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Background: Sensitive and specific blood biomarkers for early detection of colorectal (CRC), lung (LuCa) and ovarian (OvCa) cancers are highly warranted. The current blood tests often need to be complemented with other clinical methods to achieve adequate diagnostic performance. Recent progress in the molecular profiling of plasma from cancer patients holds potential for improved non-invasive screening. Here, we aimed to identify composite proteomic and metabolomic plasma biomarkers for early cancer detection with performances that exceed those of existing FDA-approved blood and stool-based diagnostic tests for CRC, LuCa and OvCa.

Methods: In a case-control study using samples from the U-CAN and EpiHealth biobanks, we measured plasma levels of 165 proteins and 244 metabolites in 818 patients with CRC, LuCa and OvCa at diagnosis, 119 patients with non-malignant conditions of the corresponding organs, and 1,129 healthy individuals. We performed an exhaustive search over all cut-off values of the ROC for all combinations of up to 4 proteins and metabolites, implementing measures to minimize the impact of cross-cohort comparisons. Ultimately, we benchmarked candidate biomarkers performance to FDA approved blood tests in clinical use for detection of cancer. External validation was performed using publicly available datasets.

Results: We found biomarkers composed of 2-4 proteins separating cases of each tumor type from healthy controls with ROC AUC, respectively for CRC: CEACAM5, FLT1, IL19, Ferritin (AUC 0.89), LuCa: FNDC5, MDK, PLAUR, CEACAM5 (AUC 0.91) and OvCa: MUC16/CA125, PLG (AUC 0.97). The diagnostic performance of these biomarkers was comparable to, and in some instances surpassed, the performance of established tests, such as Epi proColon (AUC 0.82) and Cologuard (AUC 0.93). Metabolites were informative for tumor stage discrimination, especially in LuCa and OvCa. External validation in the CancerSeek dataset showed strong agreement in biomarker performance.

Conclusions: The composite protein biomarkers identified in this study represent a novel opportunity for detection, staging and differential diagnosis of common tumor types. Metabolites are more relevant for tumor staging than early detection. A limited number of well-performing analytes enables cost-effective implementation in clinical diagnostics and merits further evaluation.

Background and purpose: Cancer therapies place an increasing financial burden on societies. In metastatic colorectal cancer (mCRC), an optimised curative-intent treatment combines metastasectomy, local ablative therapy, and perioperative systemic anti-cancer therapy (SACT) under multidisciplinary team guidance. The resource-intensive operative treatment strategy results in better survival than a non-operative approach with SACT only. The cost-effectiveness of the strategy including operative treatment has not been investigated in the era of modern treatment options.

Patient/material and methods: A Markov model was developed to estimate lifetime healthcare costs and quality-adjusted life-years (QALYs). Patients receiving operative treatment, including metastasectomy along with SACT, and those receiving non-operative treatment with SACT only, were identified from the prospective Finnish RAXO study that recruited 1,086 patients between 2012 and 2018. Cost-effectiveness analyses and sensitivity analyses were conducted from the healthcare payer's perspective using 2023 cost levels.

Results: The mean lifetime costs (158,309€) for patients with an operative treatment produced 6.57 life years and 5.91 QALYs according to the Markov model. The non-operative treatment group had costs of 77,182€, producing 1.99 life years and 1.74 QALYs. The incremental cost-effectiveness ratio (ICER) was 19,455€/QALY, with the caveat that more favourable characteristics were present in the operative group. In probabilistic sensitivity analyses with a willingness-to-pay threshold of 30,000€/QALY, the operative treatment group had an 81% probability of being cost-effective. The results were robust in adjusted sensitivity analyses, including propensity score matched subgroups.

Interpretation: An operative treatment strategy is cost-effective at a commonly referenced acceptability threshold.

IntroductionMetastatic colorectal cancer (mCRC) represents a growing burden on healthcare, yet comprehensive data on treatment costs across different disease phases remain limited. This study aims to estimate hospital resource utilization and costs of treating mCRC patients according to international up-to-date guidelines.Materials and methodsThe RAXO study aimed at maximising metastasectomy with repeated centralized assessment of resectability (inclusion 2012-2018). Cost data from the six largest Finnish hospital districts (n = 941) in RAXO were collected from mCRC diagnosis to death or the end of 2021. All patient costs were characterized day-by-day to diagnostic, curative, remission, palliative SACT, treatment break, or end-of-life disease phases. The resource utilization and mean costs, in 2021 euros, were calculated per patient per month (PPPM).ResultsThe mean PPPM cost for treating mCRC patients was 2323<euro>, when 37% had curative-intent metastasectomy. On average, each month included 0.7 ward days, 1.9 outpatient and 0.1 emergency visits. Outpatient care accounted for 64% of costs, inpatient care for 34%, and emergency room visits for 2%. The higher costs during disease phases involving active tumour-directed treatments (2963<euro>-3059<euro>/PPPM) were balanced by lower costs during remission and treatment break (453<euro>-560<euro>/PPPM). Pharmacy, ward, operating room, and outpatient costs (39%/18%/15%/15%, respectively) were the main drivers for internal hospital billing.ConclusionsResource utilization, costs, and cost drivers varied 8-fold between disease phases. Outpatient care accounted for two-thirds, and inpatient care accounted for one-third of costs.

Obesity has been associated with non-Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome-wide association studies of European ancestry (N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.18, 95% confidence interval (95% CI): 1.05–1.33, p = .005]. This finding was consistent with Mendelian randomization analyses, which demonstrated a similar increased risk of DLBCL with higher genetically determined BMI (OR_{per SD} = 1.12, 95% CI: 1.02–1.23, p = .03). No significant associations were observed with other NHL subtypes. Our study demonstrates a positive link between a genetically determined BMI and an increased risk of DLBCL, providing additional support for increased adiposity as a risk factor for DLBCL.

BACKGROUND/PURPOSE: To evaluate the advantages of including versus excluding the tumor periphery and combining diffusion-weighted imaging (DWI) with T2-weighted imaging (T2w) for outcome predictions of preoperative radio(chemo)therapy in rectal cancer.

METHODS: Four analysis strategies, based on two segmentation methods and two magnetic resonance imaging (MRI) sequences, were evaluated in 106 patients examined with pretreatment MRI. One segmentation method included the tumor periphery in the region of interest (ROI) encompassing the whole tumor (wROI), considered as the reference segmentation approach, and one included only the central part (cROI). Relevant radiomics imaging features were extracted from either T2w alone or from both T2w and DWI and used by a machine learning algorithm for the prediction of pathologic complete response (pCR), neoadjuvant rectal (NAR) score, and disease recurrence. The area under the curve (AUC) was the performance measure. AUCs were compared with a bootstrapping method based on 10⁴ bootstraps.

RESULTS: cROI applied to both T2w and DWI provided the highest numerical prediction of pCR (AUC 0.76), however, not significantly superior to the other strategies (p ≥ 0.138). cROI applied to both T2w and DWI also yielded the highest numerical prediction of NAR score (AUC 0.84), showing advantages over wROI-based analysis strategies (AUC 0.66 and 0.69; p ≤ 0.008). When compared to cROI applied to T2w alone (AUC 0.73), the benefit was borderline statistically significant (p = 0.053). For prediction of disease recurrence, no differences were found between the analysis strategies.

CONCLUSIONS: Inclusion of the tumor periphery in radiomic analysis of magnetic resonance images does not improve predictions of the preoperative therapy response in patients with rectal cancer. Excluding tumor periphery while adding DWI to T2w improves prediction of the NAR score, although it does not affect pCR or recurrence prediction.

Background


Total neoadjuvant treatment (TNT) results in more complete responses and less risk of distant metastasis (DM) compared with chemoradiotherapy in locally advanced rectal cancer (LARC). The best schedule and the most suitable patients are unknown. In Sweden, after the closure of the RAPIDO trial, all hospitals in five out of six healthcare regions treated LARC patients with an abbreviated RAPIDO schedule, LARCT-US. Long-term data are reported. 

Methods


Between July 2016 and June 2020, LARC patients with at least one high-risk criterion for recurrence according to staging MRI (cT4, cN2, mesorectal fascia involvement <1 mm, extramural vascular involvement, lateral node involvement) received TNT consisting of 5 & times; 5 Gy followed by four cycles of CAPOX/six cycles of FOLFOX. 

Results

Curatively treated patients (437 of 462) were analysed after a median of 6.5 (interquartile range 5.9-7.2) years of follow-up. cT4 was seen in 53.5%. Sixty-two patients with a cCR entered a watch-and-wait programme (21 patients with regrowth) and 375 patients underwent primary surgery. At 5 years, of the 437 patients, locoregional recurrence (LRR) occurred in 26 patients (5.9% (95% c.i. 3.7% to 8.2%)) and DM occurred in 108 patients (24.7% (95% c.i. 20.7% to 28.7%)). The distal resection margin was <= 10 mm in 8.3% of patients after a sphincter-saving procedure (a lower percentage than in RAPIDO). The 109 patients (24.9%) with a complete response (48 patients with a cCR sustained for >1 year after the start of radiotherapy and 61 patients with a pCR) had excellent outcomes (0% with LRR and 3.7% with DM). 

Conclusion 

TNT consisting of 5 & times; 5 Gy followed by four cycles of CAPOX/six cycles of FOLFOX resulted in excellent locoregional and distant control, despite inclusion of more advanced tumours than previous TNT studies. The low LRR risk in LARCT-US could be explained by more adequate distal resection margins practiced at Swedish centres.

There is limited data regarding the rare and aggressive colorectal neuroendocrine carcinoma (CR-NEC). In this large prospective study, molecular-clinical characteristics and treatment outcomes following palliative chemotherapy are reported for 163 metastatic CR-NEC patients, with a comparison to a population-based prospective cohort of 263 metastatic colorectal adenocarcinoma (CR-AC) patients. Eighty-three percent of CR-NEC received first-line platinum-etoposide, while 98% of CR-AC patients received first-line fluorouracil-based chemotherapy. Disease control rate across all first-line regimens in CR-NEC and CR-AC was 43% vs. 74%, immediate progressive disease 46% vs. 15%, progression-free survival 2.4 months (m) (95% CI 2.1-3.3) vs. 7.7 m (95% CI 6.9-8.5), and overall survival 6.7 m (95% CI 5.6-8.8) vs. 16.8 m (95% CI 13.7-20.3), all, p < .001. CR-NEC more often had synchronous metastases, worse performance status, and symptom burden at treatment initiation than CR-AC (all, p < .001). Two-year survival was 9% vs. 37% in CR-NEC and CR-AC (p < .001). BRAF mutations were frequent in CR-NEC and CR-AC (26% vs. 20%, p = .153) and associated with shorter OS in CR-NEC and CR-AC (p = .025 and p = .003). KRAS mutations were less frequent in CR-NEC than CR-AC (34% vs. 45%, p = .041), but only associated with shorter OS in rectal NEC (p = .04). The frequencies of APC and TP53 mutations were similar between the cohorts and did not impact survival. Metastatic CR-NEC and CR-AC are clinically distinct, with NEC demonstrating more aggressive features, limited treatment effect, and worse prognosis. Although they share important driver mutations, the underlying reason for their marked clinical differences remains unclear.

Introduction: Total neoadjuvant therapy (TNT) is increasingly used to treat locally advanced rectal cancer (LARC) due to more complete responses and fewer systemic recurrences. However, its impact on quality-of-life (QoL) or late toxicity remains under-investigated. This study evaluates this in a large real-world Swedish cohort treated with an abbreviated RAPIDO-TNT-protocol (LARCT-US).

Material and methods: In the prospective LARCT-US study, 273 LARC patients from 16 Swedish hospitals received short-course radiotherapy (5x5 Gy) followed by four cycles of CAPOX (or six cycles of mFOLFOX-6). An additional 189 patients who received similar treatment were included (ad modum LARCT-US, AdmL). QoL was assessed three years post-treatment using EORTC QLQ-C30, QLQ-CR29 and bowel function using the LARS-score. Physician-reported grade 3+ late toxicity was recorded at three- and five-years follow-up.

Results: Of curatively treated recurrence-free LARCT-US patients, 144/176 (82%) were included in the QoL assessment. Global health score (GHS) and all functioning scores were high (mean 73 and ∼86, respectively). Flatulence, urinary frequency, and fatigue were the most commonly reported symptoms. LARS was present in 79% of patients (n = 42/53), with 47% experiencing major LARS. Grade 3+ late toxicity occurred in 12% (n = 33/265) of LARCT-US/AdmL patients after three years and in 8% (n = 16/254) after five years. Patients with late toxicity reported worse scores for GHS, fatigue, dysuria, financial difficulties, and role and social functioning.

Conclusions: An abbreviated TNT schedule, compared with the RAPIDO-study, used in LARCT-US, achieves favourable oncological outcomes with low risk of late toxicity, and an acceptable QoL similar to other less effective neoadjuvant treatments.