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Background: This study aimed to assess the prognostic value of total tumor volume (TTV) for early recurrence (within 6 months) and overall survival (OS) in patients with colorectal liver metastases (CRLM), treated with induction systemic therapy followed by complete local treatment., Methods: Patients with initially unresectable CRLM from the multicenter randomized phase 3 CAIRO5 trial (NCT02162563) who received induction systemic therapy followed by local treatment were included. Baseline TTV and change in TTV as response to systemic therapy were calculated using the CT scan before and the first after systemic treatment, and were assessed for their added prognostic value. The findings were validated in an external cohort of patients treated at a tertiary center., Results: In total, 215 CAIRO5 patients were included. Baseline TTV and absolute change in TTV were significantly associated with early recurrence (P = 0.005 and P = 0.040, respectively) and OS in multivariable analyses (P = 0.024 and P = 0.006, respectively), whereas RECIST1.1 was not prognostic for early recurrence (P = 0.88) and OS (P = 0.35). In the validation cohort (n = 85), baseline TTV and absolute change in TTV remained prognostic for early recurrence (P = 0.041 and P = 0.021, respectively) and OS in multivariable analyses (P < 0.0001 and P = 0.012, respectively), and showed added prognostic value over conventional clinicopathological variables (increase C-statistic, 0.06; 95 % CI, 0.02 to 0.14; P = 0.008)., Conclusion: Total tumor volume is strongly prognostic for early recurrence and OS in patients who underwent complete local treatment of initially unresectable CRLM, both in the CAIRO5 trial and the validation cohort. In contrast, RECIST1.1 did not show prognostic value for neither early recurrence nor OS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors of this manuscript declare relationships with the following companies: C.J.A.P. has an advisory role for Nordic Pharma; SAS Analytics paid for traveling expenses G. Kazemier. This funding is not related to the current research. The remaining authors declare no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We developed models for tumor segmentation to automate the assessment of total tumor volume (TTV) in patients with colorectal liver metastases (CRLM)., Methods: In this prospective cohort study, pre- and post-systemic treatment computed tomography (CT) scans of 259 patients with initially unresectable CRLM of the CAIRO5 trial (NCT02162563) were included. In total, 595 CT scans comprising 8,959 CRLM were divided into training (73%), validation (6.5%), and test sets (21%). Deep learning models were trained with ground truth segmentations of the liver and CRLM. TTV was calculated based on the CRLM segmentations. An external validation cohort was included, comprising 72 preoperative CT scans of patients with 112 resectable CRLM. Image segmentation evaluation metrics and intraclass correlation coefficient (ICC) were calculated., Results: In the test set (122 CT scans), the autosegmentation models showed a global Dice similarity coefficient (DSC) of 0.96 (liver) and 0.86 (CRLM). The corresponding median per-case DSC was 0.96 (interquartile range [IQR] 0.95-0.96) and 0.80 (IQR 0.67-0.87). For tumor segmentation, the intersection-over-union, precision, and recall were 0.75, 0.89, and 0.84, respectively. An excellent agreement was observed between the reference and automatically computed TTV for the test set (ICC 0.98) and external validation cohort (ICC 0.98). In the external validation, the global DSC was 0.82 and the median per-case DSC was 0.60 (IQR 0.29-0.76) for tumor segmentation., Conclusions: Deep learning autosegmentation models were able to segment the liver and CRLM automatically and accurately in patients with initially unresectable CRLM, enabling automatic TTV assessment in such patients., Relevance Statement: Automatic segmentation enables the assessment of total tumor volume in patients with colorectal liver metastases, with a high potential of decreasing radiologist's workload and increasing accuracy and consistency., Key Points: • Tumor response evaluation is time-consuming, manually performed, and ignores total tumor volume. • Automatic models can accurately segment tumors in patients with colorectal liver metastases. • Total tumor volume can be accurately calculated based on automatic segmentations., (© 2023. The Author(s).)

Background: Consensus on resectability criteria for colorectal cancer liver metastases (CRLM) is lacking, resulting in differences in therapeutic strategies. This study evaluated variability of resectability assessments and local treatment plans for patients with initially unresectable CRLM by the liver expert panel from the randomised phase III CAIRO5 study., Methods: The liver panel, comprising surgeons and radiologists, evaluated resectability by predefined criteria at baseline and 2-monthly thereafter. If surgeons judged CRLM as resectable, detailed local treatment plans were provided. The panel chair determined the conclusion of resectability status and local treatment advice, and forwarded it to local surgeons., Results: A total of 1149 panel evaluations of 496 patients were included. Intersurgeon disagreement was observed in 50% of evaluations and was lower at baseline than follow-up (36% vs. 60%, p < 0.001). Among surgeons in general, votes for resectable CRLM at baseline and follow-up ranged between 0-12% and 27-62%, and for permanently unresectable CRLM between 3-40% and 6-47%, respectively. Surgeons proposed different local treatment plans in 77% of patients. The most pronounced intersurgeon differences concerned the advice to proceed with hemihepatectomy versus parenchymal-preserving approaches. Eighty-four percent of patients judged by the panel as having resectable CRLM indeed received local treatment. Local surgeons followed the technical plan proposed by the panel in 40% of patients., Conclusion: Considerable variability exists among expert liver surgeons in assessing resectability and local treatment planning of initially unresectable CRLM. This stresses the value of panel-based decisions, and the need for consensus guidelines on resectability criteria and technical approach to prevent unwarranted variability in clinical practice., (© 2023. The Author(s).)

Background: Large inter-surgeon variability exists in technical anatomical resectability assessment of colorectal cancer liver-only metastases (CRLM) following induction systemic therapy. We evaluated the role of tumour biological factors in predicting resectability and (early) recurrence after surgery for initially unresectable CRLM., Methods: 482 patients with initially unresectable CRLM from the phase 3 CAIRO5 trial were selected, with two-monthly resectability assessments by a liver expert panel. If no consensus existed among panel surgeons (i.e. same vote for (un)resectability of CRLM), conclusion was based on majority. The association of tumour biological (sidedness, synchronous CRLM, carcinoembryonic antigen and RAS/BRAF V600E mutation status) and technical anatomical factors with consensus among panel surgeons, secondary resectability and early recurrence (<6 months) without curative-intent repeat local treatment was analysed by uni- and pre-specified multivariable logistic regression., Results: After systemic treatment, 240 (50%) patients received complete local treatment of CRLM of which 75 (31%) patients experienced early recurrence without repeat local treatment. Higher number of CRLM (odds ratio 1.09 [95% confidence interval 1.03-1.15]) and age (odds ratio 1.03 [95% confidence interval 1.00-1.07]) were independently associated with early recurrence without repeat local treatment. In 138 (52%) patients, no consensus among panel surgeons was present prior to local treatment. Postoperative outcomes in patients with and without consensus were comparable., Conclusions: Almost a third of patients selected by an expert panel for secondary CRLM surgery following induction systemic treatment experience an early recurrence only amenable to palliative treatment. Number of CRLM and age, but no tumour biological factors are predictive, suggesting that until there are better biomarkers; resectability assessment remains primarily a technical anatomical decision., Competing Interests: Conflict of interest statement C.J.A.P. has an advisory role for Nordic Pharma. This funding is not related to the current research. The remaining authors declare no potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose To evaluate interobserver variability in the morphologic tumor response assessment of colorectal liver metastases (CRLM) managed with systemic therapy and to assess the relation of morphologic response with gene mutation status, targeted therapy, and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 measurements. Materials and Methods Participants with initially unresectable CRLM receiving different systemic therapy regimens from the randomized, controlled CAIRO5 trial (NCT02162563) were included in this prospective imaging study. Three radiologists independently assessed morphologic tumor response on baseline and first follow-up CT scans according to previously published criteria. Two additional radiologists evaluated disagreement cases. Interobserver agreement was calculated by using Fleiss κ. On the basis of the majority of individual radiologic assessments, the final morphologic tumor response was determined. Finally, the relation of morphologic tumor response and clinical prognostic parameters was assessed. Results In total, 153 participants (median age, 63 years [IQR, 56-71]; 101 men) with 306 CT scans comprising 2192 CRLM were included. Morphologic assessment performed by the three radiologists yielded 86 (56%) agreement cases and 67 (44%) disagreement cases (including four major disagreement cases). Overall interobserver agreement between the panel radiologists on morphology groups and morphologic response categories was moderate (κ = 0.53, 95% CI: 0.48, 0.58 and κ = 0.54, 95% CI: 0.47, 0.60). Optimal morphologic response was particularly observed in patients treated with bevacizumab ( P = .001) and in patients with RAS/BRAF mutation ( P = .04). No evidence of a relationship between RECIST 1.1 and morphologic response was found ( P = .61). Conclusion Morphologic tumor response assessment following systemic therapy in participants with CRLM demonstrated considerable interobserver variability. Keywords: Tumor Response, Observer Performance, CT, Liver, Metastases, Oncology, Abdomen/Gastrointestinal Clinical trial registration no. NCT02162563 Supplemental material is available for this article. © RSNA, 2022.

Objectives: Compare total tumor volume (TTV) response after systemic treatment to Response Evaluation Criteria in Solid Tumors (RECIST1.1) and assess the prognostic value of TTV change and RECIST1.1 for recurrence-free survival (RFS) in patients with colorectal liver-only metastases (CRLM)., Background: RECIST1.1 provides unidimensional criteria to evaluate tumor response to systemic therapy. Those criteria are accepted worldwide but are limited by interobserver variability and ignore potentially valuable information about TTV., Methods: Patients with initially unresectable CRLM receiving systemic treatment from the randomized, controlled CAIRO5 trial (NCT02162563) were included. TTV response was assessed using software specifically developed together with SAS analytics. Baseline and follow-up computed tomography (CT) scans were used to calculate RECIST1.1 and TTV response to systemic therapy. Different thresholds (10%, 20%, 40%) were used to define response of TTV as no standard currently exists. RFS was assessed in a subgroup of patients with secondarily resectable CRLM after induction treatment., Results: A total of 420 CT scans comprising 7820 CRLM in 210 patients were evaluated. In 30% to 50% (depending on chosen TTV threshold) of patients, discordance was observed between RECIST1.1 and TTV change. A TTV decrease of >40% was observed in 47 (22%) patients who had stable disease according to RECIST1.1. In 118 patients with secondarily resectable CRLM, RFS was shorter for patients with less than 10% TTV decrease compared with patients with more than 10% TTV decrease ( P = 0.015), while RECIST1.1 was not prognostic ( P = 0.821)., Conclusions: TTV response assessment shows prognostic potential in the evaluation of systemic therapy response in patients with CRLM., Competing Interests: C.J.A.P. has an advisory role for Nordic Pharma. This funding is not related to the current research. The remaining authors declare no potential conflicts of interest. The CAIRO5 study is supported by unrestricted scientific grants from Roche and Amgen. The funders had no role in the design, conduct, and submission of the study, or in the decision to submit the manuscript for publication., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To present short-term outcomes of liver surgery in patients with initially unresectable colorectal liver metastases (CRLM) downsized by chemotherapy plus targeted agents., Background: The increase of complex hepatic resections of CRLM, technical innovations pushing boundaries of respectability, and use of intensified induction systemic regimens warrant for safety data in a homogeneous multicenter prospective cohort., Methods: Patients with initially unresectable CRLM, who underwent complete resection after induction systemic regimens with doublet or triplet chemotherapy, both plus targeted therapy, were selected from the ongoing phase III CAIRO5 study (NCT02162563). Short-term outcomes and risk factors for severe postoperative morbidity (Clavien Dindo grade ≥ 3) were analyzed using logistic regression analysis., Results: A total of 173 patients underwent resection of CRLM after induction systemic therapy. The median number of metastases was 9 and 161 (93%) patients had bilobar disease. Thirty-six (20.8%) 2-stage resections and 88 (51%) major resections (>3 liver segments) were performed. Severe postoperative morbidity and 90-day mortality was 15.6% and 2.9%, respectively. After multivariable analysis, blood transfusion (odds ratio [OR] 2.9 [95% confidence interval (CI) 1.1-6.4], P = 0.03), major resection (OR 2.9 [95% CI 1.1-7.5], P = 0.03), and triplet chemotherapy (OR 2.6 [95% CI 1.1-7.5], P = 0.03) were independently correlated with severe postoperative complications. No association was found between number of cycles of systemic therapy and severe complications ( r = -0.038 , P = 0.31)., Conclusion: In patients with initially unresectable CRLM undergoing modern induction systemic therapy and extensive liver surgery, severe postoperative morbidity and 90-day mortality were 15.6% and 2.7%, respectively. Triplet chemotherapy, blood transfusion, and major resections were associated with severe postoperative morbidity., Competing Interests: Disclosure: C.J.A.P. has an advisory role for Nordic Pharma. The other authors declare that they have nothing to disclose. The CAIRO5 study (NCT02162563) was supported by unrestricted scientific grants from Roche and Amgen. The funders had no role in the design, conduct and submission of the study, nor in the decision to submit the manuscript for publication., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Colorectal cancer patients with unresectable liver-only metastases may be cured after downsizing of metastases by neoadjuvant systemic therapy. However, the optimal neoadjuvant induction regimen has not been defined, and the lack of consensus on criteria for (un)resectability complicates the interpretation of published results., Methods/design: CAIRO5 is a multicentre, randomised, phase 3 clinical study. Colorectal cancer patients with initially unresectable liver-only metastases are eligible, and will not be selected for potential resectability. The (un)resectability status is prospectively assessed by a central panel consisting of at least one radiologist and three liver surgeons, according to predefined criteria. Tumours of included patients will be tested for RAS mutation status. Patients with RAS wild type tumours will be treated with doublet chemotherapy (FOLFOX or FOLFIRI) and randomised between the addition of either bevacizumab or panitumumab, and patients with RAS mutant tumours will be randomised between doublet chemotherapy (FOLFOX or FOLFIRI) plus bevacizumab or triple chemotherapy (FOLFOXIRI) plus bevacizumab. Radiological evaluation to assess conversion to resectability will be performed by the central panel, at an interval of two months. The primary study endpoint is median progression-free survival. Secondary endpoints are the R0/1 resection rate, median overall survival, response rate, toxicity, pathological response of resected lesions, postoperative morbidity, and correlation of baseline and follow-up evaluation with respect to outcomes by the central panel., Discussion: CAIRO5 is a prospective multicentre trial that investigates the optimal systemic induction therapy for patients with initially unresectable, liver-only colorectal cancer metastases., Trial Registration: CAIRO 5 is registered at European Clinical Trials Database (EudraCT) (2013-005435-24). CAIRO 5 is registered at ClinicalTrials.gov: NCT02162563 , June 10, 2014.

Background: It has been demonstrated that the Doppler Perfusion Index (DPI) is increased in patients who are at risk of developing liver metastases from colorectal cancer. It has been postulated that a circulating hormonal factor is involved in the relative vasoconstriction throughout the splanchnic bed. Endothelin-1 (ET-1), a potent vasoconstrictor which has been associated with tumor growth and is produced by colorectal tumors, may play an important role in this phenomenon. In this paper the prognostic value of serum ET-1 in colorectal cancer is discussed., Methods: Preoperative serum levels of ET-1 were assessed in three groups of patients: group A underwent resection of the colorectal tumor and remained free of recurrence (n=20); group B developed metachronous liver metastases at least six months after colorectal resection (n=14); and group C presented with colorectal cancer and synchronous liver metastases (n=22)., Results: The mean (SD) serum ET-1 levels in groups A, B and C were 1.59 (0.41) pmol/L, 1.70 (0.32) pmol/L and 1.85 (0.47) pmol/L, respectively. These values were significantly different from those of healthy controls (1.22 (0.31), p<0.05). Kaplan-Meier analyses revealed no prognostic value of preoperative serum ET-1 levels., Conclusions: These preliminary results demonstrate that serum ET-1 levels are raised in patients with colorectal cancer. Serum ET-1 levels do not seem to be of prognostic value for survival.