastases (TRG 1–3 66% vs. 33%, p < 0.001) and non-hepatic non-peritoneal metastases (3%, p < 0.001). Metastases site was an independent predictor of pathological response to systemic therapy. Conclusions: Response to chemotherapy of distant metastases from colorectal cancer varies in different organs. Systemic treatment is highly effective for peritoneal metastases, more so than liver metastases, while it has a very poor impact on lung and lymph node metastases.

• chemotherapy
• colorectal hepatic and extrahepatic metastases
• lung metastases
• lymph node metastases
• peritoneal metastases
• response to chemotherapy
• systemic therapy
• targeted therapies
• tumor regression grade

Purpose: Preoperative chemotherapy is widely used for colorectal liver metastasis (CRLM). Pathological complete response (PCR) after chemotherapy indicates complete tumor regression and an extremely favorable prognosis. This study aimed to explore the characteristics and long-term survival of CRLM patients with pCR, who underwent surgery after preoperative chemotherapy.

Methods: We retrospectively analyzed the clinical data of 494 CRLM patients who underwent hepatectomy after preoperative chemotherapy between January 2006 and January 2019. pCR was defined as the absence of any cancer cells on pathological examination.

Results: Thirty (6.07%) patients achieved pCR after preoperative chemotherapy; 70% patients who achieved pCR did not experience recurrence and were cured after hepatectomy. The long-term prognosis of patients with pCR was extremely favorable, with 10-year overall and disease-free survivals of 85.2% and 73.7%, respectively; these were significantly better than those of patients without pCR (31.3% and 15.2%, respectively). Liver metastases <3 cm, preoperative carcinoembryonic antigen level ≤20 ng/mL, primary T stage 1-2, and right-sided primary tumors were independent predictors for pCR.

Conclusion: pCR occurred in 6% of patients with CRLM after preoperative chemotherapy. Patients with a smaller tumor burden are more likely to benefit from chemotherapy and achieve pCR.

• Colorectal neoplasms
• chemotherapy
• liver neoplasms
• pathological complete response
• surgery

Patients with liver metastases can be scheduled for different therapies (e.g., chemotherapy, surgery, radiotherapy, and ablation). The choice of the most appropriate treatment should rely on adequate understanding of tumor biology and prediction of survival, but reliable biomarkers are lacking. Radiomics is an innovative approach to medical imaging: it identifies invisible-to-the-human-eye radiological patterns that can predict tumor aggressiveness and patients outcome. We reviewed the available literature to elucidate the role of radiomics in patients with liver metastases. Thirty-two papers were analyzed, mostly (56%) concerning metastases from colorectal cancer. Even if available studies are still preliminary, radiomics provided effective prediction of response to chemotherapy and of survival, allowing more accurate and earlier prediction than standard predictors. Entropy and homogeneity were the radiomic features with the strongest clinical impact. In the next few years, radiomics is expected to give a consistent contribution to the precision medicine approach to patients with liver metastases.

Multidisciplinary management of patients with liver metastases (LM) requires a precision medicine approach, based on adequate profiling of tumor biology and robust biomarkers. Radiomics, defined as the high-throughput identification, analysis, and translational applications of radiological textural features, could fulfill this need. The present review aims to elucidate the contribution of radiomic analyses to the management of patients with LM. We performed a systematic review of the literature through the most relevant databases and web sources. English language original articles published before June 2020 and concerning radiomics of LM extracted from CT, MRI, or PET-CT were considered. Thirty-two papers were identified. Baseline higher entropy and lower homogeneity of LM were associated with better survival and higher chemotherapy response rates. A decrease in entropy and an increase in homogeneity after chemotherapy correlated with radiological tumor response. Entropy and homogeneity were also highly predictive of tumor regression grade. In comparison with RECIST criteria, radiomic features provided an earlier prediction of response to chemotherapy. Lastly, texture analyses could differentiate LM from other liver tumors. The commonest limitations of studies were small sample size, retrospective design, lack of validation datasets, and unavailability of univocal cut-off values of radiomic features. In conclusion, radiomics can potentially contribute to the precision medicine approach to patients with LM, but interdisciplinarity, standardization, and adequate software tools are needed to translate the anticipated potentialities into clinical practice.

• computer-assisted diagnosis
• gray level matrices
• liver metastases
• overall and recurrence-free survival
• radiomics
• response to chemotherapy
• texture analysis

• cancer
• chemotherapy
• colorectal liver metastases
• hepatectomy
• missing metastases

• Colorectal cancer
• Liver metastases
• Neoadjuvant chemotherapy
• Prognosis
• Response
• Surgery

• Adult
• Aged
• Aged, 80 and over
• Chemotherapy, Adjuvant
• Colorectal Neoplasms/pathology
• Female
• Humans
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/drug therapy
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Neoadjuvant Therapy
• Norway
• Prognosis
• Prospective Studies
• Survival Rate
• Tomography, X-Ray Computed

There are no optimal indication criteria for neoadjuvant chemotherapy (NAC) in patients with resectable colorectal liver metastases (CLM). The aim of this study was to prospectively assess the survival benefit of selective NAC administration in this patient population based on tumor characteristics.

Borderline resectable CLM (BR-CLM) were defined as four or more liver metastases, CLM larger than 5 cm, or CLM with concomitant resectable extrahepatic metastases. From 2010 to 2015, NAC was administered to BR-CLM patients. Upfront surgery without NAC was performed to patients having clearly resectable CLM (less than 3 lesions, smaller than 5 cm, and no extrahepatic metastases: CR-US group). Survival outcomes of the two groups were assessed.

The BR-NAC group comprised 73 patients and the CR-US group 172. All patients in the BR-NAC group underwent subsequent resection, as none showed disease progression or chemotherapy-associated liver damage. The 3- and 5-year overall survival rates of the CR-US group were 83.0% and 74.0%, while patients in the BR-NAC group had comparable 3-year and 5-year overall survivals (80.5% and 66.6%, P = 0.397).

Defining BR-CLM based on tumor characteristics optimizes patient selection for NAC. Favorable overall survival can be achieved by upfront surgery in patients with clearly resectable CLM and by NAC in patients with BR-CLM.

• Chemotherapy
• Colorectal cancer
• Liver metastases
• Liver resection

• Chemotherapy response
• Colorectal liver metastasis
• RAS
• Resection margin
• Tumor biology

• Colorectal cancer
• Surgery
• Synchronous liver metastases
• Systemic therapy

• Adult
• Aged
• Catheter Ablation
• Colorectal Neoplasms/pathology
• Female
• Hepatectomy
• Humans
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Male
• Middle Aged
• Neoplasm Recurrence, Local/surgery
• Radiosurgery

Clinical risk scores and response to pre-operative chemotherapy are prognostic factors of colorectal liver metastases. The aim of the present study was to evaluate the effectiveness of combining these factors to predict patient survival and to select patients for curative therapy. The study included 189 patients who underwent hepatectomy following neo-adjuvant chemotherapy, for initially resectable colorectal liver metastases, between January 2005 and December 2015. Patients were stratified into four sub-groups: A1-2, low clinical risk scores with/without a response to pre-operative chemotherapy; and B1-2, high clinical risk scores with or without a response to pre-operative chemotherapy. Treatment and survival data were analysed. Survival was significantly longer in patients with low clinical risk scores and a response to pre-operative chemotherapy; these factors were confirmed as independent prognostic factors by multivariate analysis. Combining clinical risk score and chemotherapy response classification, patient survival was significantly longer for groups A1-2/B1 compared with for group B2, in which only 10.2% of patients were alive after 5 years. Of those with no response to first-line chemotherapy, survival was significantly longer in patients who responded to second-line chemotherapy. A combined clinical risk score and chemotherapy response classification may aid in identifying suitable candidates for potentially curative therapy.

• clinical risk score
• colorectal liver metastasis
• neo-adjuvant chemotherapy
• prognostic factor
• survival
• tumor response

The long-term outcome of 228 patients with colorectal liver metastases (CRLM) who underwent preoperative chemotherapy followed by hepatectomy ± RFA were retrospectively analyzed. Stratified by chemotherapy response, patients were divided into responding (n=129) and non-responding groups (n=99). Patients who underwent hepatectomy-RFA had a greater number of metastases (median of 4 vs. 2, p=0.000), a higher incidence of bilobar involvement (66.7% vs. 49.1%, p=0.014) and longer chemotherapy cycles (median of 6 vs. 4, p=0.000). In the responding group, the median overall survival (OS) and recurrence free survival (RFS) of hepatectomy-RFA and the hepatectomy alone subgroups were comparable (38.6 months vs. 43.2 months, p=0.824; 8.2 months vs. 11.4 months, p=0.623). In the non-responding group, the median OS and RFS of patients treated with hepatectomy-RFA were significantly shorter (18.5 months vs. 34.2 months, p=0.000; 5.1 months vs. 5.9 months, p=0.002). RFA was identified as the unfavorable independent factor for both OS (HR=3.60, 95%CI=1.81-7.16, p=0.039) and RFS (HR=1.70, 95%CI=1.00-2.86, p=0.048) in non-responsive patients. Local recurrence rate after hepatectomy-RFA was higher in the non-responding group (48.1% vs. 23.6%, p=0.018). Non-response to preoperative chemotherapy may be a contraindication to hepatectomy-RFA in patients with CRLM.

• colorectal liver metastases
• hepatectomy
• preoperative chemotherapy
• radiofrequency ablation
• response

• Liver-first
• Multimodal
• Oligometastatic
• Resectability
• Synchronous

To evaluate the outcome of patients with bilobar colorectal liver metastases (CRLM) and identify clinico-pathological variables that influenced survival.

Patients with bilobar CRLM were identified from a prospectively maintained hepatobiliary database during the study period (January 2010-June 2014). Collated data included demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome. Down-staging therapy included Oxaliplatin- or Irinotecan- based regimens, and Cetuximab was also used in patients that were K-RAS wild-type. Response to neo-adjuvant therapy was assessed at the multi-disciplinary team meeting and considered for surgery if all macroscopic CRLM were resectable with a clear margin while preserving sufficient liver parenchyma.

Of the 136 patients included, thirty-two (23.5%) patients were considered inoperable and referred for palliative chemotherapy, and thirty-four (25%) patients underwent liver resection. Seventy (51.4%) patients underwent down-staging therapy, of which 37 (52.8%) patients responded sufficiently to undergo liver resection. Patients that failed to respond to down-staging therapy (n = 33, 47.1%) were referred for palliative therapy. There was a significant difference in overall survival between the three groups (surgery vs down-staging therapy vs inoperable disease, P < 0.001). All patients that underwent hepatic resection, including patients that had down-staging therapy, had a significantly better overall survival compared to patients that were inoperable (P < 0.001). On univariate analysis, only resection margin significantly influenced disease-free survival (P = 0.017). On multi-variate analysis, R0 resection (P = 0.030) and female (P = 0.036) gender significantly influenced overall survival.

Patients undergoing liver resection with bilobar CRLM have a significantly better survival outcome. R0 resection is associated with improved disease-free and overall survival in this patient group.

• Colorectal liver metastases
• Chemotherapy
• Liver resection

• Colorectal cancer
• Liver metastases
• Resection
• Surgery
• Survival

• liver resection
• recurrence free survival
• tumor regression grade

• Aged
• Aged, 80 and over
• Cell Proliferation
• Chemoembolization, Therapeutic/adverse effects
• Chemoembolization, Therapeutic/methods
• Chemotherapy, Adjuvant
• Colorectal Neoplasms/pathology
• Disease Progression
• Female
• Hepatectomy
• Humans
• Linear Models
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/secondary
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Neoadjuvant Therapy/adverse effects
• Neoadjuvant Therapy/methods
• Portal Vein
• Retrospective Studies
• Risk Factors
• Sweden
• Time Factors
• Tomography, X-Ray Computed
• Treatment Outcome
• Tumor Burden