Background: The mortality risk among cancer patients measured from the time of diagnosis is often elevated in comparison to the general population. However, for some cancer types, the patient mortality risk will over time reach the same level as the general population mortality risk. The time point at which the mortality risk reaches the same level as the general population is called the cure point and is of great interest to patients, clinicians, and health care planners. In previous studies, estimation of the cure point has been handled in an ad hoc fashion, often without considerations about margins of clinical relevance. Methods: We review existing methods for estimating the cure point and discuss new clinically relevant measures for quantifying the mortality difference between cancer patients and the general population, which can be used for cure point estimation. The performance of the methods is assessed in a simulation study and the methods are illustrated on survival data from Danish colon cancer patients. Results: The simulations revealed that the bias of the estimated cure point depends on the measure chosen for quantifying the excess mortality, the chosen margin of clinical relevance, and the applied estimation procedure. These choices are interdependent as the choice of mortality measure depends both on the ability to define a margin of clinical relevance and the ability to accurately compute the mortality measure. The analysis of cancer survival data demonstrates the importance of considering the confidence interval of the estimated cure point, as these may be wide in some scenarios limiting the applicability of the estimated cure point. Conclusions: Although cure points are appealing in a clinical context and has widespread applicability, estimation remains a difficult task. The estimation relies on a number of choices, each associated with pitfalls that the practitioner should be aware of.

Quality of life data from randomized trials are lacking in older patients with metastatic colorectal cancer (mCRC). In the randomized NORDIC9-study, reduced-dose S1+oxaliplatin (SOx) showed superior efficacy compared to full-dose S1 monotherapy. We hypothesized that treatment with SOx does not result in inferior quality of life. Patients with mCRC aged ≥70 years and that were not a candidate for standard combination chemotherapy were included and randomly assigned to receive either S1 or SOx. The EORTC QLQ-C30 questionnaire was completed at baseline, after 9, and 18 weeks. The primary endpoint was global Quality of Life (QoL) at 9 weeks. For statistical analysis, a non-inferiority design was chosen applying linear mixed effects models for repeated measurements. The results were interpreted according to statistical significance and anchor-based, clinically relevant between-group minimally important differences (MID). A total of 160 patients aged (median (Interquartile range (IQR))) 78 years (76–81) were included. The QLQ-C30 questionnaire was completed by 150, 100, and 60 patients at baseline, at 9, and 18 weeks, respectively. The difference at 9 weeks in global QoL was 6.85 (95%CI—1.94; 15.65) and 7.37 (0.70; 14.05) in the physical functioning domain in favor of SOx exceeding the threshold for MID. At 18 weeks, the between-group MID in physical functioning was preserved. Dose-reduced combination chemotherapy may be recommended in vulnerable older patients with mCRC, rather than full-dose monotherapy.

Appropriate patient selection for palliative chemotherapy is crucial in patients with metastatic colorectal cancer (mCRC). We investigated the prognostic value of C-reactive protein (CRP), derived neutrophil-to-lymphocyte ratio (dNLR), Interleukin (IL)-6, and YKL-40 on progression-free survival (PFS) and overall survival (OS) in the NORDIC9 cohort. The randomized NORDIC9-study included patients ≥70 years with mCRC not candidates for standard full-dose combination chemotherapy. Participants received either full-dose S1 (Teysuno) or a dose-reduced S1 plus oxaliplatin. Blood samples were collected at baseline and biomarkers were dichotomized according to standard cut-offs. Multivariable analyses adjusted for age, sex, ECOG performance status, and treatment allocation; furthermore, C-statistics were estimated. In total, 160 patients with a median age of 78 years (IQR: 76–81) were included between 2015 and 2017. All investigated biomarkers were significantly elevated in patients with either weight loss, ≥3 metastatic sites, or primary tumor in situ. In multivariable analyses, all markers showed significant association with OS; the highest HR was observed for CRP (HR = 3.40, 95%CI: 2.20–5.26, p < 0.001). Regarding PFS, statistically significant differences were found for CRP and IL-6, but not for dNLR and YKL-40. Applying C-statistics, CRP indicated a good prognostic model for OS (AUC = 0.72, 95%CI: 0.67–0.76). CRP is an easily available biomarker, which may support therapeutic decision-making in vulnerable older patients with mCRC.

Objective: To investigate the safety and efficacy of single-cycle pembrolizumab in patients with localized deficient mismatch repair (dMMR) colon cancer. Background: Neoadjuvant immunotherapy has induced remarkable rates of pathologic complete response (pCR) in patients with dMMR colon cancer. However, the optimal length and type of treatment are yet to be determined. Methods: This was an investigator-initiated, multicenter, single-arm, phase II study (ClinicalTrials.gov: NCT05662527) investigating the safety and efficacy of neoadjuvant pembrolizumab in patients with stage I–III dMMR colon cancer. Patients received a single cycle of pembrolizumab 4 mg/kg (maximum 400 mg) and underwent surgery 3 to 5 weeks later. An interim safety and efficacy analysis after including 42 patients was pre-planned. The primary outcomes were safety and efficacy (pCR in more than 20% of patients). Results: Between February 2023 and September 2023, 42 patients were enrolled at 5 Danish hospitals. All patients received pembrolizumab and underwent surgery, except one patient who refused to undergo surgery. Surgery was performed a median of 32 days after pembrolizumab treatment. Twenty surgical complications were observed in 16 of 41 patients (39%), 3 of which were above Clavien-Dindo grade 2. Two were grade 3b, and 1 was a surgery-related grade 5 gastric ulcer perforation. Three adverse events were grade 3. No grade 4 or 5 adverse events were reported. Of the evaluable patients, 46% (19/41) achieved a pCR, whereas 61% had a major pathologic response. Conclusions: Neoadjuvant single-cycle pembrolizumab was well tolerated and effective in patients with localized dMMR colon cancer. Thus, the inclusion of patients was continued until 85 patients.

Aim: To our knowledge, no prior studies have addressed the possible effects of tumour height on the accuracy of preoperative magnetic resonance imaging (MRI)-based staging relative to postoperative histopathological assessments in patients with adenocarcinoma of the rectum (RC). This study aimed to investigate whether the accuracy of preoperative MRI stage in RC is influenced by tumour height. Methods: A total of 489 consecutive RC patients scheduled for curative treatment between 2009 and 2013 were included. Of the 489 patients, 133 patients had preoperative chemoradiotherapy (CRT), and 356 patients underwent primary surgery. Low, mid and high RC were defined as a tumour 10 cm from the anal verge, respectively. Diagnostic MRI and, for patients with CRT, re-staging MRI features including tumour T-stage (mrT), distance between the tumour border and the distance to the mesorectal fascia (mrMRF), extramural tumour depth (mrEMD), extramural vascular invasion (mrEMVI) and nodal involvement (mrN) were correlated with the corresponding postoperative histopathological findings. Results: There were 115, 186 and 188 patients with low RC, mid RC and high RC, respectively. For all patients, the correlations between mrT and pT and between mrMRF and pCRM were not influenced by tumour height. None of the correlations between mrEMD, mrEMVI and mrN and the corresponding postoperative histopathological findings significantly differed for tumours of different heights. For patients with CRT, a remarkable proportion with low RC were overstaged as ymrT3 compared to ypT0-2. Conclusions: The ability to preoperatively use MRI to accurately stage is not influenced by tumour height. For patients with preoperative CRT, low RC may be MRI overstaged due to post-radiation fibrosis. We found that mrEMD predicts pEMD reliably and should therefore be considered in treatment decisions. Although new MRI techniques are emerging, preoperative RC staging remains incompletely definitive in daily clinical practice.

Background: Patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) have a poor prognosis. The introduction of BRAF targeted therapy with encorafenib and weekly administered cetuximab have shown improved survival with a median progression free survival (PFS) of 4.3 months. However, a regimen with cetuximab given every second week may have comparable efficacy and is more convenient for patients. While BRAF targeted therapy is a new standard therapy in pre-treated patients with BRAF V600E mutated mCRC, resistance invariably occurs and is an emerging challenge. The aim of this study is to investigate the efficacy and tolerability of cetuximab given every second week in combination with daily encorafenib and to explore the correlation between markers of resistance and outcome. Methods: The study is an open label, single arm, phase II study, investigating the efficacy and tolerability of cetuximab given every second week in combination with encorafenib in patients with BRAF V600E mutated mCRC. Furthermore, we will be investigating mechanisms of response and resistance against BRAF targeted therapy though comprehensive genomic profiling on tumor tissue and blood for circulating tumor DNA analysis. A total of 53 patients (19 + 34 in two steps) will be included according to Simon’s optimal two stage design. The primary end point of the study is 2 months PFS rate. Discussion: By combining BRAF inhibitor with cetuximab given every second week we can halve the number of visits in the hospital compared to the currently approved regimen with weekly cetuximab. This seems particularly relevant in a group of patients with a median overall survival of 9.3 months. Resistance after initial response to targeted therapy can be either adaptive (e.g., epigenetic, or transcriptomic alterations) or acquired (selective genetic alterations - e.g., activating de novo mutations) resistance. It is of great importance to untangle these complex mechanisms of resistance in patients with BRAF V600E mutated mCRC to improve treatment strategies in the future potentially even further. Trial registration: EU Clinical Trial Register, Eudract no. 2020-003283-10. Registered on 11 November 2020.