Eva Angenete

Background and purpose: Fatigue affects colorectal cancer survivors and has a significant impact on overall quality of life (QoL) and possibly overall survival. Fatigue, with focus on patients with rectal cancer, is less studied. The aim of this study was to investigate fatigue prevalence at 5 years after rectal cancersurgery. Patient/material and methods: Data were collected from the Quality of Life in RECTal cancer study, a prospective longitudinal multicenter study of patients with rectal cancer, also using data from Swedish and Danish colorectal cancer registries. Baseline characteristics and treatment-related factors were investigated as potential predictors for fatigue measured with the Piper Fatigue Scale (PFS). Patients were included at diagnosis and answered questionnaires at baseline and at 5 years after diagnosis. Results: The cohort consisted of 1024 patients who underwent surgery for rectal cancer. Five hundred and ninety three patients responded to the 5-year follow-up questionnaire. At 5 years, 52.4% of patients experienced fatigue. Moderate-severe fatigue (PFS ≥ 4) was reported by 172 patients (29%). Higher Body mass index (BMI) at baseline was associated with PFS ≥ 4 (Odds ratio [OR] 1.07, 95% Confidence interval [CI] 1.02–1.11, p = 0.004) in the univariate analysis, with similar results in multivariate analysis. A significantassociation was found between pain and moderate-to-severe fatigue in univariate analysis, OR 4.34 (p < 0.0001, 95% CI 2.91–6.49), but not in multivariate analysis, 2.8 (p < 0.0001, 95% CI 1.79–4.58). Higher QoL was negatively correlated with PFS ≥ 4 in both uni- and multivariate analyses (OR 0.37, 95% CI 0.30–0.46, p < 0.0001; OR 0.34, 95% CI 0.27–0.44 p < 0.0001). Major low-anterior resection syndrome (OR 2.17, 95% CI 1.09–4.34, p = 0.028) and permanent stoma (OR 1.92, 95% CI 1.06–3.47, p = 0.032) were associated with PFS ≥ 4 in the univariate, but not in the multivariate, analysis. Interpretation: Moderate-severe fatigue is prevalent in rectal cancer survivors. Targeted prevention of fatigue might be of interest in long-term rehabilitation of rectal cancer survivors.

Objective: The objective of this study is to explore effects on self‐reported fatigue at 4 weeks and 12 months after surgery in patients with colorectal cancer undergoing a pre‐ and postoperative exercise intervention compared to standard care in a randomized trial. Background: Fatigue after cancer surgery is common and evidence suggests it could be alleviated by physical activity. In this post hoc exploratory study, we analyzed fatigue and other secondary outcomes from a randomized trial aimed at exploring if prehabilitation by additional physical activity could improve postoperative recovery. Method: PHYSSURG C was a multicenter, controlled, randomized trial. Patients diagnosed with colorectal cancer were randomized to additional unsupervised moderate physical exercise in accordance with WHO guidelines or usual care two weeks before and four weeks after surgery. Trial‐specific questionnaires were used at baseline, at 4 weeks and 12 months. Outcomes were self‐reported fatigue as well as quality of life, pain, and mental recovery at both postoperative follow‐up times. Results: A total of 518 patients were included in this analysis. At 4 weeks after surgery, the mean difference in fatigue was 3.75 ((CI 0.01;7.49), p = 0.05) with intention to treat approach, and in a per protocol analysis at 4 weeks the mean difference was 4.04 ((CI 0.14;7.93), p = 0.04), and at 12 months it was 4.29 ((CI 0.44; 8.14), p = 0.03). There were no differences between the intervention and control groups regarding quality of life, pain, or mental recovery. Conclusion: This exploratory study found a suggestion of less postoperative fatigue in the intervention group. Further studies are needed to define the role of unsupervised moderate exercise, if any, before and after surgery in regard to postoperative fatigue in patients with colorectal cancer. Trial Registration: ClinicalTrials.gov identifier: NCT02299596

Background and purpose: Pain as a long-term outcome following rectal cancer treatment has received limited attention in previous studies. This prospective cohort study examined pain prevalence up to 5 years post-surgery in patients treated with curative intent. Secondary aims included evaluating pain intensity and its interference with daily life, and comparing pain experiences with a reference population. In addition, potential risk factors for pain were explored.Patient/material and methods: The study is based on the multicenter prospective cohort study QoLiRECT including patients from 16 surgical departments in Denmark and Sweden (2012–2015). Questionnaires regarding Quality of Life were administered at diagnosis and at 1, 2 and 5 years after treatment. Information about self-assessed pain was primarily derived from the ‘Brief Pain Inventory – Short Form’. Comparisons were made with an age- and sex- matched reference population.Results: Five years post-treatment, 37% of rectal cancer survivors reported pain exceeding common types of pain, with an average pain level of 3.8 and interference score of 3.1 (range 0–10). Pain was mainly located to the lower extremities, back and pelvis. Surprisingly, pain prevalence was higher in the reference population (53%), a difference consistent at all time points. No significant difference was found between groups regarding average pain or interference. Higher pain levels were associated with female sex, severe baseline pain, and elevated Body Mass Index (BMI).Interpretation: Pain was more common in the reference population, while intensity and interference were similar between groups. This suggests that the experience of pain may differ after surviving cancer, and such differences might be considered when studying pain in cancer survivors.

Characterizing the composition of immune cells in the tumor microenvironment (TME) has shown promise in understanding variable responses to neoadjuvant treatment in rectal cancer. Despite this, no method has been established that can confidently predict the response to pre-operative chemoradiotherapy. Tumor-associated macrophages (TAMs) in the TME can be polarized by the biochemical milieu to adopt pro-inflammatory (M1-like) and anti-inflammatory (M2-like) phenotypes. Utilizing the spectrum of TAM polarization as a biomarker to predict patient response to neoadjuvant therapy in rectal cancer patients has not been fully explored. We address this using 7-plex immunofluorescence staining to quantify 16 subsets of TAMs in rectal adenocarcinoma pretreatment biopsies. Pretreatment biopsies were obtained from 128 patients with known tumor regression grades (TRG). Through quantifying the prevalence of TAM subsets, we identified a higher density of the completely M1-polarized subset and a lower density of the completely M2-polarized subset in patients with a complete pathological response, the absence of detectable tumor cells following treatment. Predictive modeling using TAM subsets showed that only the densities of two completely polarized subsets were predictors of therapeutic response in patients with rectal cancer. Significantly, we demonstrate that the full panel of markers we employed were required to define predictive populations, as total TAMs or TAM subsets defined by fewer markers were incapable of predicting treatment response. Taken together, we validate the utility of a multiplex approach to define the spectrum of TAM polarization, which can be leveraged to identify patients that will have a complete pathological response to neoadjuvant treatment.

Background and aims: The Swedish ColoRectal Cancer Registry (SCRCR) includes data on patients with rectal cancer in Sweden with a coverage rate of 98.5%. Variables on primary diagnosis and treatment have good validity, but the validation of oncological outcomes such as local recurrence is lacking. Since data from the SCRCR are used widely in research and for clinical evaluation, with local recurrence as an important outcome, this study aimed to validate the registration of local recurrence of rectal cancer in the SCRCR. Methods: All patients registered with a diagnosis of rectal cancer in 2016 and 2017 who underwent an abdominal resection of the tumor were identified in the SCRCR. Medical records were reviewed and compared to the data registered in the SCRCR. Results: A total of 2828 patients were included, of which 166 patients (5.9%) were diagnosed with local recurrence according to medical records within the study period. Of these, 94/166 (57%) were registered with local recurrence in the SCRCR. Patients with non-reported local recurrence more often had concurrent metastases and/or were treated with palliative intent. There were 17 patients reported with local recurrence in the SCRCR without local recurrence identified in the medical records. Conclusion: There was a significant underreporting of local recurrence in the SCRCR. Ambiguities in the definition of local recurrence as well as disregarding patients with concurrent metastatic disease probably contributed to the underreporting. Clarifying the definition of local recurrence and stressing the importance of reporting local recurrence regardless of metastatic disease or palliative treatment may improve data accuracy.

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 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 × 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.

Background and purpose: Anal cancer is treated with chemoradiotherapy and with salvage surgery in case of local failure. Curation rate depends on tumour stage but is overall high (80–90%). This study explored anal cancer survivors’ perception of being cured and possible association with Quality of Life (QoL). Secondary aims were to explore fear of recurrence and if perception of cure changed over time or differed depending on tumour stage. Patients/material and methods: The ANal CAncer study comprises a cohort of patients diagnosed with anal cancer in Sweden between 2011 and 2013 (n = 388). Participants filled out a study-specific questionnaire 3 and/or 6 years after diagnosis (n = 205). In this sub-study, only patients treated with curative intent were included. The association between perception of cure and QoL was analysed using logistic regression. Descriptive analyses were performed regarding secondary aims. Results: A high proportion (80%) of the patients were either moderately or very sure of cure across all tumour stages, in both early and advanced tumour stages, and with no obvious improvement over time. Despite this 42% experienced fear of recurrence 6 years after diagnosis. A strong perception of cure was correlated with high QoL. Interpretation: Even though most patients had a perception of being cured, several patients irrespective of tumour stage, felt unsure of cure and feared recurrence years after successful treatment. A strong perception of cure was also shown to be associated with a high QoL. We suggest that improved counselling could enhance the patient’s perception of cure and to possibly improve QoL.

Introduction: Anal squamous cell carcinoma (ASCC) is primarily treated with chemoradiotherapy (CRT), but surgery can be curative following treatment failure. The treatment of ASCC was centralised in Sweden in 2017. This study aims to describe the characteristics and outcomes of surgery for ASCC nationally, focusing on short‐term morbidity and mortality. Materials and Methods: All patients with ASCC who underwent surgery from 2017 to 2021 in Sweden were retrospectively identified. Perioperative complications and mortality rates were recorded, and risk factors were analysed. Results: A total of 97 patients underwent 103 surgical procedures. The median age was 64 years (56–74), and 61% were women. Indications included recurrent tumours after CRT (43%), residual disease (34%), re‐recurrence following prior salvage surgery (8%), primary surgery due to CRT contraindication (8%) and post‐treatment sequelae (8%). Surgical procedures included 84 (82%) abdominoperineal excisions, 10 (10%) pelvic exenterations, 5 (5%) perineal excisions for local re‐recurrences and 4 (4%) lymphadenectomies. Overall, 48% of patients experienced perineal morbidity, defined as perineal wound infection, dehiscence, necrosis or pelvic abscess. Major surgical complications (Clavien‐Dindo ≥ III) were reported in 22/103 (21%) of procedures. Most reoperations (9/16) were related to flap complications. Thirty‐ and 90‐day mortality rates were 0% and 1%, respectively. Conclusion: This national cohort study presents the largest recent series of surgically treated ASCC patients in Sweden. Surgery caused substantial short‐term morbidity, particularly perineal morbidity, while short‐term mortality remained low. Although no significant risk factors for major complications were identified, these findings highlight the need for improved perineal wound management and further evaluation of long‐term outcomes.

Aspirin reduces the incidence of colorectal adenoma and colorectal cancer among high-risk persons. Observational studies suggest that aspirin may also improve disease-free survival after diagnosis, particularly among patients with tumors harboring somatic PIK3CA mutations. However, data from randomized trials are lacking. We conducted a double-blind, randomized, placebo-controlled trial involving patients with stage I, II, or III rectal cancer or stage II or III colon cancer with somatic alterations in PI3K pathway genes. The patients were assigned in a 1:1 ratio to receive 160 mg of aspirin or matched placebo once daily for 3 years. Patients with prespecified PIK3CA hotspot mutations in exon 9 or 20 (group A alterations) and those with other moderate- or high-impact somatic variants in PIK3CA, PIK3R1, or PTEN (group B alterations) were eligible for randomization. The primary end point was colorectal cancer recurrence, assessed in a time-to-event analysis, in patients with group A alterations. Secondary end points included colorectal cancer recurrence in patients with group B alterations, disease-free survival, and safety. Alterations in PI3K pathway genes were detected in 1103 of 2980 patients (37.0%) with complete genomic data. Of 515 patients with group A alterations and 588 patients with group B alterations, 314 and 312, respectively, were assigned to receive aspirin or placebo. The estimated 3-year cumulative incidence of recurrence was 7.7% with aspirin and 14.1% with placebo (hazard ratio, 0.49; 95% confidence interval [CI], 0.24 to 0.98; P = 0.04) among patients with group A alterations and 7.7% and 16.8%, respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.83), among those with group B alterations. The estimated 3-year disease-free survival was 88.5% with aspirin and 81.4% with placebo (hazard ratio, 0.61; 95% CI, 0.34 to 1.08) among patients with group A alterations and 89.1% and 78.7%, respectively (hazard ratio, 0.51; 95% CI, 0.29 to 0.88), among those with group B alterations. Severe adverse events occurred in 16.8% of aspirin recipients and 11.6% of placebo recipients. Aspirin led to a significantly lower incidence of colorectal cancer recurrence than placebo among patients with PIK3CA hotspot mutations in exon 9 or 20 and appeared to have a similar benefit among those with other somatic alterations in PI3K pathway genes. (Funded by the Swedish Research Council and others; ALASCCA ClinicalTrials.gov number, NCT02647099; EudraCT number, 2015-004240-19.).

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