Hepatic arterial infusion pump chemotherapy combined with systemic chemotherapy for borderline resectable and unresectable colorectal liver metastases: phase II feasibility study.

BACKGROUND: Hepatic arterial infusion pump chemotherapy combined with systemic chemotherapy (HAIP-SYS) for liver-only colorectal liver metastases (CRLMs) has shown promising results but has not been adopted worldwide. This study evaluated the feasibility of HAIP-SYS in the Netherlands. METHODS: This was a single-arm phase II study of patients with CRLMs who received HAIP-SYS consisting of floxuridine with concomitant systemic FOLFOX or FOLFIRI. Main inclusion and exclusion criteria were borderline resectable or unresectable liver-only metastases, suitable arterial anatomy and no previous local treatment. Patients underwent laparotomy for pump implantation and primary tumour resection if in situ. Primary end point was feasibility, defined as ≥70% of patients completing two cycles of HAIP-SYS. Sample size calculations led to 31 patients. Secondary outcomes included safety and tumour response. RESULTS: Thirty-one patients with median 13 CRLMs (i.q.r. 6-23) were included. Twenty-eight patients (90%) received two HAIP-SYS cycles. Three patients did not get two cycles due to extrahepatic disease at pump placement, definitive pathology of a recto-sigmoidal squamous cell carcinoma, and progressive disease. Five patients experienced grade 3 surgical or pump device-related complications (16%) and 11 patients experienced grade ≥3 chemotherapy toxicity (38%). At first radiological evaluation, disease control rate was 83% (24/29 patients) and hepatic disease control rate 93% (27/29 patients). At 6 months, 19 patients (66%) had experienced grade ≥3 chemotherapy toxicity and the disease control rate was 79%. CONCLUSION: HAIP-SYS for borderline resectable and unresectable CRLMs was feasible and safe in the Netherlands. This has led to a successive multicentre phase III randomized trial investigating oncological benefit (EUDRA-CT 2023-506194-35-00). Current trial registration number: clinicaltrials.gov (NCT04552093).

Extrahepatic perfusion and incomplete hepatic perfusion after hepatic arterial infusion pump implantation: incidence and clinical implications.

INTRODUCTION: This study investigates the incidence of extrahepatic perfusion and incomplete hepatic perfusion at intraoperative methylene blue testing and on postoperative nuclear imaging in patients undergoing hepatic arterial infusion pump (HAIP) chemotherapy. METHODS: The first 150 consecutive patients who underwent pump implantation in the Netherlands were included. All patients underwent surgical pump implantation with the catheter in the gastroduodenal artery. All patients underwent intraoperative methylene blue testing and postoperative nuclear imaging (99mTc-Macroaggregated albumin SPECT/CT) to determine perfusion via the pump. RESULTS: Patients were included between January-2018 and December-2021 across eight centers. During methylene blue testing, 29.3% had extrahepatic perfusion, all successfully managed intraoperatively. On nuclear imaging, no clinically relevant extrahepatic perfusion was detected (0%, 95%CI: 0.0-2.5%). During methylene blue testing, 2.0% had unresolved incomplete hepatic perfusion. On postoperative nuclear imaging, 8.1% had incomplete hepatic perfusion, leading to embolization in only 1.3%. CONCLUSION: Methylene blue testing during pump placement for intra-arterial chemotherapy identified extrahepatic perfusion in 29.3% of patients, but could be resolved intraoperatively in all patients. Postoperative nuclear imaging found no clinically relevant extrahepatic perfusion and led to embolization in only 1.3% of patients. The role of routine nuclear imaging after HAIP implantation should be studied in a larger cohort.

Survival of Patients with Deficient Mismatch Repair Versus Proficient Mismatch Repair Metastatic Colorectal Cancer Receiving Curative-Intent Local Treatment of Metastases in a Nationwide Cohort.

BACKGROUND: It is unclear whether curative-intent local therapy of metastases is of similar benefit for the biological distinct subgroup of patients with deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC) compared with proficient mismatch repair (pMMR) mCRC. PATIENTS AND METHODS: In this nationwide study, recurrence-free (RFS) and overall survival (OS) were analyzed in patients with dMMR versus pMMR mCRC who underwent curative-intent local treatment of metastases between 2015 and 2018. Subgroup analyses were performed for resection of colorectal liver metastases (CRLM) and cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy (CRS ± HIPEC). Multivariable regression was conducted. RESULTS: Median RFS was 11.1 months [95% confidence interval (CI) 8.5-41.1 months] for patients with dMMR tumors compared with 8.9 months (95% CI 8.1-9.8 months) for pMMR tumors. Two-year RFS was higher in patients with dMMR versus pMMR (43% vs. 21%). Results were similar within subgroups of local treatment (CRLM and CRS ± HIPEC). Characteristics differed significantly between patients with dMMR and pMMR mCRC; however, multivariable analysis continued to demonstrate dMMR as independent factor for improved RFS [hazard ratio (HR): 0.57, 95% CI 0.38-0.87]. Median OS was 33.3 months for dMMR mCRC compared with 43.5 months for pMMR mCRC, mainly due to poor survival of patients with dMMR in cases of recurrence in the preimmunotherapy era. CONCLUSION: Patients with dMMR eligible for curative-intent local treatment of metastases showed a comparable to more favorable RFS compared with patients with pMMR, with a clinically relevant proportion of patients remaining free of recurrence. This supports local treatment as a valuable treatment option in patients with dMMR mCRC and can aid in shared decision-making regarding upfront local therapy versus immunotherapy.

First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group.

BACKGROUND: Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens. METHODS: In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAFV600E mutation status, WHO performance status of 0-1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAFV600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAFV600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2, followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m2. FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2, followed by continuous infusion of fluorouracil at 3200 mg/m2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete. FINDINGS: Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54-69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7-53·1) in groups A and B and 49·9 months (44·5-52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7-10·5) in group A versus 10·6 months (9·9-12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60-0·98]; p=0·032), and 10·8 months (95% CI 9·9-12·6) in group C versus 10·4 months (9·8-13·0) in group D (stratified HR 1·11 [95% CI 0·84-1·48]; p=0·46). The most frequent grade 3-4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis). INTERPRETATION: In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumour. In patients with a left-sided and RAS and BRAFV600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity. FUNDING: Roche and Amgen.

Intersurgeon Variability in Local Treatment Planning for Patients with Initially Unresectable Colorectal Cancer Liver Metastases: Analysis of the Liver Expert Panel of the Dutch Colorectal Cancer Group.

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.

Bilateral diffuse uveal melanocytic proliferation mistaken for nivolumab-induced VKH-like syndrome.

PURPOSE: To describe a case of bilateral diffuse melanocytic proliferation (BDUMP) that was mistaken for nivolumab-induced Vogt-Koyanagi-Harada-like syndrome. METHODS: We present the case of a 58-year-old Caucasian male with metastatic renal clear cell carcinoma for which he was palliatively treated with intravenous nivolumab immunotherapy. Patient developed subacute onset of blurry vision and grey spots in the visual fields of both eyes, macular subretinal fluid, thickening of the RPE and swollen optic nerve heads. Differential diagnosis included nivolumab-induced Vogt-Koyanagi-Harada-disease-like syndrome (nVKH) and patient was initially treated with steroids, which gave no improvement. Investigation showed the development of dark-grey patches in the peripheral retina of both eyes and cataract, which prompted re-evaluation of the diagnosis, deeming BDUMP most likely. The patient was successfully treated with plasmapheresis. DISCUSSION: The initial presentation of the case was incorrectly diagnosed as nVKH. Upon repeat studies of the patients' symptoms and imaging, we concluded we had missed signs of BDUMP. CONCLUSION: The diagnosis BDUMP was missed in the first evaluation. We present this case to discuss the similarities and differences between this disease and nVKH. More importantly, we want to highlight that re-evaluation of the diagnosis upon worsening of a disease was key in this unusual case.

The role of tumour biological factors in technical anatomical resectability assessment of colorectal liver metastases following induction systemic treatment: An analysis of the Dutch CAIRO5 trial.

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/BRAFV600E 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.

Predicting early extrahepatic recurrence after local treatment of colorectal liver metastases.

BACKGROUND: Patients who develop early extrahepatic recurrence (EHR) may not benefit from local treatment of colorectal liver metastases (CRLMs). This study aimed to develop a prediction model for early EHR after local treatment of CRLMs using a national data set. METHODS: A Cox regression prediction model for EHR was developed and validated internally using data on patients who had local treatment for CRLMs with curative intent. Performance assessment included calibration, discrimination, net benefit, and generalizability by internal-external cross-validation. The prognostic relevance of early EHR (within 6 months) was evaluated by landmark analysis. RESULTS: During a median follow-up of 35 months, 557 of the 1077 patients had EHR and 249 died. Median overall survival was 19.5 (95 per cent c.i. 15.6 to 23.0) months in patients with early EHR after CRLM treatment, compared with not reached (45.3 months to not reached) in patients without an early EHR. The EHR prediction model included side and stage of the primary tumour, RAS/BRAFV600E mutational status, and number and size of CRLMs. The range of 6-month EHR predictions was 5.9-56.0 (i.q.r. 12.9-22.0) per cent. The model demonstrated good calibration and discrimination. The C-index through 6 and 12 months was 0.663 (95 per cent c.i. 0.624 to 0.702) and 0.661 (0.632 to 0.689) respectively. The observed 6-month EHR risk was 6.5 per cent for patients in the lowest quartile of predicted risk compared with 32.0 per cent in the highest quartile. CONCLUSION: Early EHR after local treatment of CRLMs can be predicted.

Metastatic Colorectal Cancer Treatment Response Evaluation by Ultra-Deep Sequencing of Cell-Free DNA and Matched White Blood Cells.

PURPOSE: Circulating tumor DNA (ctDNA) has the potential to guide therapy selection and monitor treatment response in patients with metastatic cancer. However, germline and clonal hematopoiesis-associated alterations can confound identification of tumor-specific mutations in cell-free DNA (cfDNA), often requiring additional sequencing of tumor tissue. The current study assessed whether ctDNA-based treatment response monitoring could be performed in a tumor tissue-independent manner by combining ultra-deep targeted sequencing analyses of cfDNA with patient-matched white blood cell (WBC)-derived DNA. EXPERIMENTAL DESIGN: In total, 183 cfDNA and 49 WBC samples, along with 28 tissue samples, from 52 patients with metastatic colorectal cancer participating in the prospective phase III CAIRO5 clinical trial were analyzed using an ultra-deep targeted sequencing liquid biopsy assay. RESULTS: The combined cfDNA and WBC analysis prevented false-positives due to germline or hematopoietic variants in 40% of patients. Patient-matched tumor tissue sequencing did not provide additional information. Longitudinal analyses of ctDNA were more predictive of overall survival than standard-of-care radiological response evaluation. ctDNA mutations related to primary or acquired resistance to panitumumab were identified in 42% of patients. CONCLUSIONS: Accurate calling of ctDNA mutations for treatment response monitoring is feasible in a tumor tissue-independent manner by combined cfDNA and patient-matched WBC genomic DNA analysis. This tissue biopsy-independent approach simplifies sample logistics and facilitates the application of liquid biopsy ctDNA testing for evaluation of emerging therapy resistance, opening new avenues for early adaptation of treatment regimens.

External Validation of Two Established Clinical Risk Scores Predicting Outcome after Local Treatment of Colorectal Liver Metastases in a Nationwide Cohort.

Optimized surgical techniques and systemic therapy have increased the number of patients with colorectal liver metastases (CRLM) eligible for local treatment. To increase postoperative survival, we need to stratify patients to customize therapy. Most clinical risk scores (CRSs) which predict prognosis after CRLM resection were based on the outcome of studies in specialized centers, and this may hamper the generalizability of these CRSs in unselected populations and underrepresented subgroups. We aimed to externally validate two CRSs in a population-based cohort of patients with CRLM. A total of 1105 patients with local treatment of CRLM, diagnosed in 2015/2016, were included from a nationwide population-based database. Survival outcomes were analyzed. The Fong and more recently developed GAME CRS were externally validated, including in pre-specified subgroups (≤70/>70 years and with/without perioperative systemic therapy). The three-year DFS was 22.8%, and the median OS in the GAME risk groups (high/moderate/low) was 32.4, 46.7, and 68.1 months, respectively (p < 0.005). The median OS for patients with versus without perioperative therapy was 47.6 (95%CI [39.8, 56.2]) and 54.9 months (95%CI [48.8, 63.7]), respectively (p = 0.152), and for below/above 70 years, it was 54.9 (95%CI [49.3−64.1]) and 44.2 months (95%CI [37.1−54.3]), respectively (p < 0.005). The discriminative ability for OS of Fong CRS was 0.577 (95%CI [0.554, 0.601]), and for GAME, it was 0.596 (95%CI [0.572, 0.621]), and was comparable in the subgroups. In conclusion, both CRSs showed predictive ability in a population-based cohort and in predefined subgroups. However, the limited discriminative ability of these CRSs results in insufficient preoperative risk stratification for clinical decision-making.

Interobserver Variability in CT-based Morphologic Tumor Response Assessment of Colorectal Liver Metastases.

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.

KRAS A146 Mutations Are Associated With Distinct Clinical Behavior in Patients With Colorectal Liver Metastases.

Somatic KRAS mutations occur in approximately half of the patients with metastatic colorectal cancer (mCRC). Biologic tumor characteristics differ on the basis of the KRAS mutation variant. KRAS mutations are known to influence patient prognosis and are used as predictive biomarker for treatment decisions. This study examined clinical features of patients with mCRC with a somatic mutation in KRAS G12, G13, Q61, K117, or A146. METHODS: A total of 419 patients with colorectal cancer with initially unresectable liver-limited metastases, who participated in a multicenter prospective trial, were evaluated for tumor tissue KRAS mutation status. For the subgroup of patients who carried a KRAS mutation and were treated with bevacizumab and doublet or triplet chemotherapy (N = 156), pretreatment circulating tumor DNA levels were analyzed, and total tumor volume (TTV) was quantified on the pretreatment computed tomography images. RESULTS: Most patients carried a KRAS G12 mutation (N = 112), followed by mutations in G13 (N = 15), A146 (N = 12), Q61 (N = 9), and K117 (N = 5). High plasma circulating tumor DNA levels were observed for patients carrying a KRAS A146 mutation versus those with a KRAS G12 mutation, with median mutant allele frequencies of 48% versus 19%, respectively. Radiologic TTV revealed this difference to be associated with a higher tumor load in patients harboring a KRAS A146 mutation (median TTV 672 cm3 [A146] v 74 cm3 [G12], P = .036). Moreover, KRAS A146 mutation carriers showed inferior overall survival compared with patients with mutations in KRAS G12 (median 10.7 v 26.4 months; hazard ratio = 2.5; P = .003). CONCLUSION: Patients with mCRC with a KRAS A146 mutation represent a distinct molecular subgroup of patients with higher tumor burden and worse clinical outcomes, who might benefit from more intensive treatments. These results highlight the importance of testing colorectal cancer for all KRAS mutations in routine clinical care.

Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases.

BACKGROUND: Recurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Postoperative circulating tumour DNA (ctDNA) is a promising prognostic biomarker. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS). METHODS: Twenty-three patients were selected from an ongoing phase-3 trial who underwent resection of RAS-mutant CRLM after induction systemic treatment. CtDNA analysis was performed by droplet digital PCR using blood samples collected at baseline, before and after resection. Pathologic response of CRLM was determined via the Tumour Regression Grading system. FINDINGS: With a median follow-up of 19.6 months, the median RFS for patients with detectable (N = 6, [26%]) and undetectable (N = 17, [74%]) postoperative ctDNA was 4.8 versus 12.1 months, respectively. Among 21 patients with available tumour tissue, pathologic response in patients with detectable compared to undetectable postoperative ctDNA was found in one of six (17%) and 15 of 15 (100%) patients, respectively (p < 0.001). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1-9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4-15, p = 0.01) were associated with poorer RFS and were strongly correlated (r = 0.88, p < 0.001). After adjusting for clinical characteristics in pairwise multivariable analyses, postoperative ctDNA status remained associated with RFS. INTERPRETATION: The detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response. FUNDING: None.

Detection of tumor-derived cell-free DNA from colorectal cancer peritoneal metastases in plasma and peritoneal fluid.

Tumor-derived cell-free DNA (cfDNA) is an emerging biomarker for guiding the personalized treatment of patients with metastatic colorectal cancer (CRC). While patients with CRC liver metastases (CRC-LM) have relatively high levels of plasma cfDNA, little is known about patients with CRC peritoneal metastases (CRC-PM). This study evaluated the presence of tumor-derived cfDNA in plasma and peritoneal fluid (i.e. ascites or peritoneal washing) in 20 patients with isolated CRC-PM and in the plasma of 100 patients with isolated CRC-LM. Among tumor tissue KRAS/BRAF mutation carriers, tumor-derived cfDNA was detected by droplet digital polymerase chain reaction (ddPCR) in plasma of 93% of CRC-LM and 20% of CRC-PM patients and in peritoneal fluid in all CRC-PM patients. Mutant allele fraction (MAF) and mutant copies per ml (MTc/ml) were lower in CRC-PM plasma than in CRC-LM plasma (median MAF = 0.28 versus 18.9%, p < 0.0001; median MTc/ml = 21 versus 1,758, p < 0.0001). Within patients with CRC-PM, higher cfDNA levels were observed in peritoneal fluid than in plasma (median MAF = 16.4 versus 0.28%, p = 0.0019; median MTc/ml = 305 versus 21, p = 0.0034). These data imply that tumor-derived cfDNA in plasma is a poor biomarker to monitor CRC-PM. Instead, cfDNA detection in peritoneal fluid may offer an alternative to guide CRC-PM treatment decisions.

Short-Term Outcomes of Secondary Liver Surgery for Initially Unresectable Colorectal Liver Metastases Following Modern Induction Systemic Therapy in the Dutch CAIRO5 Trial.

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.

The Prognostic Value of Total Tumor Volume Response Compared With RECIST1.1 in Patients With Initially Unresectable Colorectal Liver Metastases Undergoing Systemic Treatment.

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.

Conversion strategies with chemotherapy plus targeted agents for colorectal cancer liver-only metastases: A systematic review.

BACKGROUND: There is no consensus on the optimal systemic conversion therapy in patients with unresectable colorectal cancer liver-only metastases (CRLM) to achieve a complete resection. Interpretation of trials is complicated by heterogeneity of patients caused by emerging prognostic and predictive characteristics, such as RAS/BRAF mutation status, lack of consensus on unresectability criteria and lack of data on clinical outcome of secondary resections. A systematic review was performed of characteristics of study populations and methodology of trials regarding patients with initially unresectable colorectal cancer liver-only metastases. METHODS: Phase II/III randomised trials, published after 2008, regarding first-line systemic conversion therapy in patients or subgroups of patients with CRLM were included. Data on secondary resection outcomes were collected. RESULTS: Overall, 20 trials were included for analysis: seven prospective trials in patients with unresectable CRLM and 13 trials in the overall population of unresectable metastatic colorectal cancer (mCRC) with retrospective subgroup analysis of CRLM patients. Fourteen trials did not provide unresectability criteria at baseline, and criteria differed among the remaining studies. Trials and study populations were heterogeneous in prognostic/predictive factors, use of primary end-points, and reporting on long-term clinical outcomes. R0-resection rates in CRLM patients varied between CRLM studies and mCRC studies, with rates of 22-57% and 11-38%, respectively. CONCLUSIONS: Cross-study comparison of (subgroups of) studies regarding first-line systemic treatment in patients with unresectable CRLM is hampered by heterogeneity in study populations, trial designs, use of (K)RAS/BRAF mutational tumour status, and differences/absence of unresectability criteria. No optimal conversion systemic regimen can be selected from available data. Prospective studies with well-defined criteria of these issues are warranted.

Diagnostic Strategies toward Clinical Implementation of Liquid Biopsy RAS/BRAF Circulating Tumor DNA Analyses in Patients with Metastatic Colorectal Cancer.

Detection of KRAS, NRAS, and BRAF mutations in tumor tissue is currently used to predict resistance to treatment with anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (mCRC). Liquid biopsies are minimally invasive, and cell-free circulating tumor DNA (ctDNA) mutation analyses may better represent tumor heterogeneity. This study examined the incorporation of liquid biopsy RAS/BRAF ctDNA analyses into diagnostic strategies to determine mCRC patient eligibility for anti-EGFR therapy. Tumor tissue and liquid biopsies were collected from 100 mCRC patients with liver-only metastases in a multicenter prospective clinical trial. Three diagnostic strategies incorporating droplet digital PCR ctDNA analyses were compared with routine tumor tissue RAS/BRAF mutation profiling using decision tree analyses. Tissue DNA mutations in KRAS, NRAS, and BRAF were present in 54%, 0%, and 3% of mCRC patients, respectively. A 93% concordance was observed between tissue DNA and liquid biopsy ctDNA mutations. The proportion of patients with RAS/BRAF alterations increased from 57% to 60% for diagnostic strategies that combined tissue and liquid biopsy mutation analyses. Consecutive RAS/BRAF ctDNA analysis followed by tissue DNA analysis in case of a liquid biopsy-negative result appeared to be the most optimal diagnostic strategy to comprehensively determine eligibility for anti-EGFR therapy in a cost-saving manner. These results highlight the potential clinical utility of liquid biopsies for detecting primary resistance to anti-EGFR-targeted therapies.