Clinical and genetic factors associated with tumor response to neoadjuvant (chemo)radiotherapy, survival and recurrence risk in rectal cancer.

Rectal cancer poses challenges in preoperative treatment response, with up to 30% achieving a complete response (CR). Personalized treatment relies on accurate identification of responders at diagnosis. This study aimed to unravel CR determinants, overall survival (OS), and time to recurrence (TTR) using clinical and targeted sequencing data. Analyzing 402 patients undergoing preoperative treatment, tumor stage, size, and treatment emerged as robust response predictors. CR rates were higher in smaller, early-stage, and intensively treated tumors. Targeted sequencing analyzed 216 cases, while 120 patients provided hotspot mutation data. KRAS mutation dramatically reduced CR odds by over 50% (odds ratio [OR] = 0.3 in the targeted sequencing and OR = 0.4 hotspot cohorts, respectively). In contrast, SMAD4 and SYNE1 mutations were associated with higher CR rates (OR = 6.0 and 6.8, respectively). Favorable OS was linked to younger age, CR, and low baseline carcinoembryonic antigen levels. Notably, CR and an APC mutation increased TTR, while a BRAF mutation negatively affected TTR. Beyond tumor burden, SMAD4 and SYNE1 mutations significantly influenced CR. KRAS mutations independently correlated with radiotherapy resistance, and BRAF mutations heightened recurrence risk. Intriguingly, non-responding tumors with initially small sizes carried a higher risk of recurrence. The findings, even if limited in addition to the imperfect clinical factors, offer insights into rectal cancer treatment response, guiding personalized therapeutic strategies. By uncovering factors impacting CR, OS, and TTR, this study underscores the importance of tailored approaches for rectal cancer patients. These findings, based on extensive analysis and mutation data, pave the way for personalized interventions, optimizing outcomes in the challenges of rectal cancer preoperative treatment.

Atypical (non-V600E) BRAF mutations in metastatic colorectal cancer in population and real-world cohorts.

BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.

Risk Factors for Recurrence After Surgery for Rectal Cancer in a Modern, Nationwide Population-Based Cohort.

BACKGROUND: The success of modern multimodal treatment in rectal cancer is dependent on risk prediction. Better knowledge of the risk of locoregional and distant recurrence, in relation to preoperative treatment, pathological stage, and commonly used risk factors, is needed when deciding on adjuvant therapy and surveillance. METHODS: The Swedish ColoRectal Cancer Registry was used to identify patients diagnosed with rectal adenocarcinoma between 2011 and 2018. Readily available variables, including patient, tumor, and treatment factors were exposures. Cox proportional hazard models were used to identify important risk factors for recurrence and calculate recurrence risks. RESULTS: A total of 9428 curatively resected patients were included and followed for a median of 72 months. Eighteen percent had distal recurrence and 3% had locoregional recurrence at 5 years. Risk factors with major impact on distal recurrence were pT4a (hazard ratio [HR] 5.1, 95% confidence interval [CI] 3.3-8.0), pN2b (HR 3.4, 95% CI 2.7-4.2), tumor deposit (HR 1.7, 95% CI 1.5-1.9), lymph node yield (HR 1.5, 95% CI 1.3-1.8), and tumor level 0-5 cm (HR 1.5, 95% CI 1.3-1.8). Pathologic stage and number of risk factors identified groups with markedly different recurrence risks in all neoadjuvant treatment groups. CONCLUSIONS: Readily available risk factors, as a complement to stage, are still valid and robust in all neoadjuvant treatment groups. Tumor deposit is important, while circumferential resection margin might no longer be important with improved oncological treatments and high-quality TME surgery. Tailored surveillance is possible in selected groups using risk stratification based on stage and risk factors.

Detailed analysis of metastatic colorectal cancer patients who developed cardiotoxicity on another fluoropyrimidine and switched to S-1 treatment (subgroup analysis of the CardioSwitch-study).

BACKGROUND AND PURPOSE: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. MATERIALS AND METHODS: This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. RESULTS: Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. INTERPRETATION: S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.

Implications of pretreatment extramural venous invasion in rectal cancer patients: A population-based study.

AIM: Extramural venous invasion detected by MRI (mrEMVI) has in several expert centre studies been identified as an important prognostic factor in rectal cancer, and in guiding neoadjuvant therapy. However, population-based evidence for mrEMVI as a predictor for recurrent disease is lacking. METHOD: This was a multicentre retrospective study based on the Swedish Colorectal Cancer Registry. The study period encompassed patients operated with abdominal resection for rectal cancer 2017-2021, with follow-up until January 2023. Patients diagnosed at hospitals with radiological registry data coverage <90% or with metastatic disease were excluded. Pretreatment mrEMVI constituted exposure, while recurrence-free survival was the main outcome. Distant and local recurrence, and overall survival were secondary outcomes, and pretreatment and postoperative scenarios were explored using multivariable Cox regression with multiple imputation. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. RESULTS: A total of 2737 patients from 13 hospitals were eligible for analysis. Pretreatment mrEMVI was reported in 14.5% of patients, while 71.9% had negative findings and 13.6% had missing data. In the pretreatment scenario, mrEMVI was an independent predictor for worse recurrence-free survival with an adjusted HR of 1.64 (95% CI: 1.31-2.06). In the postoperative MDT setting, the influence of mrEMVI on recurrence-free survival decreased with an adjusted HR of 1.27 (95% CI: 1.00-1.61). CONCLUSION: mrEMVI at diagnosis is an independent predictor of recurrence-free survival in an unselected population of rectal cancer patients undergoing abdominal resection.

Sex differences in metastatic surgery following diagnosis of synchronous metastatic colorectal cancer.

The aim was to investigate gender differences in the likelihood to receive metastatic surgery, and to compare overall survival between men and women, among patients with synchronous metastatic colorectal cancer (mCRC) in a population-based setting. All Swedish adult patients diagnosed with synchronous mCRC in 2007-2016 were identified using the nationwide colorectal cancer database (CRCBaSe). Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression, comparing the odds of receiving treatment. The Kaplan-Meier method was used to calculate survival proportions and Cox regression models to estimate hazard ratios (HRs) and 95% CIs of all-cause mortality rates. All multivariable models were adjusted for age, ASA score, Charlson comorbidity index, year of diagnosis, location of primary tumor and single or multiple metastatic locations. A total of 12 201 patients met the study criteria. Women received 23% less metastatic surgery for mCRC (adjusted OR = 0.77, CI:0.69-0.86) and experienced a slightly higher mortality following diagnosis (adjusted HR = 1.09, CI:1.05-1.14). In analyses restricted to patients who received metastatic surgery, no significant differences in mortality were found. In conclusion, this population-based study showed that women less often received metastatic surgery of mCRC and experienced slightly higher all-cause mortality compared with men. The differences persisted despite adjustments of patient and cancer characteristics. Gender differences in receiving treatment are unacceptable if the underlying explanation cannot be motivated. Further studies are needed to understand if the differences are based on sex (i.e., biology) or gender (including clinically unmotivated differences in treatment approach).

Locoregional Failure During and After Short-course Radiotherapy Followed by Chemotherapy and Surgery Compared With Long-course Chemoradiotherapy and Surgery: A 5-Year Follow-up of the RAPIDO Trial.

OBJECTIVE: To analyze risk and patterns of locoregional failure (LRF) in patients of the RAPIDO trial at 5 years. BACKGROUND: Multimodality treatment improves local control in rectal cancer. Total neoadjuvant treatment (TNT) aims to improve systemic control while local control is maintained. At 3 years, LRF rate was comparable between TNT and chemoradiotherapy in the RAPIDO trial. METHODS: A total of 920 patients were randomized between an experimental (EXP, short-course radiotherapy, chemotherapy, and surgery) and a standard-care group (STD, chemoradiotherapy, surgery, and optional postoperative chemotherapy). LRFs, including early LRF (no resection except for organ preservation/R2 resection) and locoregional recurrence (LRR) after an R0/R1 resection, were analyzed. RESULTS: Totally, 460 EXP and 446 STD patients were eligible. At 5.6 years (median follow-up), LRF was detected in 54/460 (12%) and 36/446 (8%) patients in the EXP and STD groups, respectively ( P =0.07), in which EXP patients were more often treated with 3-dimensional-conformed radiotherapy ( P =0.029). In the EXP group, LRR was detected more often [44/431 (10%) vs. 26/428 (6%); P =0.027], with more often a breached mesorectum (9/44 (21%) vs. 1/26 (4); P =0.048). The EXP treatment, enlarged lateral lymph nodes, positive circumferential resection margin, tumor deposits, and node positivity at pathology were the significant predictors for developing LRR. Location of the LRRs was similar between groups. Overall survival after LRF was comparable [hazard ratio: 0.76 (95% CI, 0.46-1.26); P =0.29]. CONCLUSIONS: The EXP treatment was associated with an increased risk of LRR, whereas the reduction in disease-related treatment failure and distant metastases remained after 5 years. Further refinement of the TNT in rectal cancer is mandated.

CRCBaSe: a Swedish register-based resource for colorectal adenocarcinoma research.

OBJECTIVES: To facilitate high-quality register-based research on colorectal cancer (CRC) in Sweden by constructing a database consisting of CRC patients, matched comparators, and relatives. MATERIAL AND METHODS: Patients with adenocarcinoma in the colon and/or rectum were identified in the Swedish Colorectal Cancer Register, a nationwide quality-of-care register. For each patient, six comparators from the general population were matched on birth year, sex, year of CRC diagnosis, and county. Comparators were free from CRC at the time of matching, but could later become cases. For both patients and comparators, first-degree relatives (parents, siblings, and children) were identified. Information from nationwide population-based registers was retrieved and linked to each individual in the database using the personal identification number unique to all Swedish residents. RESULTS: A total of 76,831 CRC patients diagnosed between 1995 and 2016 were identified (51% colon, 49% rectal; before 2007 only rectal cancer patients were included). Among all patients, 37% were stage I-II, 22% stage III, and 22% stage IV. The median follow-up time was 11.9 years (inter-quartile range, IQR: 8.6-15.3). Together with comparators and relatives, the database contains 2,413,139 individuals with information on demographics, dates and causes of death, in- and outpatient healthcare records, cancer diagnoses, prescribed and dispensed drugs, childbirths (among women), and social security information (such as sick leave and early retirement). CONCLUSION: The Colorectal Cancer Database Sweden (CRCBaSe) is a large and unique register-based data research platform, which opens up for clinically important, large epidemiological studies with innovative design in the field of colorectal adenocarcinoma.

Prognostic role of tumour-infiltrating lymphocytes and macrophages in relation to MSI, CDX2 and BRAF status: a population-based study of metastatic colorectal cancer patients.

BACKGROUND: Tumour-infiltrating CD3, CD8 lymphocytes and CD68 macrophages are associated with favourable prognosis in localised colorectal cancer, but the effect in metastatic colorectal cancer (mCRC) is not established. METHODS: A Scandinavian population-based cohort of non-resectable mCRC patients was studied. Tissue microarrays (n = 460) were stained with CD3, CD8 and CD68 using fluorescence-based multiplex immunohistochemistry. Associations with clinicopathological variables, overall survival (OS) and progression-free survival were estimated. RESULTS: Two-thirds of microsatellite instable (MSI) and one-fourth of microsatellite stable (MSS) tumours displayed the highest quartile density of CD8. For CD3 high vs low cases, median OS was 20 vs 16 months (HR: 0.76, 95% CI: 0.59, 0.76, p = 0.025) with 3-year OS of 27 vs 13%. For CD68 high vs low cases, median OS was 23 vs 15 months (HR: 0.69, 95% CI: 0.54, 0.88, p = 0.003) with 3-year OS of 28 vs 12%. MSI, BRAF mutation and CDX2 loss were negative prognostic markers independent of tumour immune infiltration. CONCLUSIONS: In mCRC, high lymphocyte infiltration was found in proportions of MSI and MSS tumours-potential subgroups of immunotherapy response. Tumour-infiltrating CD3 lymphocytes and CD68 macrophages were associated with median and long-term survival. MSI was a significant negative prognostic marker despite high immunogenicity.

Hospital factors and metastatic surgery in colorectal cancer patients, a population-based cohort study.

BACKGROUND: Only a limited proportion of patients with metastatic colorectal cancer (mCRC) receives metastatic surgery (including local ablative therapy). The aim was to investigate whether hospital volume and hospital level were associated with the chance of metastatic surgery. METHODS: This national cohort retrieved from the CRCBaSe linkage included all Swedish adult patients diagnosed with synchronous mCRC in 2009-2016. The association between annual hospital volume of incident mCRC patients and the chance of metastatic surgery, and survival, were assessed using logistic regression and Cox regression models, respectively. Hospital level (university/non-university) was evaluated as a secondary exposure in a similar manner. Both uni- and multivariable (adjusted for sex, age, Charlson comorbidity index, year of diagnosis, cancer characteristics and socioeconomic factors) models were fitted. RESULTS: A total of 1,674 (17%) out of 9,968 mCRC patients had metastatic surgery. High hospital volume was not associated with increased odds of metastatic surgery after including hospital level in the model, whereas hospital level was (odds ratio (OR) (95% confidence interval (CI)): 1.94 (1.68-2.24)). All-cause mortality was lower in university versus non-university hospitals (hazard ratio (95% CI): 0.83 (0.78-0.88)). CONCLUSIONS: Patients with mCRC initially cared for by a university hospital experienced a greater chance to receive metastatic surgery and had superior overall survival. High hospital volume in itself was not associated with a greater chance to receive metastatic surgery nor a greater survival probability. Additional efforts should be imposed to provide more equal care for mCRC patients across Swedish hospitals.

Current controversies in TNM for the radiological staging of rectal cancer and how to deal with them: results of a global online survey and multidisciplinary expert consensus.

OBJECTIVES: To identify the main problem areas in the applicability of the current TNM staging system (8th ed.) for the radiological staging and reporting of rectal cancer and provide practice recommendations on how to handle them. METHODS: A global case-based online survey was conducted including 41 image-based rectal cancer cases focusing on various items included in the TNM system. Cases reaching < 80% agreement among survey respondents were identified as problem areas and discussed among an international expert panel, including 5 radiologists, 6 colorectal surgeons, 4 radiation oncologists, and 3 pathologists. RESULTS: Three hundred twenty-one respondents (from 32 countries) completed the survey. Sixteen problem areas were identified, related to cT staging in low-rectal cancers, definitions for cT4b and cM1a disease, definitions for mesorectal fascia (MRF) involvement, evaluation of lymph nodes versus tumor deposits, and staging of lateral lymph nodes. The expert panel recommended strategies on how to handle these, including advice on cT-stage categorization in case of involvement of different layers of the anal canal, specifications on which structures to include in the definition of cT4b disease, how to define MRF involvement by the primary tumor and other tumor-bearing structures, how to differentiate and report lymph nodes and tumor deposits on MRI, and how to anatomically localize and stage lateral lymph nodes. CONCLUSIONS: The recommendations derived from this global survey and expert panel discussion may serve as a practice guide and support tool for radiologists (and other clinicians) involved in the staging of rectal cancer and may contribute to improved consistency in radiological staging and reporting. KEY POINTS: • Via a case-based online survey (incl. 321 respondents from 32 countries), we identified 16 problem areas related to the applicability of the TNM staging system for the radiological staging and reporting of rectal cancer. • A multidisciplinary panel of experts recommended strategies on how to handle these problem areas, including advice on cT-stage categorization in case of involvement of different layers of the anal canal, specifications on which structures to include in the definition of cT4b disease, how to define mesorectal fascia involvement by the primary tumor and other tumor-bearing structures, how to differentiate and report lymph nodes and tumor deposits on MRI, and how to anatomically localize and stage lateral lymph nodes. • These recommendations may serve as a practice guide and support tool for radiologists (and other clinicians) involved in the staging of rectal cancer and may contribute to improved consistency in radiological staging and reporting.

Temporal development in survival, and gender and regional differences in the Swedish population of patients with synchronous and metachronous metastatic colorectal cancer.

BACKGROUND: Survival in patients with metastatic colorectal cancer (mCRC) has markedly improved in patients included in clinical trials. In population-based materials, improvements were seen until about a decade ago, but it is unclear if survival has continued to improve. It is also unclear if regional or gender differences exist. MATERIAL AND METHODS: All patients with mCRC (N = 19,566) in Sweden between 2007 and 2016 were identified from the national quality register, SCRCR, with almost complete coverage. Overall survival (OS) from diagnosis of metastatic disease was calculated in two calendar periods, 2007-2011 and 2012-2016. Differences between groups were compared using Cox regression. RESULTS: Median age was 72 years, 55% were males, synchronous presentation was seen in 13,630 patients and metachronous in 5936. In synchronous disease, the primary tumour was removed more often during the first than the second period (51% vs 41%, p < 0.001). Median OS (mOS) was 14.0 months. It was longer in those with metachronous than synchronous disease (17.6 vs 13.1 months, p < 0.001) and in males (15.0 vs 12.8 months, p < 0.001), and markedly influenced by age and primary location. It was longer in patients diagnosed during the second period than during the first (14.9 vs 13.1 months, HR 0.89 (95% CI 0.86-0.92), p < 0.001). This difference was seen in all subgroups according to sex, age, presentation, and sidedness. mOS was about one month shorter in 1/6 healthcare regions, most pronounced during the first period. Differences in median of up to 5 months were seen between the region with the shortest and longest mOS. CONCLUSIONS: Overall survival in Swedish patients with mCRC has improved during the past decade but is still substantially worse than reported from clinical trials/hospital-based series, reflecting the selection of patients to trials. Regional differences were seen, but they decreased with time. Women did not have a poorer prognosis in multivariable analyses.

Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.

BACKGROUND: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. FINDINGS: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). INTERPRETATION: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. FUNDING: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

Clinicopathological factors associated with tumour-specific mutation detection in plasma of patients with RAS-mutated or BRAF-mutated metastatic colorectal cancer.

Detection of tumour-specific circulating cell-free DNA in plasma (ctDNA) fails in a significant number of cases depending on the clinical context. The primary aim was to investigate clinicopathological factors associated with detection of ctDNA in patients with RAS-/BRAF-mutated metastatic colorectal cancer (mCRC) prior to first-line therapy. A secondary aim was to evaluate the prognostic impact of ctDNA compared to other biomarkers. Patients were included from the NORDIC-VII study (N = 253). ctDNA was sampled prior to treatment and analysed for hotspot tissue mutations (KRAS, NRAS, and BRAF) using droplet digital PCR. Multivariable regression models were constructed to predict the probability of mutation detection and survival. Increasing radiological size of target lesions by increments of 1 cm (odds ratio [OR] = 1.18; 95% confidence interval [CI] 1.09-1.27; P < .001), intact primary tumour (OR = 3.17; 95% CI 1.22-8.22; P = .018) and more than one metastatic site (OR = 3.08; 95% CI 1.32-7.19; P = .009) were associated with mutation detection in plasma. Metastatic involvement of the lung was associated with non-detection (OR = 0.26; 95% CI 0.12-0.58; P = .001). Preanalytical and analytical factors modulated detection. High allele frequencies of ctDNA indicated poor prognosis independently of CEA and CA19-9 (hazard ratio [HR] = 2.38; 95% CI 1.74-3.26; P < .001; N = 206). Clinicopathological characteristics should be carefully considered when evaluating ctDNA results from mCRC patients, especially when confronted with a plasma negative result. ctDNA may prove to be a clinically useful marker in the evaluation of mCRC treatment.

Completeness and accuracy of the registration of recurrences in the Swedish Colorectal Cancer Registry (SCRCR) and an update of recurrence risk in colon cancer.

BACKGROUND: The completeness and accuracy of the registration of synchronous metastases and recurrences in the Swedish Colorectal Cancer Registry has not been investigated. Knowing how accurate these parameters are in the registry is a prerequisite to adequately measure the current recurrence risk. METHODS: All charts for patients diagnosed with stage I-III colorectal cancer (CRC) in two regions were reviewed. In one of the regions, all registrations of synchronous metastases were similarly investigated. After the database had been corrected, recurrence risk in colon cancer was calculated stratified by risk group as suggested by ESMO in 2020. RESULTS: In patients operated upon more than five years ago (N = 1235), there were 20 (1.6%) recurrences not reported. In more recent patients, more recurrences were unreported (4.0%). Few synchronous metastases were wrongly registered (3.6%) and, likewise, few synchronous metastases were not registered (about 1%). The five-year recurrence risk in stage II was 6% for low-risk, 11% for intermediate risk, and 23% for high-risk colon cancer patients. In stage III, it was 25% in low- and 45% in high-risk patients. Incorporation of risk factors in stage III modified the risks substantially even if this is not considered by ESMO. Adjuvant chemotherapy lowered the risk in stage III but not to any relevant extent in stage II. CONCLUSION: The registration of recurrences in the registry after 5 years is accurate to between 1 and 2% but less accurate earlier. A small number of unreported recurrences and falsely reported recurrences were discovered in the chart review. The recurrence risk in this validated and updated patient series matches what has been recently reported, except for the risk of recurrence in stage II low risk colon cancers which seem to be even a few percentage points lower (6 vs. 9%).

Does exercise intensity matter for fatigue during (neo-)adjuvant cancer treatment? The Phys-Can randomized clinical trial.

Exercise during cancer treatment improves cancer-related fatigue (CRF), but the importance of exercise intensity for CRF is unclear. We compared the effects of high- vs low-to-moderate-intensity exercise with or without additional behavior change support (BCS) on CRF in patients undergoing (neo-)adjuvant cancer treatment. This was a multicenter, 2x2 factorial design randomized controlled trial (Clinical Trials NCT02473003) in Sweden. Participants recently diagnosed with breast (n = 457), prostate (n = 97) or colorectal (n = 23) cancer undergoing (neo-)adjuvant treatment were randomized to high intensity (n = 144), low-to-moderate intensity (n = 144), high intensity with BCS (n = 144) or low-to-moderate intensity with BCS (n = 145). The 6-month exercise intervention included supervised resistance training and home-based endurance training. CRF was assessed by Multidimensional Fatigue Inventory (MFI, five subscales score range 4-20), and Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F, score range 0-52). Multiple linear regression for main factorial effects was performed according to intention-to-treat, with post-intervention CRF as primary endpoint. Overall, 577 participants (mean age 58.7 years) were randomized. Participants randomized to high- vs low-to-moderate-intensity exercise had lower physical fatigue (MFI Physical Fatigue subscale; mean difference -1.05 [95% CI: -1.85, -0.25]), but the difference was not clinically important (ie <2). We found no differences in other CRF dimensions and no effect of additional BCS. There were few minor adverse events. For CRF, patients undergoing (neo-)adjuvant treatment for breast, prostate or colorectal cancer can safely exercise at high- or low-to-moderate intensity, according to their own preferences. Additional BCS does not provide extra benefit for CRF in supervised, well-controlled exercise interventions.

Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes.

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients.

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year PFS than those with TP53/KRAS/NRAS wild-type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.

Evaluation of the antibody response to the EBV proteome in EBV-associated classical Hodgkin lymphoma.

The humoral immune response to Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (cHL) stratified by EBV tumor status is unclear. We examined IgG and IgA antibody responses against 202 protein sequences representing 86 EBV proteins using a microarray and sera from 139 EBV-positive cHL cases, 70 EBV-negative cHL cases and 141 population-based controls frequency matched to EBV-positive cHL cases on sex and age by area (UK, Denmark and Sweden). We leveraged existing data on the proportion of circulating B-cells infected by EBV and levels of serum CCL17, a chemokine secreted by cHL tumor cells, from a subset of the cHL cases in the UK. Total IgG but not IgA response level was significantly different between EBV-positive cHL cases and controls. The distinct serological response included significant elevations in 16 IgG antibodies and 2 IgA antibodies, with odds ratioshighest vs. lowest tertile > 3 observed for the following EBV proteins: LMP1 (oncogene), BcLF1 (VCAp160, two variants) and BBLF1 (two variants). Our cHL IgG signature correlated with the proportion of circulating EBV-infected B-cells, but not serum CCL17 levels. We observed no differences in the anti-EBV antibody profile between EBV-negative cHL cases and controls. BdRF1(VCAp40)-IgG and BZLF1(Zta)-IgG were identified as the serological markers best able to distinguish EBV-positive from EBV-negative cHL tumors. Our results support the hypothesis that differences in the EBV antibody profile are specific to patients with EBV-positive cHL and are not universally observed as part of a systematically dysregulated immune response present in all cHL cases.

No excess long-term mortality in stage I-IIA Hodgkin lymphoma patients treated with ABVD and limited field radiotherapy.

When treating limited stage classical Hodgkin lymphoma (cHL), balancing treatment efficacy and toxicity is important. Toxicities after extended-field radiotherapy are well documented. Investigators have aimed at reducing toxicity without compromising efficacy, mainly by using combined modality treatment (CMT), i.e. chemotherapy and limited-field radiotherapy. In some clinical trials, radiotherapy has been omitted. We evaluated 364 patients with stage I-IIA cHL treated between 1999 and 2005. Patients were treated with two or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) according to presence of risk factors, followed by 30 Gy limited-field (reduced compared to involved-field) radiotherapy. After a median follow-up of 16 years for survival, freedom from progression at five and ten years was 93% and overall survival at 5 and 10 years was 98% and 96%, respectively. Only two relapses, out of 27, occurred after more than 5 years. There was no excess mortality compared to the general population. Of the analysed subgroups, only patients with progression within five years showed significant excess mortality. The absence of excess mortality questions the concept of omitting radiotherapy after short-term chemotherapy, a strategy that has been associated with an elevated risk of relapse but not yet with a proven reduced long-term excess mortality.