A consensus molecular subtypes classification strategy for clinical colorectal cancer tissues.

Consensus Molecular Subtype (CMS) classification of colorectal cancer (CRC) tissues is complicated by RNA degradation upon formalin-fixed paraffin-embedded (FFPE) preservation. Here, we present an FFPE-curated CMS classifier. The CMSFFPE classifier was developed using genes with a high transcript integrity in FFPE-derived RNA. We evaluated the classification accuracy in two FFPE-RNA datasets with matched fresh-frozen (FF) RNA data, and an FF-derived RNA set. An FFPE-RNA application cohort of metastatic CRC patients was established, partly treated with anti-EGFR therapy. Key characteristics per CMS were assessed. Cross-referenced with matched benchmark FF CMS calls, the CMSFFPE classifier strongly improved classification accuracy in two FFPE datasets compared with the original CMSClassifier (63.6% versus 40.9% and 83.3% versus 66.7%, respectively). We recovered CMS-specific recurrence-free survival patterns (CMS4 versus CMS2: hazard ratio 1.75, 95% CI 1.24-2.46). Key molecular and clinical associations of the CMSs were confirmed. In particular, we demonstrated the predictive value of CMS2 and CMS3 for anti-EGFR therapy response (CMS2&3: odds ratio 5.48, 95% CI 1.10-27.27). The CMSFFPE classifier is an optimized FFPE-curated research tool for CMS classification of clinical CRC samples.

Efficacy-effectiveness analysis on survival in a population-based real-world study of BRAF-mutated metastatic colorectal cancer patients treated with encorafenib-cetuximab.

BACKGROUND: Encorafenib-cetuximab has been approved for pretreated BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients based on efficacy demonstrated in the randomized phase III BEACON trial. The aim of this real-world effectiveness study is to improve knowledge on the generalizability of trial results. METHODS: This population-based real-world study includes all mCRC patients in the Netherlands treated with encorafenib-cetuximab since approval. Individual patient data and pathology reports were collected. Overall survival (OS) was compared to BEACON and subgroup analyses were conducted for patients who would have been eligible and ineligible for BEACON. RESULTS: 166 patients were included with a median follow-up time of 14.5 months. Median OS was 6.7 months (95% CI:6.0-8.3) and differed from BEACON (9.3 months; 95% CI:8.0-11.3, p-value 0.002). Thirty-six percent of real-world patients would have been ineligible for the BEACON trial. Trial ineligible subgroups with symptomatic brain metastases and WHO performance status ≥2 had the poorest median OS of 5.0 months (95% CI:4.0-NR) and 3.9 months (95% CI:2.4-NR). CONCLUSION: This real-world cohort of mCRC patients treated with encorafenib-cetuximab showed a clinically relevant efficacy-effectiveness gap for OS. The chance of survival benefit from encorafenib-cetuximab in patients with brain metastases and/or WHO performance status ≥2 is negligible as neither efficacy nor effectiveness has been demonstrated.

The Assessment of Burden of ColoRectal Cancer (ABCRC)-tool; a validity and reliability study.

INTRODUCTION: Follow-up care after treatment for colorectal cancer (CRC) is increasingly focused on health-related quality of life (HRQoL) and functional outcomes. The Assessment of Burden of ColoRectal Cancer (ABCRC)-tool is developed to measure these outcomes and support patient-oriented care. The tool comprises items assessing burden of disease and lifestyle parameters. It consists of a generic module combined with one of the three CRC specific modules. The objective of this study is to assess the construct validity and reliability of the items of the ABCRC-tool. METHODS: Patients who were receiving follow-up care after surgical CRC treatment were invited to complete the ABCRC-tool together with other validated patient-reported outcome measures (PROMs). Construct validity was assessed by testing expected correlations between items of the ABCRC-tool and domains of other PROMs and by examining predefined hypotheses regarding differences in subgroups of patients. Patients completed the ABCRC-tool twice, with 8 days apart, to evaluate its reliability. RESULTS: In total, 177 patients participated (64% male) with a mean age of 67 years (range 33-88). The colon, rectum and stoma module were completed by subsequently 89, 53 and 35 patients. Most items correlated as expected with anticipated domains of the EORTC QLQ-C30 or EORTC QLQ-CR29 (all p-values <0.05). Furthermore, the ABCRC-tool could discriminate between subgroups of patients. The intraclass correlation coefficient (ICC) was good (>0.70) for most items, indicating good reliability. CONCLUSION: The ABCRC-tool is a valid and reliable instrument that is ready for use in a clinical setting to support personalized follow-up care after CRC treatment.

Oncologic outcomes of screen-detected and non-screen-detected T1 colorectal cancers.

BACKGROUND: The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program. METHODS: Data from T1 CRC patients diagnosed between 2014 and 2017 were collected from 12 hospitals in the Netherlands. The presence of lymph node metastasis (LNM) at diagnosis was compared between screen-detected and non-screen-detected patients using multivariable logistic regression. Cox proportional hazard regression was used to analyze differences in the time to recurrence (TTR), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival. Additionally, the performance of conventional risk factors for LNM was evaluated across the groups. RESULTS: 1803 patients were included (1114 [62%] screen-detected), with median follow-up of 51 months (interquartile range 30). The proportion of LNM did not significantly differ between screen- and non-screen-detected patients (12.6% vs. 8.9%; odds ratio 1.41; 95%CI 0.89-2.23); a prediction model for LNM performed equally in both groups. The 3- and 5-year TTR, MFS, and CSS were similar for patients within and outside the screening program. However, overall survival was significantly longer in screen-detected T1 CRC patients (adjusted hazard ratio 0.51; 95%CI 0.38-0.68). CONCLUSIONS: Screen-detected and non-screen-detected T1 CRCs have similar stage distributions and oncologic outcomes and can therefore be treated equally. However, screen-detected T1 CRC patients exhibit a lower rate of non-CRC-related mortality, resulting in longer overall survival.

Cumulative Incidence, Risk Factors, and Overall Survival of Disease Recurrence after Curative Resection of Stage II-III Colorectal Cancer: A Population-based Study.

Real-world data are necessitated to counsel patients about the risk for recurrent disease after curative treatment of colorectal cancer. This study provided a population-based overview of the epidemiology of recurrent disease in patients with surgically resected stage II/III colorectal cancer.Patients diagnosed with stage II/III primary colorectal cancer between July and December 2015 were selected from the Netherlands Cancer Registry (N = 3,762). Cumulative incidence of recurrent disease was estimated, and multivariable competing risk regression was used to identify risk factors for recurrent disease in patients with primary colon and rectal cancer. Moreover, overall survival (OS) after diagnosis of recurrent colorectal cancer was estimated.Median clinical follow-up was 58 months (Q1-Q3: 22-62). Five-year cumulative incidence of recurrent disease was 21.6% [95% confidence interval (CI): 20.0-23.2] and 30.0% (95% CI: 28.3-33.5) for patients with primary colon and rectal cancer, respectively. Stage III disease and incomplete resection margin in patients with primary colon cancer and extramural vascular invasion in patients with primary rectal cancer were strongly (HR ≥ 2) associated with recurrent disease. Median OS of patients with distant, locoregional, or the synchronous combination of distant and locoregional recurrent disease was 29, 27, and 13 months, respectively (P < 0.001). Patients with distant recurrences limited to liver or lung showed a median OS of 46 and 48 months, respectively. The incidence of recurrent disease was higher in patients with rectal cancer than in patients with colon cancer, predominantly due to higher rates of distant recurrences. OS after recurrent disease was impaired, but subgroups of patients diagnosed with recurrent disease limited to one site showed statistically significantly longer OS. SIGNIFICANCE: Population-based data on recurrent colorectal cancer are rare, but crucial for counseling patients and their physicians. This large nationwide, population-based study provides an up-to-date overview of the epidemiology of recurrent disease in patients with stage II and III primary colon and rectal cancer treated with surgical resection.

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.

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.

A scenario-drafting study to explore potential future implementation pathways of circulating tumor DNA testing in oncology.

Circulating tumor DNA (ctDNA) detection has multiple promising applications in oncology, but the road toward implementation in clinical practice is unclear. We aimed to support the implementation process by exploring potential future pathways of ctDNA testing. To do so, we studied four ctDNA-testing applications in two cancer types and elicited opinions from 30 ctDNA experts in the Netherlands. Our results showed that the current available evidence differed per application and cancer type. Tumor profiling and monitoring treatment response were found most likely to be implemented in non-small cell lung cancer (NSCLC) within 5 years. For colorectal cancer, applications of ctDNA testing were found to be at an early stage in the implementation process. Demonstrating clinical utility was found a key aspect for successful implementation, but there was no consensus regarding the evidence requirements. The next step toward implementation is to define how clinical utility of biomarkers should be evaluated. Finally, these data indicate that specific challenges for each clinical application and tumor type should be appropriately addressed in a deliberative process involving all stakeholders to ensure implementation of ctDNA testing and timely access for patients.

Towards patient-led follow-up after curative surgical resection of stage I, II and III colorectal cancer (DISTANCE-trial): a study protocol for a stepped-wedge cluster-randomised trial.

BACKGROUND: Colorectal cancer (CRC) is among the most frequently diagnosed cancers. Approximately 20-30% of stage I-III CRC patients develop a recurrent tumour or metastases after curative surgical resection. Post-operative follow-up is indicated for the first five years after curative surgical resection. As intensified follow-up after curative surgical resection has shown no effect on survival, patient organisations and policy makers have advocated for a more patient-centred approach to follow-up. The objective of this study is to successfully implement patient-led, home-based follow-up (PHFU) in six hospitals in The Netherlands, with as ultimate aim to come to a recommendation for a patient-centred follow-up schedule for stage I-III CRC patients treated with surgical resection with curative intent. METHODS: This study is designed as a stepped-wedge cluster-randomised trial (SW-CRT) in six participating centres. During the trial, three centres will implement PHFU after six months; the other three centres will implement PHFU after 12 months of inclusion in the control group. Eligible patients are those with pT2-4N0M0 or pT1-4N1-2M0 CRC, who are 18 years or older and have been free of disease for 12 months after curative surgical resection. The studied intervention is PHFU, starting 12 months after curative resection. The in-hospital, standard-of-care follow-up currently implemented in the participating centres functions as the comparator. The proportion of patients who had contact with the hospital regarding CRC follow-up between 12-24 months after curative surgical resection is the primary endpoint of this study. Quality of life, fear of cancer recurrence, patient satisfaction, cost-effectiveness and survival are the secondary endpoints. DISCUSSION: The results of this study will provide evidence on whether nationwide implementation of PHFU for CRC in The Netherlands will be successful in reducing contact between patient and health care provider. Comparison of PROMs between in-hospital follow-up and PHFU will be provided. Moreover, the cost-effectiveness of PHFU will be assessed. TRIAL REGISTRATION: Dutch Trail Register (NTR): NL9266 (Registered on January 1st, 2021).

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.

Comparison of NTRK fusion detection methods in microsatellite-instability-high metastatic colorectal cancer.

Tropomyosin receptor kinase (TRK) inhibitors have been approved for metastatic solid tumors harboring NTRK fusions, but the detection of NTRK fusions is challenging. International guidelines recommend pan-TRK immunohistochemistry (IHC) screening followed by next generation sequencing (NGS) in tumor types with low prevalence of NTRK fusions, including metastatic colorectal cancer (mCRC). RNA-based NGS is preferred, but is expensive, time-consuming, and extracting good-quality RNA from FFPE tissue is challenging. Alternatives in daily clinical practice are warranted. We assessed the diagnostic performance of RNA-NGS, FFPE-targeted locus capture (FFPE-TLC), fluorescence in situ hybridization (FISH), and the 5'/3' imbalance quantitative RT-PCR (qRT-PCR) after IHC screening in 268 patients with microsatellite-instability-high mCRC, the subgroup in which NTRK fusions are most prevalent (1-5%). A consensus result was determined after review of all assay results. In 16 IHC positive tumors, 10 NTRK fusions were detected. In 33 IHC negative samples, no additional transcribed NTRK fusions were found, underscoring the high sensitivity of IHC. Sensitivity of RNA-NGS, FFPE-TLC, FISH, and qRT-PCR was 90%, 90%, 78%, and 100%, respectively. Specificity was 100% for all assays. Robustness, defined as the percentage of samples that provided an interpretable result in the first run, was 100% for FFPE-TLC, yet more limited for RNA-NGS (85%), FISH (70%), and qRT-PCR (70%). Overall, we do not recommend FISH for the detection of NTRK fusions in mCRC due to its low sensitivity and limited robustness. We conclude that RNA-NGS, FFPE-TLC, and qRT-PCR are appropriate assays for NTRK fusion detection, after enrichment with pan-TRK IHC, in routine clinical practice.

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.

Quality of life of patients with rare cancer: a comparison with patients with colorectal cancer and the association with disease trajectory-related factors.

PURPOSE: Differences in quality of life (QoL) between patients with rare and common cancer might be explained by the specific challenges patients with rare cancer face during their disease trajectory, but research is scarce. This study aimed to (1) assess the difference in QoL between patients with rare and common cancer (i.e. colorectal cancer (CRC)) and (2) examine the association between disease trajectory-related factors and QoL in patients with rare cancer. METHODS: Cross-sectional data were collected among adults with rare cancer by a nationwide online survey in the Netherlands. For comparison with patients with CRC, data from the Prospective Dutch Colorectal Cancer (PLCRC) cohort were used. Associations were assessed by linear regression analyses. RESULTS: Data from 1525 patients with rare cancer and 1047 patients with CRC were analysed. Having a rare cancer was significantly associated with a lower QoL compared to having CRC (p < 0.001). Disease trajectory-related factors significantly associated with QoL in patients with rare cancer were time until diagnosis, misdiagnoses, information on best treatment options, information on late and/or long-term effects, and both satisfaction with physician and specialized nurse care (all: p < 0.05). CONCLUSION: Patients with rare cancers have a lower self-reported QoL than patients with CRC, and several disease trajectory-related factors are associated with QoL in patients with rare cancer. IMPLICATIONS FOR CANCER SURVIVORS: To improve QoL of patients with rare cancer, appropriate guidance and support by healthcare professionals throughout the disease trajectory are needed, as well as early diagnosis and proper referral to centres of expertise.

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.

External Validation of the Colon Life Nomogram for Predicting 12-Week Mortality in Dutch Metastatic Colorectal Cancer Patients Treated with Trifluridine/Tipiracil in Daily Practice.

BACKGROUND: Predicting prognosis in refractory metastatic colorectal cancer (mCRC) patients is needed to guide decision making. The Colon Life nomogram was developed to predict 12-week mortality in refractory mCRC patients. The aim of this study is to validate the Colon Life nomogram in last line/refractory patients receiving trifluridine/tipiracil (FTD/TPI) in daily practice. METHODS: The validation cohort consists of 150 QUALITAS study patients, an observational substudy of the Prospective Dutch CRC cohort, who were treated with FTD/TPI between 2016 and 2019. Model performance was assessed on discrimination, calibration, and clinical usefulness. The additional prognostic value of baseline quality of life (QoL) and thymidine kinase (TK1) expression in tissue was explored. RESULTS: Of the 150 patients, 25 (16.7%) died within 12 weeks of starting FTD/TPI treatment. The C-statistic was 0.63 (95% C.I. 0.56-0.70). The observed/expected ratio was 0.52 (0.37-0.73). The calibration intercept and slope were -1.06 (-1.53 to -0.58) and 0.41 (0.01-0.81), respectively, which indicated overestimation of 12-week mortality by the nomogram. Decision curve analysis showed the nomogram did not yield a positive net benefit at clinically meaningful thresholds for predicted 12-week mortality. Addition of QoL to the nomogram improved the C-statistic to 0.85 (0.81-0.89). TK1 expression was associated with progression-free survival but not with overall survival. CONCLUSION: We demonstrated evident miscalibration of the Colon Life nomogram upon external validation, which hampers its use in clinical practice. We recommend conducting a study with a sufficiently large sample size to update the Colon Life nomogram or to develop a new model including QoL.

The impact of surgery and adjuvant chemotherapy on health-related quality of life in patients with colon cancer: Changes at group level versus individual level.

OBJECTIVE: This study aims to evaluate changes in health-related quality of life (HR-QoL) 1 year after surgical treatment in patients with primary resectable colon cancer and to assess whether changes at group level differ from changes at individual level. In addition, we assess which characteristics are associated with a decline of HR-QoL. METHODS: Patients with primary resectable colon cancer who received surgical treatment and adjuvant chemotherapy if indicated were selected from the Prospective Dutch ColoRectal Cancer cohort (PLCRC). HR-QoL was assessed using EORTC-QLQ-C30 questionnaire before surgery and 12 months post-surgery. Outcomes were assessed at group and individual levels. Logistic regression analysis was conducted to assess which socio-demographic and clinical characteristics were associated with a clinically relevant decline of HR-QoL at 12 months. RESULTS: Of all 324 patients, the baseline level of HR-QoL summary score was relatively high with a mean of 88.1 (SD 11.4). On group level, the change of HR-QoL at 12 months varied between -2% for cognitive functioning and +9% for emotional functioning. On individual level, 15% of all patients experienced a clinically relevant decline in HR-QoL summary score at 12 months. Older age, comorbidity burden or the reception of adjuvant chemotherapy was independently associated with a decline of HR-QoL in one of the functional subscales of EORTC-QLQ-C30 at 12 months. CONCLUSION: Only trivial changes of HR-QoL were observed after colon cancer treatment on group level, whereas on individual level, at least 1 out of 10 patients experienced a decline of HR-QoL 12 months post-surgery. It is important to consider individual differences while making a treatment decision.

Limited impact of the COVID-19 pandemic on colorectal cancer care in the Netherlands in 2020.

PURPOSE: The COVID-19 pandemic had a major impact on the health services worldwide. We aimed to investigate the impact of the pandemic on colorectal cancer (CRC) care in the Netherlands in 2020. METHODS: CRC patients, diagnosed in 2018-2020 in the Netherlands, were selected from the Netherlands Cancer Registry (NCR). The year 2020 was divided in four periods reflecting COVID-19 developments in the Netherlands (pre-COVID, 1st peak, recovery period, 2nd peak) and compared with the same periods in 2018/2019. Patient characteristics and treatment were compared using the Chi-squared test. Median time between diagnosis and treatment, and between (neo)adjuvant therapy and surgery were analyzed by the Mann-Whitney U test. RESULTS: In total, 38,021 CRC patients were diagnosed in 2018/2019 (n = 26,816) and 2020 (n = 11,205). Median time between diagnosis and initial treatment decreased on average 4 days and median time between neoadjuvant radiotherapy and surgery in clinical stage II or III rectal cancer patients increased on average 34 days during the three COVID-19 periods compared to the same periods of 2018/2019. The proportion of colon cancer patients that underwent elective surgery significantly decreased with 3.0% during the 1st peak. No differences were found in the proportion of patients who received (neo)adjuvant therapy, systemic therapy, or no anti-cancer treatment. CONCLUSION: Only minor changes in the care for CRC patients occurred during the COVID-19 pandemic, mostly during the 1st peak. In conclusion, the impact on CRC care in the Netherlands was found to be limited. However, long-term effects cannot be precluded.

Translation of IDEA trial results into clinical practice: Analysis of the implementation of a new guideline for colon cancer.

The IDEA trial showed no clinical relevant differences in efficacy between 3 and 6 months of oxaliplatin-based adjuvant chemotherapy (ACT) in colon cancer (CC), while toxicity was substantially lower in the 3 months regimen. Therefore, in 2017 the Dutch colorectal cancer guideline was revised and currently recommends 3 months of oxaliplatin-based ACT. Furthermore, the definition of high-risk stage II CC was restricted to pT4 tumors. We analyzed changes in ACT between 2015 and 2019. From the Netherlands Cancer Registry all 16 721 patients ≥18 years with resected high-risk stage II and stage III CC during 2015 to 2019 were selected. Differences in patient and treatment characteristics were analyzed per calendar year according to stage and age. Mean duration of oxaliplatin-based ACT decreased from 18.6 (±8.0) to 9.5 (±3.8) weeks between 2015 and 2019. In patients receiving ACT (n = 8170), the proportion treated with oxaliplatin increased from 74% to 83%. The proportion of patients receiving ACT was stable, 61% to 69% in stage III and 26% to 29% in pT4 stage II. ACT in previous high-risk pT3N0 disease decreased from 15% to 3%. Use of oxaliplatin increased from 27% to 49% in patients aged ≥75 years. The revised guideline was rapidly implemented and led to an increase in oxaliplatin-based ACT in the elderly and increased guideline-adherence in high-risk stage II CC.

Cell-Free Circulating (Tumor) DNA before Surgery as a Prognostic Factor in Non-Metastatic Colorectal Cancer: A Systematic Review.

Identification of non-metastatic colorectal cancer (CRC) patients with a high risk of recurrence after tumor resection is important to select patients who might benefit from adjuvant treatment. Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) analyses after surgery are promising biomarkers to predict recurrence in these patients. However, these analyses face several challenges and do not allow guidance of neoadjuvant treatment, which might become a novel standard option in colon cancer treatment. The prognostic value of cfDNA/ctDNA before surgery is unclear. This systematic review aims to provide an overview of publications in which the prognostic value of presurgery cfDNA/ctDNA in non-metastatic CRC patients was studied and is performed according to PRISMA guidelines. A total of 29 out of 1233 articles were included and categorized into three groups that reflect the type of approach: measurement of cfDNA, ctDNA somatic alterations, and ctDNA methylation. Overall, a clear association between presurgery cfDNA/ctDNA and the outcome was not observed, but large studies that primarily focus on the prognostic value of presurgery cfDNA/ctDNA are lacking. Designing and performing studies that focus on the value of presurgery cfDNA/ctDNA is needed, in addition to standardization in the reporting of cfDNA/ctDNA results according to existing guidelines to improve comparability and interpretation among studies.

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.