Harnessing the Potential of Real-World Evidence in the Treatment of Colorectal Cancer: Where Do We Stand?

OPINION STATEMENT: Treatment guidelines for colorectal cancer (CRC) are primarily based on the results of randomized clinical trials (RCTs), the gold standard methodology to evaluate safety and efficacy of oncological treatments. However, generalizability of trial results is often limited due to stringent eligibility criteria, underrepresentation of specific populations, and more heterogeneity in clinical practice. This may result in an efficacy-effectiveness gap and uncertainty regarding meaningful benefit versus treatment harm. Meanwhile, conduct of traditional RCTs has become increasingly challenging due to identification of a growing number of (small) molecular subtypes. These challenges-combined with the digitalization of health records-have led to growing interest in use of real-world data (RWD) to complement evidence from RCTs. RWD is used to evaluate epidemiological trends, quality of care, treatment effectiveness, long-term (rare) safety, and quality of life (QoL) measures. In addition, RWD is increasingly considered in decision-making by clinicians, regulators, and payers. In this narrative review, we elaborate on these applications in CRC, and provide illustrative examples. As long as the quality of RWD is safeguarded, ongoing developments, such as common data models, federated learning, and predictive modelling, will further unfold its potential. First, whenever possible, we recommend conducting pragmatic trials, such as registry-based RCTs, to optimize generalizability and answer clinical questions that are not addressed in registrational trials. Second, we argue that marketing approval should be conditional for patients who would have been ineligible for the registrational trial, awaiting planned (non) randomized evaluation of outcomes in the real world. Third, high-quality effectiveness results should be incorporated in treatment guidelines to aid in patient counseling. We believe that a coordinated effort from all stakeholders is essential to improve the quality of RWD, create a learning healthcare system with optimal use of trials and real-world evidence (RWE), and ultimately ensure personalized care for every CRC patient.

Adjuvant chemotherapy in patients with clinically node-negative but pathologically node-positive rectal cancer in the Netherlands: A retrospective analysis.

INTRODUCTION: Accurate clinical staging of rectal cancer is hampered by suboptimal sensitivity of MRI in the detection of regional lymph node metastases. Consequently, some patients may be understaged and have been withheld neoadjuvant (chemo)radiotherapy in retrospect. Although Dutch guidelines do not advocate adjuvant chemotherapy (ACT) in rectal cancer, some of these clinically understaged patients receive ACT according to local policy. We aim to assess the benefit of ACT in these patients. METHODS: Population-based data from patients with clinically node-negative (cN0) but pathologically node-positive (pN+) rectal cancer that underwent total mesorectal excision (TME) without neoadjuvant treatment between 2008 and 2018 were obtained from the Netherlands Cancer Registry. Missing data were handled by multiple imputation. Stabilised inverse probability treatment weighting (sIPTW) was used to balance clinical characteristics. Overall survival (OS) was compared in ACT and non-ACT patients. RESULTS: Of 34,724 patients, 13,861 had cN0 disease of whom 3016 were pN+ (21.8%). 1466 (48.6%) of these patients underwent upfront TME and were included. Median follow-up was 84 months (95% confidence interval [CI] 76-97) versus 79 months (95% CI 77-81) in patients that did (n = 290, 19.8%) and did not (n = 1176, 80.2%) receive ACT, respectively. After sIPTW adjustment, ACT was associated with improved OS (hazard ratio 0.70; 95% CI 0.49-0.99; p = 0.04). The estimated 5-year OS rate was 74.2% versus 65.3%, respectively. CONCLUSION: In this population-based cohort of patients with cN0 but pN+ rectal cancer who underwent upfront TME, ACT was associated with a significant OS benefit. These data support to discuss ACT in this population.

Impact of colorectal cancer screening on survival after metachronous metastasis.

BACKGROUND: An increasing proportion of colorectal cancer (CRC) cases in Europe are detected by screening with faecal immunochemical testing (FIT). Previous studies showed that population screening with FIT leads to a decrease in CRC incidence and to detection at an earlier stage. However, approximately twenty percent of patients with CRC without metastases at initial diagnosis still develop metachronous metastases. We investigated the association between detection mode of the primary tumor and overall survival (OS) after metachronous metastasis in patients with CRC. METHODS: Nationwide registry-based data was obtained of 794 patients who developed metachronous metastases after being diagnosed with stage I-III CRC between January and June 2015. With multivariable Cox PH regression modelling, we analyzed the (causal) association between detection mode of the primary tumor (FIT screen-detected versus non-screen-detected) and OS after metachronous metastasis while adjusting for potential confounders. RESULTS: Median OS and five-year OS after metachronous metastasis were significantly higher for patients with screen-detected (n = 152) vs. non-screen-detected primary tumors (n = 642): 38.3 vs. 19.2 months, and 35.4% vs. 18.8%, respectively, p < 0.0001). After adjustment for potential confounders, the association between detection mode and OS after metachronous metastasis remained significant (HR 0.70 [95% CI 0.56-0.89]). CONCLUSIONS: Screen-detection of the primary tumor was independently associated with longer OS after metachronous metastasis. This may support the clinical utility of the population screening program and it shows the prognostic value of detection mode of the primary tumor once metachronous metastasis is diagnosed.

Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Whether adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent peritoneal metastases after curative surgery for high-risk colon cancer is an ongoing debate. This study aimed to determine 5-year oncologic outcomes of the randomized multicenter COLOPEC trial, which included patients with clinical or pathologic T4N0-2M0 or perforated colon cancer and randomly assigned (1:1) to either adjuvant systemic chemotherapy and HIPEC (n = 100) or adjuvant systemic chemotherapy alone (n = 102). HIPEC was performed using a one-time administration of oxaliplatin (460 mg/m2, 30 minutes, 42°C, concurrent fluorouracil/leucovorin intravenously), either simultaneously (9%) or within 5-8 weeks (91%) after primary tumor resection. Outcomes were analyzed according to the intention-to-treat principle. Long-term data were available of all 202 patients included in the COLOPEC trial, with a median follow-up of 59 months (IQR, 54.5-64.5). No significant difference was found in 5-year overall survival rate between patients assigned to adjuvant HIPEC followed by systemic chemotherapy or only adjuvant systemic chemotherapy (69.6% v 70.9%, log-rank; P = .692). Five-year peritoneal metastases rates were 63.9% and 63.2% (P = .907) and 5-year disease-free survival was 55.7% and 52.3% (log-rank; P = .875), respectively. No differences in quality-of-life outcomes were found. Our findings implicate that adjuvant HIPEC should still be performed in trial setting only.

Deep learning models for automatic tumor segmentation and total tumor volume assessment in patients with colorectal liver metastases.

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.

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.

Evaluation of Intratumoral Response Heterogeneity in Metastatic Colorectal Cancer and Its Impact on Patient Overall Survival: Findings from 10,551 Patients in the ARCAD Database.

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). PATIENTS AND METHODS: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. RESULTS: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. CONCLUSION: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes.

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.

Prognostic value of Lynch syndrome, BRAFV600E , and RAS mutational status in dMMR/MSI-H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts.

BACKGROUND: Current knowledge on prognostic biomarkers (especially BRAFV600E /RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors. METHODS: This observational cohort study combined a population-based Dutch cohort (2014-2019) and a large French multicenter cohort (2007-2017). All mCRC patients with a histologically proven dMMR tumor were included. RESULTS: In our real-world data cohort of 707 dMMR mCRC patients, 438 patients were treated with first-line palliative systemic chemotherapy. Mean age of first-line treated patients was 61.9 years, 49% were male, and 40% had Lynch syndrome. BRAFV600E mutation was present in 47% of tumors and 30% harbored a RAS mutation. Multivariable regression analysis on OS showed significant hazard rates (HR) for known prognostic factors as age and performance status, however showed no significance for Lynch syndrome (HR: 1.07, 95% CI: 0.66-1.72), BRAFV600E mutational status (HR: 1.02, 95% CI: 0.67-1.54), and RAS mutational status (HR: 1.01, 95% CI: 0.64-1.59), with similar results for PFS. CONCLUSION: BRAFV600E and RAS mutational status are not associated with prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Lynch syndrome is also not an independent prognostic factor for survival. These findings underline that prognostic factors of patients with dMMR mCRC are different of those with pMMR, which could be taken into consideration when prognosis is used for clinical decision-making in dMMR mCRC patients and underline the complex heterogeneity of mCRC.

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.

Treatment patterns and survival in older adults with unresected nonmetastatic biliary tract cancers.

INTRODUCTION: The optimal treatment for unresected nonmetastatic biliary tract cancer (uBTC) is not well-established. The objective of this study was to analyze the treatment patterns and compare the differences in overall survival (OS) between different treatment strategies amongst older adults with uBTC. MATERIALS AND METHODS: We identified patients aged ≥65 years with uBTC using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2004-2015). Treatments were classified into chemotherapy, chemoradiotherapy, and radiotherapy. The primary outcome was OS. The differences in OS were analyzed using Kaplan-Meier curves and multivariable Cox proportional hazard regression. RESULTS: A total of 4352 patients with uBTC were included. The median age was 80 years and median OS was 4.1 months. Most patients (67.3%, n = 2931) received no treatment, 19.1% chemotherapy (n = 833), 8.1% chemoradiotherapy (n = 354), and 5.4% radiotherapy alone (n = 234). Patients receiving no treatment were older and had more comorbidities. Chemotherapy was associated with significantly longer OS than no treatment in uBTC (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.79-0.95), but no difference was found in the subgroups of intrahepatic cholangiocarcinoma (iCCA; HR 0.87, 95% CI 0.75-1.00) and gallbladder carcinoma (GBC; HR 1.09, 95% CI 0.86-1.39). In the sensitivity analyses, capecitabine-based chemoradiotherapy showed significantly longer OS in uBTC compared to chemotherapy (adjusted HR 0.71, 95% CI 0.53-0.95). DISCUSSION: A minority of older patients with uBTC receive systemic treatments. Chemotherapy was associated with longer OS compared to no treatment in uBTC, but not in the subgroups of iCCA and GBC. The efficacy of chemoradiotherapy, especially in perihilar cholangiocarcinoma using capecitabine-based chemoradiotherapy, may be further evaluated in prospective clinical trials.

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.

Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer.

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1-57.8) months with pembrolizumab and 43.9 (range 36.6-55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months-NR) with pembrolizumab versus 10.4 (95% CI 6.3-22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26-1.20). Median OS was NR (range 13.8 months-NR) versus 30.0 (14.7-NR) months (HR 0.65, 95% CI 0.27-1.55) and ORR was 50% (95% CI 28-72) versus 46% (95% CI 27-67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.

Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer.

BACKGROUND: Here we present updated survival of the CAIRO2 trial and assessed whether the addition of anti-EGFR to anti-VEGF therapy could still be an effective treatment option for patients with extended RAS/BRAF wildtype and left-sided metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: Retrospective updated survival and extended RAS and BRAF V600E mutational analysis were performed in the CAIRO2 trial, a multicenter, randomized phase III trial on the effect of adding cetuximab to a combination of capecitabine, oxaliplatin (CAPOX), and bevacizumab in mCRC. RESULTS: Updated survival analysis confirmed that the addition of cetuximab did not provide a benefit on either progression free (PFS) or overall survival (OS) in the intention-to-treat population. With the extended mutational analyses 31 KRAS, 31 NRAS and 12 BRAF V600E additional mutations were found. No benefit of the addition of cetuximab was observed within the extended wildtype group, even when selecting only left-sided tumors (PFS HR 0.96, p = 0.7775). However, compared to the original trial an increase of 6.5 months was seen for patients with both extended wildtype and left-sided tumors (median OS 28.6 months). CONCLUSION: Adding cetuximab to CAPOX and bevacizumab does not provide clinical benefit in patients with mCRC, even in the extended wildtype group with left-sided tumors. However, in the extended wildtype group we did observe clinically relevant higher survival compared to the initial trial report, indicating that it is important to analyze a broader panel of RAS and BRAF variants using more recent sequencing techniques when assessing survival benefit after anti-EGFR therapy.

Time-varying prognostic value of primary tumor sidedness in metastatic colorectal cancer: A population-based study and meta-analysis.

We studied the prognostic value of primary tumor sidedness in metastatic colorectal cancer over time and across treatment lines. Population data on synchronous metastatic colorectal cancer patients were extracted from the Netherlands Cancer Registry and SEER database. Pubmed, EMBASE and Cochrane library were searched for prospective studies on metastatic colorectal cancer to conduct a meta-analysis. Inclusion criteria consisted of metastatic disease, systemic treatment with palliative intent and specification of primary tumor location. Data were pooled using a random-effects model. For the population-based data, multivariable Cox models were constructed. The Grambsch-Therneau test was conducted to evaluate the potential time-varying nature of sidedness. Meta-regression incorporating treatment-line as variable was conducted to test the pre-specified hypothesis that the prognostic value of sidedness varies over time. Analysis of 12 885 and 16 160 synchronous metastatic colorectal cancer patients registered in the Netherlands Cancer Registry and SEER database, respectively, indicated a time-varying prognostic value of sidedness (P < .01). Thirty-one studies were selected for the meta-analysis (9558 patients for overall survival analysis). Pooled univariable hazard ratioleft-sided/right-sided for overall survival was 0.71 (95% CI: 0.65-0.76) in 1st-line, 0.76 (0.54-1.06) in 2nd-line and 1.01 (0.86-1.19) in 3rd-line studies. Hazard ratios were significantly influenced by treatment line (P = .035). The prognostic value of sidedness of the primary tumor in metastatic colorectal cancer patients treated with palliative systemic therapy decreases over time since diagnosis, suggesting that sidedness may not be a useful stratification factor in late-line trials. This decrease in prognostic value should be taken into account when providing prognostic information to patients.