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Item does not contain fulltext, 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.

Item does not contain fulltext, BACKGROUND: Colon cancer affects a patient's ability to work. Many patients who have colon cancer are employed at the time of diagnosis. OBJECTIVE: We evaluated work ability during the first 2 years after colon cancer diagnosis. DESIGN: This study is a national prospective study, the Prospective Dutch ColoRectal Cancer cohort, including clinical data and patient-reported outcomes. SETTINGS: Data were collected in 59 medical centers in the Netherlands. PATIENTS: Patients <67 years of age with stage I to IV colon cancer and who completed Work Ability Index questionnaires were selected. MAIN OUTCOME MEASURES: Work ability was assessed at baseline, 3, 6, 12, 18, and 24 months. The Work Ability Index (range, 0 to 49) was evaluated using linear mixed models. Outcomes were matched to population controls without cancer. RESULTS: Of 390 patients, 84% had paid employment. Work ability of patients with stage I to IV colon cancer was significantly lower at the time of diagnosis than in matched population controls (31 ± 8.2 and 41 ± 5.6). Patients with stage I to III disease receiving surgery only regained Work Ability Index scores comparable to matched population controls at 18 months. Patients receiving adjuvant systemic treatment initially demonstrated a decrease in work ability with improvements from 6 months onward and normalization at 24 months. Patients with stage IV disease did not demonstrate improvements in work ability outcomes over time. Work ability scores were negatively influenced by the administration of systemic treatment and ≥1 comorbidities. LIMITATIONS: Only patients with patient-reported outcomes and work at baseline were included in this analysis. Also, questionnaire response rates decreased over time. CONCLUSIONS: Work ability in patients with colon cancer is decreased for a prolonged time. Recovery depends on disease stage, type of treatment, and comorbidities. Patients with stage I to III disease treated with curative surgery alone were the first to rega

Contains fulltext : 292736.pdf (Publisher’s version ) (Open Access), A Trial within Cohorts (TwiCs) study design is a trial design that uses the infrastructure of an observational cohort study to initiate a randomized trial. Upon cohort enrollment, the participants provide consent for being randomized in future studies without being informed. Once a new treatment is available, eligible cohort participants are randomly assigned to the treatment or standard of care. Patients randomized to the treatment arm are offered the new treatment, which they can choose to refuse. Patients who refuse will receive standard of care instead. Patients randomized to the standard of care arm receive no information about the trial and continue receiving standard of care as part of the cohort study. Standard cohort measures are used for outcome comparisons. The TwiCs study design aims to overcome some issues encountered in standard Randomized Controlled Trials (RCTs). An example of an issue in standard RCTs is the slow patient accrual. A TwiCs study aims to improve this by selecting patients using a cohort and only offering the intervention to patients in the intervention arm. In oncology, the TwiCs study design has gained increasing interest during the last decade. Despite its potential advantages over RCTs, the TwiCs study design has several methodological challenges that need careful consideration when planning a TwiCs study. In this article, we focus on these challenges and reflect on them using experiences from TwiCs studies initiated in oncology. Important methodological challenges that are discussed are the timing of randomization, the issue of non-compliance (refusal) after randomization in the intervention arm, and the definition of the intention-to-treat effect in a TwiCs study and how this effect is related to its counterpart in standard RCTs.

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01 augustus 2023, Contains fulltext : 294875.pdf (Publisher’s version ) (Open Access), Limited data are available to guide the decision-making process for clinicians and their patients regarding palliative treatment options for patients with isolated synchronous colorectal cancer peritoneal metastases (CRC-PM). Therefore, the aim of this study is to analyze the outcome of the different palliative treatments for these patients. All patients diagnosed with isolated synchronous CRC-PM between 2009 and 2020 (Netherlands Cancer Registry) who underwent palliative treatment were included. Patients who underwent emergency surgery or curative intent treatment were excluded. Patients were categorized into upfront palliative primary tumor resection (with or without additional systemic treatment) or palliative systemic treatment only. Overall survival (OS) was compared between both groups and multivariable cox regression analysis was performed. Of 1031 included patients, 364 (35%) patients underwent primary tumor resection and 667 (65%) patients received systemic treatment only. Sixty-day mortality was 9% in the primary tumor resection group and 5% in the systemic treatment group (P = 0.007). OS was 13.8 months in the primary tumor resection group and 10.3 months in the systemic treatment group (P < 0.001). Multivariable analysis showed that primary tumor resection was associated with improved OS (HR 0.68; 95%CI 0.57-0.81; P < 0.001). Palliative primary tumor resection appeared to be associated with improved survival compared to palliative systemic treatment alone in patients with isolated synchronous CRC-PM despite a higher 60-day mortality. This finding must be interpreted with care as residual bias probably played a significant role. Nevertheless, this option may be considered in the decision-making process by clinicians and their patients.

Contains fulltext : 298873.pdf (Publisher’s version ) (Open Access), In this study, a data feedback program to improve teachers' science and technology (S&T) teaching skills was designed and tested. The aim was to understand whether and how the four design principles underlying this program stimulated the intended teacher support. We examined how teachers in different phases of their career applied and experienced the employed design principles' key aspects. Eight in-service teachers and eight pre-service teachers attended the data feedback program and kept a logbook in the meantime. Group interviews were held afterwards. Findings show that applying the four employed design principles' key aspects did support and stimulate in-and pre-service teachers in carrying out data feedback for improving their S&T teaching. However, some key aspects were not applied and/or experienced as intended by all attending teachers. The findings provide possible implications for the development and implementation of professional development programs to support in-and pre-service teachers' S&T teaching using data feedback., 13 p.

Background: A growing body of real-world evidence (RWE) aims to better reflect outcomes of cancer patients treated in real-world settings. We aimed to conduct a first comprehensive mapping review of the RWE produced over the past 3 years in terms of tumor type, treatment strategies, setting, and data sources, focusing on targeted therapies (TT) in solid tumors. Methods: We conducted a systematic review in PubMed of RWE studies published between 01/2020 and 12/2022. We identified non-interventional studies using observational data, focusing on solid tumors exposure to targeted therapies, excluding immunotherapies. Abstract and full-text screening were performed by 11 independent reviewers. Results: A total of 7,774 publications were retrieved with 1,251 considered eligible and extracted. The number of publications per year progressively increased during this period (328 in 2020; 421 in 2021; 502 in 2022). Most studies (50%) were performed in Asia, followed by Europe (25%) and North America (17%). Only 8% of studies had patients treated in more than one country. Treatment effectiveness and safety were assessed in 71% and 42% of studies respectively. Main data sources were medical records. Conclusions: RWE publications on TT for solid tumors are heterogeneous and mostly rely on retrospective data such as medical records. Population-based and international studies are rare. Collaborative efforts towards international representativeness and the use of routinely collected and/or standardized data sources must be encouraged to increase the relevance and future quality of publications and their potential impact on oncology practice.

Background: While Real-world Evidence (RWE) has documented value for safety monitoring and disease epidemiology, its objective contribution to safety and efficacy evaluations for regulatory purposes is still unclear. Here, we aim to describe the prevalence and type of RWE considered by European Medicines Agency (EMA) as contribution to efficacy and safety-related evidence generation among approved oncology targeted therapies... Methods: On March 10, 2023, we screened the medicines listing of EMA to identify all anti-cancer targeted therapies for solid malignancies with a decision date (initial marketing authorizations and extension of indications) between 2018-2022. We screened the European public assessment reports (EPARs) using a standardized approach to collect data on RWE. When generated pre-authorization, the RWE contribution to the final regulatory decision was classified as definitive, supportive, or non-supportive. For... Results: Out of a total of 1976 medicines, we identified 55 oncology targeted therapies, corresponding to 75 EPARs (indications), which are described in the table. The use of RWE in regulatory deliberations occurred in 24/75 (32%) EPARs, increasing from 30% in 2018-2020, to 34% in 2021-2022. Pre-authorization RWE was described in 20/24 (83%) EPARs, among which none were definitive, 8 RWE studies (in 7 EPARs) non-supportive, and 20 RWE studies (in 15 EPARs) were supportive of the decision. Published RWE... Conclusions: Over the past 5 years, RWE involvement in the approval of oncology targeted therapies in Europe tends to increase, with the majority being supportive for EMA regulatory decision making complementary to traditional clinical trials...

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BACKGROUND: We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. METHODS: Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. RESULTS: Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). CONCLUSIONS: Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy.

OBJECTIVES: This study aimed to provide detailed guidance on modeling approaches for implementing competing events in discrete event simulations based on censored individual patient data (IPD). METHODS: The event-specific distributions (ESDs) approach sampled times from event-specific time-to-event distributions and simulated the first event to occur. The unimodal distribution and regression approach sampled a time from a combined unimodal time-to-event distribution, representing all events, and used a (multinomial) logistic regression model to select the event to be simulated. A simulation study assessed performance in terms of relative absolute event incidence difference and relative entropy of time-to-event distributions for different types and levels of right censoring, numbers of events, distribution overlap, and sample sizes. Differences in cost-effectiveness estimates were illustrated in a colorectal cancer case study. RESULTS: Increased levels of censoring negatively affected the modeling approaches' performance. A lower number of competing events and higher overlap of distributions improved performance. When IPD were censored at random times, ESD performed best. When censoring occurred owing to a maximum follow-up time for 2 events, ESD performed better for a low level of censoring (ie, 10%). For 3 or 4 competing events, ESD better represented the probabilities of events, whereas unimodal distribution and regression better represented the time to events. Differences in cost-effectiveness estimates, both compared with no censoring and between approaches, increased with increasing censoring levels. CONCLUSIONS: Modelers should be aware of the different modeling approaches available and that selection between approaches may be informed by data characteristics. Performing and reporting extensive validation efforts remains essential to ensure IPD are appropriately represented.

Item does not contain fulltext, IMPORTANCE: The role of primary tumor resection (PTR) in synchronous patients with metastatic colorectal cancer (mCRC) who had unresectable metastases and few or absent symptoms of their primary tumor is unclear. Studying subgroups with low postoperative mortality may identify patients who potentially benefit from PTR. OBJECTIVE: To determine the difference in 60-day mortality between patients randomized to systemic treatment only vs PTR followed by systemic treatment, and to explore risk factors associated with 60-day mortality. DESIGN, SETTING, AND PARTICIPANTS: CAIRO4 is a randomized phase 3 trial initiated in 2012 in which patients with mCRC were randomized to systemic treatment only or PTR followed by systemic treatment with palliative intent. This multicenter study was conducted by the Danish and Dutch Colorectal Cancer Group in general and academic hospitals in Denmark and the Netherlands. Patients included between August 2012 and December 2019 with histologically proven colorectal cancer, unresectable metastases, and a primary tumor with few or absent symptoms were eligible. INTERVENTIONS: Systemic treatment, consisting of fluoropyrimidine-based chemotherapy with bevacizumab vs PTR followed by fluoropyrimidine-based chemotherapy with bevacizumab. MAIN OUTCOMES AND MEASURES: The aim of the current analysis was to compare 60-day mortality rates in both treatment arms. A secondary aim was the identification of risk factors for 60-day mortality in the treatment arms. These aims were not predefined in the study protocol. RESULTS: A total of 196 patients were included in the intention-to-treat analysis (112 [57%] men; median [IQR] age, 65 [59-70] years). Sixty-day mortality was 3% (95% CI, 1%-9%) in the systemic treatment arm and 11% (95% CI, 6%-19%) in the PTR arm (P = .03). In a per-protocol analysis, 60-day mortality was 2% (95% CI, 1%-7%) vs 10% (95% CI, 5%-18%; P = .048). Patients with elevated serum levels of lactate dehydrogenase, aspartate aminotransferase

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Contains fulltext : 235447.pdf (Publisher’s version ) (Closed access)

Item does not contain fulltext, PURPOSE: This population-based study determined the cumulative incidence (CI) of local, regional, and distant recurrences, examined metastatic patterns, and identified risk factors for recurrence after curative treatment for CRC. METHODS: All patients undergoing resection for pathological stage I-III CRC between January 2015 and July 2015 and registered in the Netherlands Cancer Registry were selected (N = 5412). Additional patient record review and data collection on recurrences was conducted by trained administrators in 2019. Three-year CI of recurrence was calculated according to sublocation (right-sided: RCC, left-sided: LCC and rectal cancer: RC) and stage. Cox competing risk regression analyses were used to identify risk factors for recurrence. RESULTS: The 3-year CI of recurrence for stage I, II, and III RCC and LCC was 0.03 vs. 0.03, 0.12 vs. 0.16, and 0.31 vs. 0.24, respectively. The 3-year CI of recurrence for stage I, II, and III RC was 0.08, 0.24, and 0.38. Distant metastases were found in 14, 12, and 16% of patients with RCC, LCC, and RC. Multiple site metastases were found often in patients with RCC, LCC, and RC (42 vs. 32 vs. 28%). Risk factors for recurrence in stage I-II CRC were age 65-74 years, pT4 tumor size, and poor tumor differentiation whereas in stage III CRC, these were ASA III, pT4 tumor size, N2, and poor tumor differentiation. CONCLUSIONS: Recurrence rates in recently treated patients with CRC were lower than reported in the literature and the metastatic pattern and recurrence risks varied between anatomical sublocations.