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Supplementary Figure S1. Annual distribution of patients by extent of annual work loss (0, 1-180, 181-359 and >360 days) from two years before to five years after rectal cancer diagnosis for relapse-free patients without pre-diagnostic work loss before diagnosis (n=2529) and with pre-diagnostic work loss (sick leave only n=500, or disability pension n=409).

Supplementary Table S1. Numbers of patients at risk and mean days of work loss for clinical subgroups among relapse-free patients without pre-diagnostic work loss between 2 years before diagnosis and 5 years after diagnosis. Supplementary Table S2. Incidence rate ratio of work loss related to demographic covariates following diagnosis among relapse-free rectal cancer patients stratified by pre-diagnostic work loss Supplementary Table S3. Incidence rate ratio (IRR) of work loss following rectal cancer diagnosis associated with clinical covariates among relapse-free rectal cancer patients with pre-diagnostic sick leave (SL) only or disability pension (DP).

Background: The number of working-age rectal cancer survivors is increasing due to early detection and improved treatment. However, work loss duration and predictors among them have not been studied thoroughly.Methods: We identified 3,438 patients with stage I–III rectal cancer, 18 to 61 years of age in the Swedish Colorectal Cancer Register 1996–2009. Information on work loss due to sick leave or disability pension was collected from 2 years before diagnosis to 5 years after (until December 31st, 2013). Incidence rate ratios (IRR) of work loss were estimated in a negative binominal model by clinical characteristics for the 1st and 2nd–5th years after diagnosis. Patients were stratified by prediagnostic work loss.Results: Patients without prediagnostic work loss (74%) experienced median 147 days (25th and 75th percentile: 55 and 281) of work loss during the 1st year after diagnosis. Work loss rates (2nd–5th years) were significantly increased among relapse-free patients diagnosed in stage III [IRR = 1.92; 95% confidence interval (CI), 1.52–2.43], operated with abdominoperineal resection (IRR = 1.26; 95% CI, 1.03–1.56), and treated with neoadjuvant (chemo)radiotherapy (IRR = 1.46; 95% CI, 1.06–2.02). Patients with prediagnostic work loss (26%) experienced median 336 days (25th and 75th percentile: 183 and 365) of work loss during the 1st year, and rates did not vary clinically till 5 years.Conclusion: Without prediagnostic work loss, disease- and treatment-related factors could help identify rectal cancer patients in need of early interventions to facilitate return to work.Impact: Clinical awareness around prediagnostic and postdiagnostic work loss and individualized cancer rehabilitation programs should be emphasized among cancer survivors. Cancer Epidemiol Biomarkers Prev; 25(6); 987–94. ©2016 AACR.

Watch and wait after neoadjuvant treatment in rectal cancer: comparison of outcomes in patients with and without a complete response at first reassessment in the International Watch & Wait Database (IWWD)

Background: Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy.Methods: In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS.Results: Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46-0.85).Conclusion: A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients. Background: Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy.Methods: In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS.Results: Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46-0.85).Conclusion: A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients.

The purpose of this study is to present and evaluate a surgical method using gluteal flap for combined perineal and vaginal reconstruction after abdominoperineal excision (APE) with partial vaginectomy for anorectal malignancy. The method is a two-centre study of consecutive patients undergoing APE including partial vaginectomy for anorectal tumours, with immediate combined perineal and vaginal reconstruction using gluteal flaps. Follow-up data were retrieved via retrospective review of medical records, questionnaires and gynaecological examinations. Some 34 patients fulfilled the inclusion criteria. At the time of follow-up, 14 (78%) of the 18 patients alive responded to questionnaires. Seven (50%) of the survey responders agreed to undergo gynaecological examination. Major flap-specific complications (Clavien–Dindo > 2) were observed in 3 (9%) patients. Among survey responders, 11 (79%) had been sexually active preoperatively of which five (45%) resumed sexual activity postoperatively and three (27%) resumed vaginal intercourse. These three patients had all implemented an active vaginal health promotion strategy postoperatively. Perineo-vaginal reconstruction using gluteal flap after extended APE for anorectal malignancy is feasible. Although comparable to other methods of reconstruction, the rate of perineo-vaginal complications is high and post-operative sexual dysfunction is substantial. Postoperative strategies for vaginal health promotion may improve sexual function after vaginal reconstruction.

Simple Summary Early onset of colorectal cancer (EOCRC) is increasing in developed countries. The aim was to investigate autoimmune and metabolic conditions as risk factors for EOCRC. We investigated preexisting autoimmune and metabolic diagnoses of 2626 EOCRC patients in Sweden, diagnosed in 2007-2016, together with 15,756 controls matched for birth year, sex, and county. Comorbid diagnoses were collected from the National Patient Register. A history of metabolic disease nearly doubled the incidence of EOCRC, and presence of inflammatory bowel disease (IBD) was associated with a sixfold increased incidence of EOCRC. Patients with both IBD and metabolic disease had a lower incidence of EOCRC compared with IBD patients without metabolic condition. Non-IBD autoimmune disease was not associated with an increased incidence of EOCRC. IBD and metabolic disease are risk factors for EOCRC and should be considered in screening guidelines. Incidence of early-onset (Funding Agencies|Swedish Research Council; Swedish Cancer Society; Stockholm Cancer Society; Medical Research Council of Southeast Sweden; Region Stockholm (ALF project); Bengt Ihre Foundation; Mag-Tarmfonden

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).

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. 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. 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). 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.

Neoadjuvant short-course radiotherapy (SCRT) followed by full-dose systemic chemotherapy is an established treatment modality in locally advanced rectal cancer (LARC). Until recently, SCRT has been exclusively delivered with photons. Proton beam therapy (PBT) may minimize acute toxicity, which in turn likely impacts favorably on the tolerability to subsequent chemotherapy. The aim of this study is a dosimetric comparison between SCRT with photons and protons in the randomized phase II trial PRORECT (NCT04525989).From June 2021 to June 2022, twenty consecutive patients with LARC have been treated according to study protocol. For each patient, both a VMAT and a PBT treatment plans have been generated and compared pairwise.Dose-volume histogram (DVH) analysis revealed that SCRT with protons significantly reduced radiation dose to pelvic organs at risk including bladder, bones, and bowel in comparison to SCRT with photons. Photon and proton treatment plans had equivalent conformity and homogeneity indexes.Preoperative SCRT with protons offers a significant reduction of radiation dose to normal tissues compared with current photon-based radiotherapy technique. Demonstrated dosimetric advantages may translate into measurable clinical benefits in patients with LARC. Clinical implications of the dosimetric superiority of SCRT with protons will be presented in the coming reports from the PRORECT trial.

BACKGROUND/AIM For patients with locally recurrent rectal cancer (LRRC) extensive surgery is often the only curative option and patient selection is crucial. This study aimed to investigate whether magnetic resonance imaging (MRI) characteristics of the primary tumour can predict oncological outcome after surgery for locally recurrent rectal cancer (LRRC). PATIENTS AND METHODS All patients undergoing surgery for LRRC with a curative intent at the Karolinska University Hospital 2003-2013 were included. MRI examinations of the primary tumour were re-evaluated. RESULTS In total, 54 patients were included. A tumour volume decrease of

Purpose To longitudinally investigate overall and diagnosis-specific sickness absence (SA) and disability pension (DP) in colorectal cancer (CRC) survivors and references and to identify potential risk factors. Methods This longitudinal register-based cohort study included all patients living in Sweden, diagnosed with a first primary CRC in 2008–2011 when aged 18–62 (n=6679), and their matched references (n=26 716). Net days of SA (in SA spells >14 days) and DP were analyzed from 2 years before through 5 years after diagnosis, overall and by specific diagnoses. Among survivors, risk factors for future SADP were explored using logistic regression. Results In survivors, SA peaked in year 1 postdiagnosis, with 62.5% having at least some SA, and then gradually decreased to 20.1% in year 5. In the 2 years after diagnosis, CRC was the most common SA diagnosis in survivors, while SA due to mental diagnoses remained similar to the references. Notable risk factors for postdiagnostic SA or DP were rectal cancer diagnosis, advanced cancer stage at diagnosis, lower educational level, born outside of Sweden, and pre-diagnostic SA, mental morbidity, and comorbidities. Conclusion During 5 years after a CRC diagnosis, CRC survivors had higher levels of postdiagnostic SA and DP than the references, which was mostly due to CRC diagnoses. Although their SA lowered gradually, it did not return to pre-diagnostic levels. Implications for Cancer Survivors Our results provide valuable information for patients with CRC diagnosis, especially that most have none or low levels of SA/DP after a few years.

In this study, preoperative radiotherapy for rectal cancer was found to result in a dose-dependent impairment of spermatogenesis and Sertoli cell function, reflected both by decreased sperm count and characteristic changes in hormonal response, with signs of partial recovery between 12 and 24 months after surgery. Decreased semen volume was also observed, indicating ejaculatory tract dysfunction, that seemed to be longer-lasting and not related to testicular dose. This threatens fertility in men treated for rectal cancer, and suggests that pretreatment cryopreservation and anticonception after treatment should be discussed individually.

Summary Background Watch and wait is a novel management strategy in patients with rectal cancer who have a clinical complete response after neoadjuvant chemoradiotherapy. Surveillance of these patients is generally intensive, because local regrowth (with the potential for salvage) occurs in 25% of patients, and distant metastases occur in 10% of patients. It is unclear for how long these patients should be followed up. To address this issue, we did conditional survival modelling using the International Watch & Wait Database (IWWD), which is a large-scale registry of patients with a clinical complete response after neoadjuvant chemotherapy who have been managed by a watch-and-wait strategy. Methods We did a retrospective, multicentre registry study using a dataset from the IWWD, which includes data from 47 clinics across 15 countries. We selected patients (aged ≥18 years) with rectal cancer who had a clinical complete response after neoadjuvant chemotherapy, and who were subsequently managed by a watch-and-wait strategy between Nov 25, 1991, and Dec 31, 2015. Patients who had not achieved a clinical complete response or who had undergone any surgical procedure were excluded. The criteria used for defining a clinical complete response and the specific surveillance strategies were at the discretion of each participating centre. We used conditional survival modelling to estimate the probability of patients remaining free of local regrowth or distant metastasis for an additional 2 years after sustaining a clinical complete response or being distant metastasis-free for 1, 3, and 5 years from the date of the decision to commence watch and wait. The primary outcomes were conditional local regrowth-free survival at 3 years, and conditional distant metastasis-free survival at 5 years. Findings We identified 793 patients in the IWWD with clinical complete response who had been managed by a watch-and-wait strategy. Median follow-up was 55·2 months (IQR 36·0–75·6). The probability of remaining free from local regrowth for an additional 2 years if a patient had a sustained clinical complete response for 1 year was 88·1% (95% CI 85·8–90·9), for 3 years was 97·3% (95·2–98·6), and for 5 years was 98·6% (97·6–100·0). The probably of remaining free from distant metastasis for a further 2 years in patients who had a clinical complete response without distant metastasis for 1 year was 93·8% (92·3–95·9), for 3 years was 97·8% (96·6–99·3), and for 5 years was 96·6% (94·0–98·9). Interpretation These results suggest that the intensity of active surveillance in patients with rectal cancer managed by a watch-and-wait approach could be reduced if they achieve and maintain a clinical complete response within the first 3 years of starting this approach. Funding European Registration of Cancer Care, financed by the European Society of Surgical Oncology, the Champalimaud Foundation Lisbon, the Bas Mulder Award, granted by the Alpe d’HuZes Foundation and the Dutch Cancer Society, the European Research Council Advanced Grant, and the National Institute of Health and Research Manchester Biomedical Research Centre.

Aim The Stockholm‐Gotland Regional Cancer Plan was launched in 2012 to improve cancer care. A personal contact nurse (CN), an individual written care plan (IWCP) and a standardized care pathway (SCP) were introduced. The aim of the current study was to evaluate whether these efforts have resulted in an improved experience for patients treated for colorectal cancer. Method Patients treated with bowel resection for colorectal cancer in the Stockholm‐Gotland region between 1 January 2013 and 31 December 2017 were identified through the Swedish Colorectal Cancer Registry. Six to eight months postoperatively, the patients received a patient‐reported experience questionnaire. Patients were classified as ‘satisfied’ or ‘not satisfied’. Results The questionnaire was sent to 4465 patients, and 3154 (70.64%) responded. The proportion of patients assigned a CN increased over time (79.84%–88.44%) and so did the proportion of patients receiving an IWCP (39.36%–70.00%). The waiting times were significantly shortened during the study period. In multivariable analysis, access to a CN and an IWCP was independently associated with increased patient satisfaction (OR 3.03, 95% CI 2.28–4.02 and OR 1.64, 95% CI 1.38–1.94). Patients with a long waiting time were significantly less satisfied than patients with a short waiting time (OR 0.72, 95% CI 0.60–0.88). Conclusion Implementation of a CN, IWCP and SCP has been successful, measured by a higher proportion of patients gaining access to these assets and shortened waiting times. This has led to an improved patient experience in patients treated for colorectal cancer in the Stockholm‐Gotland region.

Background The incidence of colorectal cancer in patients aged less than 50 years is increasing in Western countries. This population‐based study investigated the age‐ and sex‐specific incidence of colorectal cancer over time in Sweden, and characterized trends in tumour localization and stage at diagnosis. Methods Patients diagnosed with colorectal cancer between 1970 and 2016 were identified from the Swedish Cancer Registry, and categorized by sex, age and tumour location. The incidence and average annual percentage change (AAPC) were estimated and compared between age groups. Results There was an overall increase in the incidence of colorectal cancer between 1970 and 2006, but a decrease in 2006–2016 (AAPC −0·55 (95 per cent c.i. −1·02 to −0·07) per cent). The largest increase in colonic cancer was in 1995–2005 in women aged less than 50 years (AAPC 2·30 (0·09 to 4·56) per cent versus 0·04 (−1·35 to 1·44) and − 0·67 (−1·62 to 0·28) per cent in women aged 50–74 and 75 years or more respectively). Since 1990, rectal cancer increased in patients of both sexes aged below 50 years, with higher AAPC values in women (2006–2016: 2·01 (−1·46 to 5·61) per cent versus 0·20 (−2·25 to 2·71) per cent in men). Younger patients were more likely than those aged 50–74 and 75 years or more to present with stage III–IV colonic (66·2, 57·6 and 49·6 per cent respectively) and rectal (61·2, 54·3 and 51·3 per cent) cancer. From the mid 1990s, rates of proximal and distal colorectal cancer, and rectal cancer were increased in patients aged less than 50 years. Conclusion The overall incidence of colorectal cancer in Sweden decreased in the past decade. However, in patients under 50 years of age the incidence of colorectal cancer – proximal, distal and rectal – continued to increase over time., The overall incidence of colorectal cancer in Sweden increased between 1970 and 2006, with a decrease observed only in the last decade, 2006–2016. However, in patients younger than 50 years of age there was an ongoing increase, more marked in women. Early onset colorectal cancer in sweden

Objectives A family history of colorectal cancer (CRC) is an established risk factor for developing CRC, whilst the impact of family history on prognosis is unclear. The present study assessed the association between family history and prognosis and, based on current evidence, explored whether this association was modified by age at diagnosis. Methods Using data from the Swedish Colorectal Cancer Registry (SCRCR) linked with the Multigeneration Register and the National Cancer Register, we identified 31 801 patients with a CRC diagnosed between 2007 and 2016. The SCRCR is a clinically rich database which includes information on the cancer stage, grade, location, treatment, complications and postoperative follow‐up. Results We estimated excess mortality rate ratios (EMRR) for relative survival and hazard ratios (HR) for disease‐free survival with 95% confidence intervals (CIs) using flexible parametric models. We found no association between family history and relative survival (EMRR = 0.96, 95% CIs: 0.89–1.03, P = 0.21) or disease‐free survival (HR = 0.98, 95% CIs: 0.91–1.06, P = 0.64). However, age was found to modify the impact of family history on prognosis. Young patients (

The aim was to evaluate differences in stage, treatment and prognosis in patients aged less than 50 years with colorectal cancer compared with older age groups.This population-based study included all patients diagnosed with colorectal cancer in Sweden, 2010-2015. Disease stage, treatment, 5-year disease-free survival (DFS) and relative survival were analysed in relation to age groups: less than 50, 50-74 and at least 75 years.Of 34 434 patients included, 24·1, 19·7 and 14·0 per cent of patients aged less than 50, 50-74 and at least 75 years respectively were diagnosed with stage IV disease (P 0·001). Adverse histopathological features were more common in young patients. Among patients aged less than 50 years, adjuvant chemotherapy was given to 18·9, 42·0 and 93·9 per cent of those with stage I, III and III disease respectively, compared with 0·7, 4·4 and 29·6 per cent of those aged 75 years or older (P 0·001). Stage-adjusted DFS at 5 years for patients under 50 years old was 0·96, 0·90 and 0·77 in stage I, II and III respectively. Corresponding proportions were 0·88, 0·82 and 0·68 among patients aged 50-74 years, and 0·69, 0·62 and 0·49 for those aged 75 years or older. Relative survival was better for young patients only among those with stage III disease.Patients younger than 50 years with colorectal cancer had a poorer stage at diagnosis and received more intensive oncological treatment. DFS was better than that among older patients in early-stage disease.El objetivo del estudio fue evaluar las diferencias en estadio, tratamiento y pronóstico en pacientes con cáncer colorrectal (colorectal cancer, CRC) de edad inferior a 50 años en comparación con los grupos de mayor edad. MÉTODOS: Estudio de base poblacional de todos los pacientes con CRC en Suecia 2010-2015. Se analizaron el estadio, tratamiento, supervivencia libre de enfermedad (disease-free survival, DFS) a los 5 años y supervivencia relativa (relative survival, RS) en los grupos de edad de 50, 50-74, ≥ 75 años.De 34.434 pacientes incluidos, tenían un estadio IV en el momento del diagnóstico en el 24,1%, 19,7% y 14,0% de los pacientes de 50, 50-74 y ≥ 75 años de edad, respectivamente (P 0,001). Las características histopatológicas desfavorables fueron más frecuentes en pacientes jóvenes. Se administró quimioterapia adyuvante al 18,9%, 42,0% y 93,9% de los pacientes con edad inferior a 50 años con estadios I, II y III de la enfermedad respectivamente, en comparación con el 0,7%, 4,4% y 29,6% de los pacientes ≥ 75 años con estadios I, II y III, respectivamente (P 0,001). La DFS ajustada por estadio de la enfermedad en los pacientes de 50 años fue 0,96, 0,94 y 0,77 para los estadios I, II y III, respectivamente. Las proporciones correspondientes de DFS en los pacientes de edad entre 50-74 años fueron 0,88, 0,82 y 0,68, respectivamente, y, para los pacientes de ≥ 75 de edad fueron 0,69, 0,62 y 0,49, respectivamente. La RS fue solo mejor en los pacientes jóvenes con estadio III de la enfermedad. CONCLUSIÓN: Los pacientes menores de 50 años con CRC tenían un estadio peor de la enfermedad en el momento del diagnóstico y recibieron un tratamiento oncológico más intenso. La DFS fue mejor en comparación con pacientes mayores con estadio más temprano de la enfermedad.

AIM: The aim of this study is to analyze postoperative adverse events (AE) in relation to acute primary testicular failure after radiotherapy (RT) for rectal cancer. METHOD: This relation was assessed in 104 men, included in a previous prospective cohort study of men treated with surgical resection of the rectum for rectal cancer stage I-III. Postoperative AE were graded according to Clavien-Dindo (2004). Grade 3 or more was set as cut-off for severe postoperative AE. The impact of primary testicular failure on postoperative AE was related to the cumulative mean testicular dose (TD) and the change in Testosterone (T) and Luteinizing hormone (LH) sampled at baseline and after RT. RESULTS: Twenty-six study participants (25%) had severe postoperative AE. Baseline characteristics and endocrine testicular function did not differ significantly between groups with (AE+) and without severe postoperative AE (AE-). After RT, the LH/T-ratio was higher in AE+, 0.603 (0.2–2.5) vs 0.452 (0.127–5.926) (p=0.035). The longitudinal regression analysis showed that preoperative change in T (OR 0.844, 95% CI 0.720 – 0.990, p=0.034), LH/T-ratio (OR 2.020, 95% CI 1.010 – 4.039, p=0.047) and low T (

International audience; BackgroundThis article reviews the current knowledge on circulating tumor DNA (ctDNA) in early stage colon cancer and ongoing trials on ctDNA-guided treatment in the adjuvant setting.MethodsA literature search of Pubmed was performed to identify studies on ctDNA in early stage colon cancer and neoadjuvant or adjuvant treatment. For ongoing trials, we searched clinicaltrials.gov and the Australian New Zealand Clinical Trials Registry (ANZCTR).ResultsSeveral studies show that ctDNA is a strong predictor for recurrence and survival after surgery and adjuvant chemotherapy. The specificity of this marker is extremely high, and the sensitivity is increasing with the development of technology. Recurrences can be detected very early and the analysis can potentially be used to guide neoadjuvant and adjuvant treatment. Ongoing and planned studies are now looking into escalation and de-escalation of therapy according to ctDNA-status after surgery.ConclusionSerial measurement of ctDNA shows great promise as a marker for both prognosis and response to treatment in early colon cancer. Future studies will show whether we can use this analysis for tailoring treatment for patients in the adjuvant and neoadjuvant setting. With improved technology, ctDNA has the potential of becoming a ‘game-changer’ in the treatment of early stage colon cancers.

Introduction: Pelvic radiotherapy (RT) increases the risk of pelvic insufficiency fractures. The aim was to investigate if RT is associated with changes in serum bone biomarkers in women with rectal cancer, and to examine the incidence of radiation-induced bone injuries and the association with bone biomarkers.Material and methods: Women diagnosed with rectal cancer stage I-III, planned for abdominal surgery +/- preoperative (chemo) RT, were prospectively included and followed one year. Serum bone biomarkers comprised sclerostin (regulatory of bone formation), CTX (resorption), BALP and PINP (for-mation). A subgroup was investigated with annual pelvic magnetic resonance imaging (MRI). The as-sociation between RT and bone biomarkers was explored in regression models.Results: Of 134 included women, 104 had surgery with preoperative RT. The formation markers BALP and PINP increased from baseline to one year in the RT-exposed group (p < 0.001, longitudinal comparison). In the adjusted regression analysis, the mean increase in PINP was higher in the RT-exposed than the unexposed group (17.6 (3.6-31.5) mg/L, p = 0.013). Sclerostin and CTX did not change within groups nor differed between groups. Radiation-induced injuries were detected in 16 (42%) of 38 women with available MRI. At one year, BALP was higher among women with than without bone injuries (p = 0.018, cross-sectional comparison).Conclusions: Preoperative RT was associated with an increase in the formation marker PINP, which could represent bone recovery following RT-induced injuries, commonly observed in participants evaluated with MRI. These findings should be further explored in larger prospective studies on bone health in rectal cancer patients.(c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Funding Agencies|Swedish Cancer Society; Stockholm Cancer Society; Bengt Ihre Research Fellowship; Bengt Ihre Foundation; Stockholm County Council; Karolinska Institutet; Region Ostergotland

Clinical experience and limited data show that female sexual function is influenced negatively by preoperative radiotherapy (RT) for rectal cancer. The aim of this prospective study was to investigate the impact of RT on sexual function and ovarian reserve measured by levels of anti-Müllerian hormone (AMH).Women with stage I-III rectal cancer scheduled for surgery with or without preoperative (chemo)RT were included and followed for 2 years. Female Sexual Function Index (FSFI) questionnaire responses and blood samples for hormone analyses, including AMH in women aged 45 years or less, were collected at baseline and during follow-up.In the group of 109 women who received preoperative RT, median scores in all FSFI domains decreased over time, as did the total FSFI score (from 18·5 (range 2·0-36·0) at baseline to 10·8 (2·0-34·8) at 2 years; P 0·001). In the group of 30 women who did not receive preoperative RT, only satisfaction declined over time (from 3·2 (0·8-6·0) to 1·8 (0·8-6·0); P = 0·012). In longitudinal regression analysis, the mean decline in FSFI total score was -9·33 (95 per cent c.i. -16·66 to -1·99; P = 0·013) for women who had preoperative RT compared with those who did not, with adjustment for age, Psychological General Well-being Index score and relationship with partner. A corresponding association was seen for arousal, lubrication, orgasm and pain. Five of six women aged 45 years or less with detectable serum levels of AMH at baseline had undetectable levels after RT.Preoperative RT was associated with impairment in sexual function in women with rectal cancer. This needs to be considered when discussing choice of treatment and rehabilitation. In younger women, undetectable AMH levels after RT indicate an irreversible loss of ovarian follicles.La experiencia clínica y los datos limitados que han sido publicados indican que la radioterapia (RT) preoperatoria por cáncer rectal influye negativamente en la función sexual femenina. El obejtivo de este estudio fue investigar prospectivamente el impacto de la RT en la funcion sexual y en la reserva ovárica evaluada por el nivel de hormona antimülleriana (anti-Müllerian hormone, AMH). MÉTODOS: Las mujeres con cáncer rectal estadio I-III en las que se planeaba un tratamiento quirúrgico con o sin (quimio)radioterapia ((chemo)radiotherapy (C)RT)) se incluyeron en el estudio y fueron seguidas durante 2 años. Se recogieron datos a nivel basal y durante el seguimiento del cuestionario del índice de función sexual femenina (Female Sexual Function Index, FSFI), así como se obtuvieron muestras de sangre para los análisis hormonales, incluyendo AMH en mujeres de ≤ 45 años de edad.En el grupo expuesto a RT (n = 109), la mediana de las puntuaciones disminuyó a lo largo del tiempo en todos los dominios del FSFI y en la puntuación total del FSFI (de 18,5 (2,0-36) a 10,8 (2,0-34,8), P 0,001). En el grupo no expuesto a RT (n = 30), solamente el grado de satosfacciòn disminuyó a lo largo del tiempo (de 3,2 (0,8-6,0) a 1,8 (0,8-6,0), P = 0,012). En el análisis longitudinal de regresión, la disminución media de la puntuación total del FSFI fue de -9,33 (i.c. del 95% -16,66; -1,99), P = 0,013) en el grupo expuesto a RT en comparacion con las mujeres no expuestas, durante los 2 años postoperatorios, ajustado por edad, índice de bienestar psicológico (Psychological General Well Being Index, PGWI) y vida en pareja. Se observó una asociación correspondiente con la exitación, lubricación, orgasmo y dolor. Cinco de seis mujeres de ≤ 45 años de edad con niveles séricos detectables de AMH en situación basal presentaron niveles indetectables tras la RT. CONCLUSIÓN: La RT preoperatoria se asociaba con alteración de la función sexual en mujeres con cáncer rectal. Este aspecto debe ser considerado a la hora de discutir la eleccion del tratamiento y la rehabilitación. En mujeres jóvenes, los niveles indetectables de AMH tras la RT indican una pérdida irreversible de folículos ováricos.

The aim of this study was to determine the effect of testosterone administration on trunk and pelvic floor muscle area in women with low testosterone levels.Participants were hysterectomized women with total testosterone31 ng/dL and/or free testosterone3.5 pg/mL; participating in the Testosterone Dose Response in Surgically Menopausal Women (TDSM) trial. All participants received a standardized transdermal estradiol regimen during the 12-week run-in period, and were then randomized to receive weekly intramuscular injections of placebo, or 3, 6.25, 12.5, or 25 mg testosterone enanthate for 24 weeks. Muscle areas of the trunk and pelvis were measured at baseline and end of treatment using 1.5 Tesla magnetic resonance imaging. Total and free testosterone levels were measured by liquid chromatography-tandem mass spectrometry and equilibrium dialysis, respectively. Testosterone effect on muscle areas was analyzed using linear regression models.A total of 24 women who had available baseline and posttreatment magnetic resonance imaging were included in the analysis. Increased cross-sectional areas of the paraspinal, psoas, and abdominal wall muscles were seen after testosterone administration. The estimated mean change (95% CI; P value) between treatment groups was 4.07 cm (1.26-6.88; P = 0.007) for paraspinal, 1.60 cm (0.10-3.09; P = 0.038) for psoas major, and 7.49 cm (1.96-13.02; P = 0.011) for abdominal wall muscles. Increases in psoas muscle area were significantly associated with changes in free testosterone concentrations. No significant changes in obturator internus and pelvic floor muscle areas were observed.Short-term testosterone administration in women with low testosterone levels was associated with increased trunk muscle area.

Background The optimal treatment for patients with locally recurrent rectal cancer (LRRC) is controversial. The aim of this study was to investigate different treatment strategies in two leading tertiary referral hospitals in Europe. Methods All patients who underwent curative surgery for LRRC between January 2003 and December 2017 in Catharina Hospital, Eindhoven, the Netherlands (CHE), or Karolinska University Hospital, Stockholm, Sweden (KAR), were studied retrospectively. Available MRIs were reviewed to obtain a uniform staging for optimal comparison of both cohorts. The main outcomes studied were overall survival (OS), local re-recurrence-free survival (LRFS), and metastasis-free survival (MFS). Results In total, 377 patients were included, of whom 126 and 251 patients came from KAR and CHE respectively. At 5 years, the LRFS rate was 62.3 per cent in KAR versus 42.3 per cent in CHE (P = 0.017), whereas OS and MFS were similar. A clear surgical resection margin (R0) was the strongest prognostic factor for survival, with a hazard ratio of 2.23 (95 per cent c.i. 1.74 to 2.86; P < 0.001), 3.96 (2.87 to 5.47; P < 0.001), and 2.00 (1.48 to 2.69; P < 0.001) for OS, LRFS, and MFS respectively. KAR performed more extensive operations, resulting in more R0 resections than in CHE (76.2 versus 61.4 per cent; P = 0.004), whereas CHE relied more on neoadjuvant treatment and intraoperative radiotherapy, to reduce the morbidity of multivisceral resections (P < 0.001). Conclusion In radiotherapy-naive patients, neoadjuvant full-course chemoradiation confers the best oncological outcome. However, neoadjuvant therapy does not diminish the need for extended radical surgery to increase R0 resection rates.

Reliable predictors of a sustained clinical complete tumour response (cCR) after neoadjuvant therapy in rectal cancer (RC) are lacking. The aim of this study was to determine if the tumour regression grade (TRG) assessed by magnetic resonance imaging (MRI), at the first restaging after neoadjuvant therapy can predict organ preservation, and to estimate the time interval after which surgery should be recommended in patients who remain in near cCR.Eighty-three consecutive patients were assessed by MRI as having a cCR (mrTRG 1) or near cCR (mrTRG 2) after neoadjuvant therapy. Cox proportional hazards regression models and Kaplan-Meier survival analyses were used to determine associations between resection-free survival (RFS) and mrTRG at the first restaging, and in relation to mrTRG with a landmark period. mrTRG and pathological findings were compared in operated patients.mrTRG 2 at the first restaging significantly predicted poorer RFS during follow up. The best prediction of RFS was mrTRG at landmark 16 weeks after termination of radiotherapy; 42 out of 49 patients (86%) evaluated as mrTRG 1 had cCR at one year of follow up. In contrast, 12 out of 15 patients (80%) evaluated as mrTRG 2 had clinical signs of tumour and were recommended surgery.The first mrTRG, and to an even greater extent mrTRG at landmark 16 weeks predicts RFS. Patients who remain mrTRG 2 at 5-6 months after radiotherapy with signs of tumour should be recommended surgery. These findings may help in patient counselling and surgical decision-making.

Background Non-operative management of rectal cancer is increasingly being used in selected patients. Most reports include patients treated with chemoradiotherapy (CRT) before inclusion into a Watch & Wait (W&W) programme. The aim of this study was to report outcomes from a single-centre W&W programme involving a large cohort of patients. Methods Patients treated with chemoradiotherapy (CRT) or short-course radiotherapy (SCRT) with or without chemotherapy, between 2008 and 2020, who showed signs of a clinical complete response (cCR) were reviewed. Patients were assessed using digital rectal examination, flexible endoscopy, carcinoembryonic antigen measurement, MRI, and CT imaging, discussed at the multidisciplinary tumour board meeting, and followed up in a dedicated W&W programme as from 2015. Outcomes including regrowth and 3-year survival (time to regrowth or death) were prospectively evaluated. Results Of 142 patients who were assessed, 88 fulfilled the criteria for cCR. Treatment before cCR included CRT, SCRT with chemotherapy, and SCRT alone in 16 (18 per cent), 28 (32 per cent), and 44 (50 per cent) patients, respectively. Patients treated with CRT and SCRT with chemotherapy had more advanced clinical T- and N-stage, compared with patients treated with SCRT alone (clinical T-stage > 2: 81 per cent and 89 per cent versus 47 per cent, respectively; clinical N-stage > 0: 75 per cent and 93 per cent versus 68 per cent, respectively). Overall rate of regrowth was 19 per cent, with 31 per cent, 21 per cent, and 14 per cent following CRT, SCRT with chemotherapy, and SCRT alone, respectively. Uni- and multivariable analyses evaluating the clinical parameters revealed no statistically significant associations with risk of local regrowth. All but one patient with regrowth underwent salvage surgery. The 3-year survival rate (death with regrowth as competing risk) was 93 per cent, with no significant difference between treatment groups. Conclusion In this cohort of W&W patients, the vast majority received SCRT with or without chemotherapy and results consistent with previous W&W reports were obtained. No statistically significant differences in terms of regrowth rate were obtained when comparing CRT, SCRT with chemotherapy, and SCRT alone. SCRT can induce sustained cCR and may precede a W&W strategy., This study describes the prospective evaluation of outcomes in 88 Watch & Wait rectal cancer patients (72 treated with short-course radiotherapy with or without chemotherapy). Overall regrowth rate was 19 per cent, and all but one patient underwent salvage surgery. Short-course radiotherapy can lead to sustained complete response and precede a Watch & Wait strategy.

Background Patients with colorectal cancer were examined to determine (1) whether elevated carcinoembryonic antigen (CEA) levels, either before treatment or after surgery, was associated with an increased risk of overall or colorectal cancer-specific mortality or recurrence, and (2) whether high intensity follow-up would benefit those patients. Materials and methods Post-hoc analysis based on 2509 patients that underwent surgery for colorectal cancer, stage II or III, in the COLOFOL randomized trial with 5-year follow-up. Serum CEA levels were ascertained before treatment and one month after surgery. Follow-up examinations included computed tomography of the thorax and abdomen and serum CEA sampling. Patients were randomized to examinations at either 6, 12, 18, 24, and 36 months (high-intensity group) or at 12 and 36 months after surgery (low-intensity group). Levels of CEA >5 μg/l were defined as elevated. Results Elevated CEA levels before treatment were associated with increased risk of recurrence (hazard ratio [HR], 1.49; 95% confidence interval [CI]: 1.22–1.83), colorectal cancer-specific mortality (HR, 1.44; 95% CI: 1.08–1.91), and overall mortality (HR, 1.38; 95% CI: 1.07–1.78). Elevated CEA levels after surgery were associated with increased colorectal cancer-specific mortality (HR, 1.68; 95% CI: 1.08–2.61) and overall mortality (HR, 1.79; 95% CI: 1.22–2.63). The intensity of the follow-up regimen had no effect on 5-year outcomes in patients with elevated CEA levels. Conclusion Both pre-treatment and post-surgery elevated serum CEA levels were associated with increased overall and cancer-specific mortality. Intensified follow-up showed no benefit over low-intensity follow-up in this high-risk group of patients with elevated CEA levels.

Background The Stockholm III trial randomly assigned 840 patients to short-course radiotherapy of 5 × 5 Gy with surgery within 1 week (SRT), short-course radiotherapy of 5 × 5 Gy with surgery after 4–8 weeks (SRT-delay), or long-course radiotherapy of 25 × 2 Gy with surgery after 4–8 weeks (LRT-delay). This study details the long-term oncological outcomes and health-related quality of life (HRQoL). Methods Patients with biopsy-proven resectable adenocarcinoma of the rectum were included. Primary outcome was time to local recurrence (LR), and secondary endpoints were distant metastases (DMs), overall survival (OS), recurrence-free survival (RFS), and HRQoL. Patients were analysed in a three-arm randomization and a short-course radiotherapy comparison. Results From 1998 to 2013, 357, 355, and 128 patients were randomized to the SRT, SRT-delay, and LRT-delay groups respectively. Median follow-up time was 5.7 (range 5.3–7.6) years. Comparing patients in the three-arm randomization, the incidence of LR was three of 129 patients, four of 128, and seven of 128, and DM 31 of 129 patients, 38 of 128, and 38 of 128 in the SRT, SRT-delay, and LRT-delay groups respectively. In the short-course radiotherapy comparison, the incidence of LR was 11 of 357 patients and 13 of 355, and DM 88 of 357 patients and 82 of 355 in the SRT and SRT-delay groups respectively. No comparisons showed statistically significant differences. Median OS was 8.1 (range 6.9–11.2), 10.3 (range 8.2–12.8), and 10.5 (range 7.0–11.3) years after SRT, SRT-delay, and LRT-delay respectively. Median OS was 8.1 (range 7.2–10.0) years after SRT and 10.2 (range 8.5–11.7) years after SRT-delay. There were no statistically significant differences in HRQoL. Conclusion After a follow-up of 5 years, delaying surgery for 4–8 weeks after radiotherapy treatment with 5 × 5 Gy was oncologically safe. Long-term HRQoL was similar among the treatment arms. Trial registration number NTC00904813, Analysis of long-term follow-up after radiotherapy and surgery for rectal cancer showed that delaying surgery for 4–8 weeks after radiotherapy treatment with 5 × 5 Gy seems oncologically safe. HRQoL does not seem to differ between treatment arms with radiotherapy and immediate surgery, compared with delayed surgery.

Besides clinical evaluation, all patients with rectal cancer must be examined with CT of the chest and abdomen to assess the presence of metastases, pelvic MRI to stage the tumour locally, and if possible, colonoscopy to detect synchronous lesions. The recommended treatment is then discussed at an MDT conference and neoadjuvant radio- or chemoradiotherapy given according to national guidelines. A new digital rectal examination (DRE) and proctoscopy, CT and pelvic MRI should be performed around six weeks after treatment. The purpose is to detect potential new metastases and to assess tumour response after treatment. It is crucial to do a second MDT with careful MRI evaluation to detect a possible clinical complete response. If the post-treatment MRI shows a complete or near complete response, corresponding to clinical findings on DRE and endoscopy, the patient should be offered a prospective watch and wait protocol in a dedicated institution. With proper management of patients with rectal cancer, 20-25 procent may be saved from a rectal resection and the potential risk of a permanent stoma.

Background Sociodemographic and spatial disparities in incidence and mortality burden of colorectal cancer (CRC) are important to consider in the implementation of population screening, in order to achieve expected benefit and not increase health inequities. Analytic methods should be adapted to provide rational support for targeted interventions. Methods CRC incidence rates by tumor stage (I-IV) and location (colon vs. rectum) were analyzed for the time period 2008–2016 within a screening-relevant age interval of 55–74 years for the population of South and West Sweden, where screening is planned for. The study population was stratified by sex, country of birth, educational level (for Swedish-born citizens) and residential area. We also estimated disparities in excess mortality from CRC across groups of patients accordant to relevant population groups. Results The analyses were based on 8961 patients with a first CRC diagnosis. There were marked socioeconomic gradients in the stage II-IV CRC incidence rates among Swedish-born men and women. Compared to men with high educational level, the incidence rate ratios (IRRs) of stage II, III, and IV CRC in men with low educational level were 1.38 (95% confidence interval 1.18, 1.62), 1.09 (0.95, 1.26), and 1.18 (1.02, 1.37), respectively. In women, the corresponding figures were 1.26 (1.06, 1.51), 1.19 (1.01, 1.39), and 1.45 (1.20, 1.80). The groups of patients with low educational level showed relatively high excess mortality burdens from CRC. Conclusions Our analytic approach provided rational support for targeted intervention when implementing CRC screening, aiming at optimizing participation in groups with low educational level.

Background This population-based cohort study aimed to evaluate occurrence of low anterior resection syndrome (LARS) and correlate this to health-related quality of life in patients who had undergone segmental colonic resection for colonic cancer in the Stockholm-Gotland region. The hypothesis was that there is a difference in occurrence of LARS depending on whether a right- or a left-sided resection was performed. Methods Patients who underwent segmental colonic resection for colonic cancer stages I-III in the Stockholm-Gotland region in 2013-2015 received EORTC QLQ-C30, QLQ-CR29 and LARS score questionnaires 1 year after surgery. Clinical patient and tumour data were collected from the Swedish ColoRectal Cancer Registry. Patient-reported outcome measures were analysed in relation to type of colonic resection. Results Questionnaires were sent to 866 patients and complete responses were provided by 517 (59·7 per cent). After right-sided resection 20·6 per cent reported major LARS. After left-sided resection the proportion with major LARS was 15·6 per cent. The odds ratio (OR) for major LARS after right-sided resection was 1·45 (95 per cent c.i. 1·02 to 2·06; P = 0·037) compared with left-sided resection. After adjustment for age and sex, an increase in the risk of major LARS after right- versus left-sided resection remained (OR 1·48, 1·03 to 2·13; P = 0·035). Major LARS correlated with impaired quality of life. Conclusion Major LARS was more frequent after right-sided than following left-sided colonic resection. Major LARS reflected impaired quality of life.

Introduction Pelvic local recurrence of colorectal cancer (PRCRC) may be cured if radical surgery is performed. Preoperative assessment normally includes magnetic resonance imaging (MRI). The aim of this study was to evaluate the influence of specific MRI-related findings on outcome of surgery of PRCRC. Materials and methods Clinical data from 95 consecutive patients, operated with a curative intent for PRCRC at Karolinska University Hospital during 2003–2013, were collected from medical records. Preoperative MRI examinations of the PRCRC were re-evaluated. The potential influence of clinical factors and specific MRI-findings (location, solid/mucinous, size, volume and border) on surgical resection margins (R0-R1) and survival were calculated with logistic and cox regression. Results Eighty-seven patients had available MRI scans and were included in the study. Sixty-five patients (75%) had a R0 resection and 22 patients (25%) had a R1 resection of their PRCRC. In all, 47 patients (54%) had an involved lateral compartment. Lateral location was the only MRI finding associated with both an increased risk of R1 resection (OR 3.97, 95%CI: 1.31–12.04) and death (HR 1.94, 95%CI: 1.07–3.51). Lateral location entailed an increased risk of death also after R0 resection (HR2.09, 95%CI: 1.07–4.10). Five-year survival was 35% for all patients, 44% after R0 resection and 7% after R1 resection. Conclusion Tumour involvement of the lateral and posterior compartments on MRI was a predictor for R1 resection, but only lateral involvement was associated with an increased risk of death. An increased risk of death associated with lateral involvement was still present after R0 resection.

Introduction Complete Mesocolic Excision (CME) has been proposed as the preferred surgical technique for resection of colon cancer. This prospective cohort study evaluates the effect of CME surgery on colon cancer mortality after right-sided hemicolectomy on a population level. Methods Data from the Swedish Colorectal Cancer Registry and the Cause of Death Registry on all patients treated with elective right-sided hemicolectomy for colon cancer stage I to III in the Stockholm County 2008-2012 were analyzed. Adherence to principles of CME surgery was determined by structured analysis of anonymized surgical reports regarding presence of five essential features. The exposure to CME was graded as group 0 (not exposed to CME), group 1 (intermediate) and group 2 (exposed to CME). Results In total 1171 patients were analysed with 234 (20.0%) patients in CME group 0, 453 (38.7%) patients in CME group 1 and 484 (41.3%) in CME group 2. The 5-year colon cancer mortality was 20.2% in CME group 0, 13.9% in CME group 1 and 13.1% in CME group 2 (p=0.026). The adjusted hazard ratio for colon cancer mortality was 0.61 (95% CI 0.42 - 0.91; p=0.014) for CME group 1 and 0.52 (95% 0.35 - 0.77; p=0.001) for CME group 2. Discussion The presence of predefined CME features in surgical reports was related to a graded benefit on cancer specific mortality after right-sided hemicolectomy for colon cancer stage I to III.

Background Women treated for rectal cancer are at risk of sexual dysfunction and impaired ovarian androgen production. Aim To investigate a possible association between serum levels of endogenous androgens and sexual function in women with rectal cancer. Methods Women diagnosed with stage I–III rectal cancer were consecutively included and prospectively followed with the Female Sexual Function Index (FSFI) questionnaire from baseline to 2 years postoperatively and blood samples for hormone analyses, baseline to 1 year. Androgens were measured with liquid chromatography−mass spectrometry and electrochemiluminescence. The associations between the 4 measured androgens (testosterone, free testosterone, androstenedione, and dehydroepiandrosterone sulphate) and sexual function were assessed with generalized least squares random effects regression analysis in sexually active women. Outcomes The primary outcome measure was the mean change observed in the FSFI total score when the serum androgen levels changed with one unit. Secondary outcomes were the corresponding mean changes in the FSFI domain scores: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain/discomfort. RESULTS In the 99 participants, the median FSFI total score decreased from 21.9 (range 2.0 – 36.0) to 16.4 (3.5 – 34.5) and 11.5 (2.0 to 34.8) at 1 and 2-years follow-up. After adjustment for age, partner, psychological well-being, preoperative (chemo)radiotherapy, and surgery, total testosterone and androstenedione were significantly associated with FSFI total score (β-coefficients 3.45 (95% CI 0.92 – 5.97) and 1.39 (0.46 – 2.33) respectively). Testosterone was significantly associated with the FSFI-domains lubrication and orgasm, free testosterone with lubrication, androstenedione with all domains except desire and satisfaction, and dehydroepiandrosterone sulphate with none of the domains. Strengths and Limitations This is the first study investigating whether androgen levels are of importance for the impaired sexual function seen in women following rectal cancer treatment. The prospective design allows for repeated measures and the use of the FSFI for comparisons across studies. No laboratory data were collected at the 2-year follow-up, and the missing data could have further clarified the studied associations. Conclusion and Clinical Implication Testosterone and androstenedione were associated with sexual function in female rectal cancer patients. The results are of interest for future intervention studies and contribute to the understanding of sexual problems, which is an essential component of the rehabilitation process in pelvic cancer survivors.

Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer.Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts.Conclusions and Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

Background Mortality in the first postoperative year represents an accurate reflection of the perioperative risk after colorectal cancer surgery. This research compares one-year mortality after surgery divided into three age-categories (18-64, 65-74, ≥75 years), focusing on time trends and comparing treatment strategies. Material Population-based data of all patients diagnosed and treated surgically for stage I-III primary colorectal cancer from 2007 to 2016, were collected from Belgium, the Netherlands, Norway, and Sweden. Stratified for age-category and stage, treatment was evaluated, and 30-day, one-year and one-year excess mortality were calculated for colon and rectal cancer separately. Results were evaluated over two-year time periods. Results Data of 206,024 patients were analysed. Postoperative 30-day and one-year mortality reduced significantly over time in all countries and age-categories. Within the oldest age category, in 2015–2016, one-year excess mortality varied from 9% in Belgium to 4% in Sweden for colon cancer and, from 9% in Belgium to 3% in the other countries for rectal cancer. With increasing age, patients were less likely to receive additional therapy besides surgery. In Belgium, colon cancer patients were more often treated with adjuvant chemotherapy (p < 0.001). For neoadjuvant treatment of rectal cancer, patients in Belgium and Norway were mostly treated with chemoradiotherapy. In the Netherlands and Sweden, radiotherapy alone was preferred (p < 0.001). Conclusions Despite improvement over time in all countries and age-categories, substantial variation exists in one-year postoperative mortality. Differences in one-year excess postoperative mortality could be due to differences in treatment strategies, highlighting the consequences of under- and over-treatment on cancer survival. publishedVersion

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BACKGROUND: The strategy of watch and wait (W&W) in patients with rectal cancer who achieve a complete clinical response (cCR) after neoadjuvant therapy is new and offers an opportunity for patients to avoid major resection surgery. However, evidence is based on small-to-moderate sized series from specialist centres. The International Watch & Wait Database (IWWD) aims to describe the outcome of the W&W strategy in a large-scale registry of pooled individual patient data. We report the results of a descriptive analysis after inclusion of more than 1000 patients in the registry.METHODS: Participating centres entered data in the registry through an online, highly secured, and encrypted research data server. Data included baseline characteristics, neoadjuvant therapy, imaging protocols, incidence of local regrowth and distant metastasis, and survival status. All patients with rectal cancer in whom the standard of care (total mesorectal excision surgery) was omitted after neoadjuvant therapy were eligible to be included in the IWWD. For the present analysis, we only selected patients with no signs of residual tumour at reassessment (a cCR). We analysed the proportion of patients with local regrowth, proportion of patients with distant metastases, 5-year overall survival, and 5-year disease-specific survival.FINDINGS: Between April 14, 2015, and June 30, 2017, we identified 1009 patients who received neoadjuvant treatment and were managed by W&W in the database from 47 participating institutes (15 countries). We included 880 (87%) patients with a cCR. Median follow-up time was 3·3 years (95% CI 3·1-3·6). The 2-year cumulative incidence of local regrowth was 25·2% (95% CI 22·2-28·5%), 88% of all local regrowth was diagnosed in the first 2 years, and 97% of local regrowth was located in the bowel wall. Distant metastasis were diagnosed in 71 (8%) of 880 patients. 5-year overall survival was 85% (95% CI 80·9-87·7%), and 5-year disease-specific survival was 94% (91-96%).INTERPRETATION: This dataset has the largest series of patients with rectal cancer treated with a W&W approach, consisting of approximately 50% data from previous cohort series and 50% unpublished data. Local regrowth occurs mostly in the first 2 years and in the bowel wall, emphasising the importance of endoscopic surveillance to ensure the option of deferred curative surgery. Local unsalvageable disease after W&W was rare.FUNDING: European Registration of Cancer Care financed by European Society of Surgical Oncology, Champalimaud Foundation Lisbon, Bas Mulder Award granted by the Alpe d'Huzes Foundation and Dutch Cancer Society, and European Research Council Advanced Grant.

Testosterone dose-dependently increases appendicular muscle mass. However, the effects of testosterone administration on the core muscles of the trunk and the pelvis have not been evaluated. The present study evaluated the effects of testosterone administration on truncal and pelvic muscles in a dose-response trial. Participants were young healthy men aged 18-50 years participating in the 5α-Reductase (5aR) Trial. All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone production and weekly injections of 50, 125, 300, or 600 mg of testosterone enanthate and were randomized to receive either 2.5 mg dutasteride (5aR inhibitor) or placebo daily for 20 weeks. Muscles of the trunk and the pelvis were measured at baseline and the end of treatment using 1.5-Tesla magnetic resonance imaging. The dose effect of testosterone on changes in the psoas major muscle area was the primary outcome; secondary outcomes included changes in paraspinal, abdominal, pelvic floor, ischiocavernosus, and obturator internus muscles. The association between changes in testosterone levels and muscle area was also assessed. Testosterone dose-dependently increased areas of all truncal and pelvic muscles. The estimated change (95% confidence interval) of muscle area increase per 100 mg of testosterone enanthate dosage increase was 0.622 cm2 (0.394, 0.850) for psoas; 1.789 cm2 (1.317, 2.261) for paraspinal muscles, 2.530 cm2 (1.627, 3.434) for total abdominal muscles, 0.455 cm2 (0.233, 0.678) for obturator internus, and 0.082 cm2 (0.003, 0.045) for ischiocavernosus; the increase in these volumes was significantly associated with the changes in on-treatment total and free serum testosterone concentrations. In conclusion, core muscles of the trunk and pelvis are responsive to testosterone administration. Future trials should evaluate the potential role of testosterone administration in frail men who are predisposed to falls and men with pelvic floor dysfunction.

Background Local recurrence of rectal cancer (LRRC) is associated with poor survival unless curative treatment is performed. The aim of this study was to investigate predictive factors for treatment with curative intent in patients with LRRC. Methods Population-based data for patients treated for primary rectal cancer between 1995 and 2002, and with LRRC reported as first event were collected from the Swedish Colorectal Cancer Registry and medical records. The associations between patient-, primary tumour- and LRRC-related factors and intention of the treatment for LRRC were determined. The impact of the identified predictive factors on prognosis after treatment with curative intent was also assessed. Results A total of 426 patients were included in the study, of whom 149 (35·0 per cent) received treatment with curative intent. Factors significantly associated with treatment of the LRRC with palliative intent were primary surgery with abdominoperineal resection (odds ratio (OR) 5·16, 95 per cent c.i. 2·97 to 8·97), age at diagnosis of LRRC at least 80 years (OR 4·82, 2·37 to 9·80), symptoms at diagnosis (OR 2·79, 1·56 to 5·01) and non-central location of the LRRC (OR 1·79, 1·15 to 2·79). The overall 5-year survival rate was 8·9 per cent for all patients and 23·1 per cent among those treated with curative intent. In patients treated with curative intent, factors associated with increased risk of death were age 80 years or more (hazard ratio (HR) 2·44, 95 per cent c.i. 1·55 to 3·86), presence of symptoms (HR 1·92, 1·20 to 3·05), non-central tumour location (HR 1·51, 1·01 to 2·26) and presence of hydronephrosis (HR 2·02, 1·18 to 3·44). Conclusion Non-central location of the LRRC, presence of symptoms and age at least 80 years at diagnosis of the LRRC were associated with treatment with palliative intent.

The main results from the Stockholm III trial have recently been published [1]. In the trial 840 intermediate risk (often designated locally advanced) rectal cancer patients were randomized to preo...

Summary Background Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery. Methods In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 × 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4–8 weeks (short-course radiotherapy with delay) or 25 × 2 Gy radiation dose with surgery after 4–8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1·7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813. Findings Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33·4 months (range 18·2–62·2) in the short-course radiotherapy group and 19·3 months (8·5–39·5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33·3 months (range 17·8–114·3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1·44 [95% CI 0·41–5·11]; long-course radiotherapy with delay 2·24 [0·71–7·10]; p=0·48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient ( vs short-course radiotherapy: short-course radiotherapy with delay 0·59 [95% CI 0·36–0·97], long-course radiotherapy with delay 0·63 [0·38–1·04], p=0·075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 [53%] of 355 vs 188 [41%] of 357; OR 0·61 [95% CI 0·45–0·83] p=0·001). Interpretation Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery. Funding Swedish Research Council, Swedish Cancer Society, Stockholm Cancer Society, and the Regional Agreement on Medical Training and Clinical Research in Stockholm.

The impact of quality of surgery, colorectal surgical specialization, training and expertise has been far greater on survival outcomes than adjuvant and neoadjuvant therapies. The review of the evidence by Professor Martling and expert discussion addresses the evidence base and the crucial importance of the surgeon as a prognostic factor, and how this has been relatively neglected in comparison to other resources invested in improving the treatment of colorectal cancer.

Background and purpose Neoadjuvant radiotherapy (RT) in rectal cancer induces tumour regression with a possible complete response (pCR). The optimal fractionation and timing to surgery is not established. The Stockholm III trial randomly assigned 840 patients to 5 × 5 Gy surgery within one week (SRT), 5 × 5 Gy with surgery after 4–8 weeks, and 2 Gy × 25 with surgery after 4–8 weeks (LRT-delay). The aim of this substudy was to assess tumour regression and correlation to survival. Material and methods All available microscopy slides were assessed by one pathologist, blinded to treatment, regarding tumour regression, graded according to the Dworak system (TRG), TNM-stage and other standard histopathology characteristics. Patients’ data were collected from the Swedish ColoRectal Cancer Registry. Outcomes were TRG, pCR-rates, overall survival (OS) and time to recurrence (TTR). Results 318, 285 and 94 patients were included in the SRT, SRT-delay and LRT-delay groups. Median follow up was 5.7 years. There were significantly lower tumour stages after SRT-delay. pCR was seen in 1 (0.3%), 29 (10.4%) and 2 (2.2%) patients in SRT, SRT-delay and LRT-delay, respectively. The pCR and Dworak grade 4 were associated with superior survival. pCR vs no-pCR Hazard Ratio (95% Confidence Interval) OS: 0.51 (0.26–0.99) p = 0.046, TTR: 0.27 (0.09–0.86) p = 0.027. Conclusion SRT-delay induces pCR in about 10% of the patients and is in this aspect superior to 25 × 2 Gy. A complete tumour response, TRG 4 using the Dworak system, or a pCR, is associated with superior OS and TTR.

Background: Decreased cancer specific survival in older colorectal patients is mainly due to mortality in the first year, emphasizing the importance of the first postoperative year. This study aims to gain an overview and time trends of short-term mortality in octogenarians (>= 80 years) with colorectal cancer across four North European countries.Methods: Patients of 80 years or older, operated for colorectal cancer (stage I-Ill) between 2005 and 2014, were included. Population-based cohorts from Belgium, Denmark, the Netherlands, and Sweden were collected. Separately for colon- and rectal cancer, 30-day, 90-day, one-year, and excess one-year mortality were calculated. Also, short-term mortality over three time periods (2005-2008, 2009-2011, 2012-2014) was analyzed.Results: In total, 35,158 colon cancer patients and 10,144 rectal cancer patients were included. For colon cancer, 90-day mortality rate was highest in Denmark (15%) and lowest in Sweden (8%). For rectal cancer, 90-day mortality rate was highest in Belgium (11%) and lowest in Sweden (7%). One-year excess mortality rate of colon cancer patients decreased from 2005 to 2008 to 2012-2014 for all countries (Belgium: 17%-11%, Denmark: 21%-15%, the Netherlands: 18%-10%, and Sweden: 10%-8%). For rectal cancer, from 2005 to 2008 to 2012-2014 one-year excess mortality rate decreased in the Netherlands from 16% to 7% and Sweden: 8%-2%).Conclusions: Short-term mortality rates were high in octogenarians operated for colorectal cancer. Short-term mortality rates differ across four North European countries, but decreased over time for both colon and rectal cancer patients in all countries. (C) 2019 Published by Elsevier Ltd.