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 (<1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 50% of 129 patients in the short-course radiotherapy group; 48 38% of 128 patients in the short-course radiotherapy with delay group; 50 39% of 128 patients in the long-course radiotherapy with delay group; odds ratio OR 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 rate of local recurrence of rectal cancer (LRRC) has decreased but the condition remains a therapeutic challenge. This study aimed to examine treatment and prognosis in patients with LRRC in ...Sweden. Special focus was directed towards potential differences between geographical regions and time periods.
All patients with LRRC as first event, following primary surgery for rectal cancer performed during the period 1995–2002, were included in this national population-based cohort-study. Data were collected from the Swedish Colorectal Cancer Registry and from medical records. The cohort was divided into three time periods, based on the date of diagnosis of the LRRC.
In total, 426 patients fulfilled the inclusion criteria. Treatment with curative intent was performed in 149 patients (35%), including 121 patients who had a surgical resection of the LRRC. R0-resection was achieved in 64 patients (53%). Patients with a non-centrally located tumour were more likely to have positive resection margins (R1/R2) (OR 5.02, 95% CI:2.25–11.21). Five-year survival for patients resected with curative intent was 43% after R0-resection and 14% after R1-resection. There were no significant differences in treatment intention or R0-resection rate between time periods or regions. The risk of any failure was significantly higher in R1-resected patients compared with R0-resected patients (HR 2.04, 95% CI:1.22–3.40).
A complete resection of the LRRC is essential for potentially curative treatment. Time period and region had no influence on either margin status or prognosis.
Background Only a limited proportion of patients with metastatic colorectal cancer (mCRC) receives metastatic surgery (including local ablative therapy). The aim was to investigate whether hospital ...volume and hospital level were associated with the chance of metastatic surgery. Methods This national cohort retrieved from the CRCBaSe linkage included all Swedish adult patients diagnosed with synchronous mCRC in 2009-2016. The association between annual hospital volume of incident mCRC patients and the chance of metastatic surgery, and survival, were assessed using logistic regression and Cox regression models, respectively. Hospital level (university/non-university) was evaluated as a secondary exposure in a similar manner. Both uni- and multivariable (adjusted for sex, age, Charlson comorbidity index, year of diagnosis, cancer characteristics and socioeconomic factors) models were fitted. Results A total of 1,674 (17%) out of 9,968 mCRC patients had metastatic surgery. High hospital volume was not associated with increased odds of metastatic surgery after including hospital level in the model, whereas hospital level was (odds ratio (OR) (95% confidence interval (CI)): 1.94 (1.68-2.24)). All-cause mortality was lower in university versus non-university hospitals (hazard ratio (95% CI): 0.83 (0.78-0.88)). Conclusions Patients with mCRC initially cared for by a university hospital experienced a greater chance to receive metastatic surgery and had superior overall survival. High hospital volume in itself was not associated with a greater chance to receive metastatic surgery nor a greater survival probability. Additional efforts should be imposed to provide more equal care for mCRC patients across Swedish hospitals. Keywords: Colorectal neoplasms, High-volume hospitals, Low-volume hospitals, Neoplasm metastasis, Secondary, Surgery, Survival, University hospitals
: The aim of this population-based study was to assess treatment and outcome in patients resected for low rectal cancer, focusing on differences relating to the type of resection.
All patients in ...Stockholm with a rectal cancer within 6 cm of the anal verge, diagnosed from January 1995 to December 2003, and treated with abdominoperineal resection, anterior resection, or Hartmann procedure were included (n = 613). Clinical data, histopathology, and outcome were analyzed in relation to the type of surgery performed.
Bowel perforations and incomplete tumor clearance were more common in the abdominoperineal group (12%) than in the anterior (4%) and Hartmann procedure groups (9%; P = .03). Incomplete tumor clearance was also more common in the abdominoperineal group (18%) than in the anterior (5%) or Hartmann groups (14%; P < .01). In multivariate analysis, local pelvic control was significantly associated with neoadjuvant radiotherapy and complete tumor resection, and survival was significantly associated with neoadjuvant radiotherapy, lower tumor stage, female gender, younger age, and complete tumor resection. Although local control and survival were poorer after abdominoperineal than after anterior resection, the type of operation was not an independent prognostic factor.
Inadvertent bowel perforations and tumor-involved margins are more common after abdominoperineal than after anterior resection in low rectal cancer. Although previous studies have shown that abdominoperineal resection is also associated with poorer oncological outcomes, the present study could not confirm that the type of procedure per se is a significant determinant of prognosis.
Over the past decade, the treatment of rectal cancer has changed considerably. The implementation of TME surgery has, in addition to decreasing the number of local recurrences, improved surgical ...morbidity and mortality. At the same time, the optimisation of radiotherapy in the preoperative setting has improved oncological outcomes even further, although higher perineal infection rates have been reported. Radiotherapy regimens have evolved through the adjustment of radiotherapy techniques and fields, increased waiting intervals, and, for more advanced tumours, adding chemotherapy. Concurrently, imaging techniques have significantly improved staging accuracy, facilitating more precise selection of advanced tumours. Although chemoradiotherapy does lead to the downsizing and -staging of these tumours, a very clear effect on sphincter-preserving surgery and the negative resection margin has not been proven. Aiming to decrease distant metastasis and improve overall survival for locally advanced rectal cancer, systemic chemotherapy can be added to radiotherapy, known as total neoadjuvant treatment (TNT). High complete response rates, both pathological (pCR) and clinical (cCR), are reported after TNT. Patients who follow a Watch & Wait program after a cCR can potentially avoid surgical morbidity and colostomy. For both early and more advanced tumours, trials are now investigating optimal regimens in an attempt to offer organ preservation as much as possible. Multidisciplinary deliberation should include patient preference, treatment toxicity, and likelihood of end colostomy, but also the burden of intensive surveillance in a W&W program.
Incidence of early-onset (<50 years) colorectal cancer (EOCRC) is increasing in developed countries. The aim was to investigate autoimmune and metabolic conditions as risk factors for EOCRC. In a ...nationwide nested case-control study, we included all EOCRC cases in Sweden diagnosed during 2007-2016, together with controls, matched for birth year, sex, and county. Information on exposure of autoimmune or metabolic disease was collected from the National Patient Register and Prescribed Drugs Registry. Hazard ratios (HR) as measures of the association between EOCRC and the exposures were estimated using conditional logistic regression. In total, 2626 EOCRC patients and 15,756 controls were included. A history of metabolic disease nearly doubled the incidence hazard of EOCRC (HR 1.82, 95% CI 1.66-1.99). A sixfold increased incidence hazard of EOCRC (HR 5.98, 95% CI 4.78-7.48) was seen in those with inflammatory bowel disease (IBD), but the risk increment decreased in presence of concomitant metabolic disease (HR 3.65, 95% CI 2.57-5.19). Non-IBD autoimmune disease was not statistically significantly associated with EOCRC. IBD and metabolic disease are risk factors for EOCRC and should be considered in screening guidelines.
Background
Results from previous studies indicate that use of aspirin may improve colorectal cancer (CRC) survival. The aim of this study was to assess whether use of aspirin influences overall ...survival or CRC‐specific survival in an unselected cohort of patients diagnosed with CRC.
Methods
The study was performed using the Colorectal Cancer Data Base Sweden (CRCBaSe), a mega‐linkage originating from the Swedish Colorectal Cancer Register, with additional linkages to other national health care registers. All patients diagnosed with primary CRC stage I–III treated with curative surgery, aged 18–85 years at diagnosis, from 2007 through 2016 were identified. Information on low‐dose aspirin use was extracted from the Swedish Prescribed Drug Register. Exposure was defined as dispensed prescription for at least 6 months. Aspirin exposure was analyzed at the time of surgery (yes/no) and as a time‐varying exposure during follow‐up. Follow‐up was restricted to a maximum 6 years, to model 5‐year survival. Cox regression models were fitted to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Adjustments were performed for sex, age, year of diagnosis, Charlson comorbidity index, hypertension, and ASA score as potential confounders.
Results
A total of 32,195 patients diagnosed with CRC were included. 6764 (21%) were exposed to aspirin at the time of CRC surgery. The median time of follow‐up was 4.2 years. Aspirin use at the time of surgery was not associated with all‐cause (adjusted HR = 1.03, 95% CI: 0.97–1.08) nor CRC‐specific mortality (adjusted HR = 0.99, 95% CI: 0.91–1.07). Aspirin use during follow‐up was associated with increased all‐cause (adjusted HR = 1.09, 95% CI: 1.04–1.15) but not CRC‐specific mortality (adjusted HR = 0.98, 95% CI: 0.91–1.06). A CRC‐specific effect associated with aspirin was noted from approximately 3 years following surgery.
Conclusions
In this large nation‐wide cohort study there was no convincing association between aspirin use after CRC and OS or CRC‐specific survival.
It is well established that regular use of aspirin can reduce the relative risk of developing colorectal cancer. However, the impact of aspirin on survival after colorectal cancer diagnosis is not well understood. Studies have shown conflicting results. In this population‐based cohort study, the largest one to date, of all patients diagnosed with colorectal cancer in 2007‐2016, we found that aspirin was not associated with neither overall, colorectal cancer‐specific or disease‐free survival.
Signaling proteins driving the proliferation of stem and progenitor cells are often encoded by proto-oncogenes. EphB receptors represent a rare exception; they promote cell proliferation in the ...intestinal epithelium and function as tumor suppressors by controlling cell migration and inhibiting invasive growth. We show that cell migration and proliferation are controlled independently by the receptor EphB2. EphB2 regulated cell positioning is kinase-independent and mediated via phosphatidylinositol 3-kinase, whereas EphB2 tyrosine kinase activity regulates cell proliferation through an Abl-cyclin D1 pathway. Cyclin D1 regulation becomes uncoupled from EphB signaling during the progression from adenoma to colon carcinoma in humans, allowing continued proliferation with invasive growth. The dissociation of EphB2 signaling pathways enables the selective inhibition of the mitogenic effect without affecting the tumor suppressor function and identifies a pharmacological strategy to suppress adenoma growth.
Eighty percent of all male rectal cancer patients are sexually active at the time of diagnosis. Because of modern multimodal therapy many can expect long‐term survival. The testes can be exposed to ...scattered or direct radiation during radiotherapy, depending on their position in relation to the targeted volume.
This review analyzes the current literature providing data on testicular exposure to radiation during radiotherapy for rectal cancer and the consequences on testicular function.
A systematic search was conducted in PubMed, Embase, and Cochrane. Ten original articles providing data on testicular exposure to radiation and testicular function in men with primary rectal cancer were included for qualitative synthesis.
Data on testicular exposure to radiation and testosterone levels in men with rectal cancer are reported.
On average, the testes were exposed to 0.24–8.4 Gy during long‐course radiotherapy for rectal cancer. Testosterone levels after radiation were significantly lower compared with pretreatment levels or compared with patients treated with surgery alone. After radiotherapy, the absolute risk increase was 0.17–0.30 for posttreatment testosterone levels below 8 nmol/L. In the largest study, the relative risk was 2.7 for testosterone levels below 8 nmol/L for men treated with radiotherapy compared with men treated with surgery alone.
Current data generate three hypotheses: (i) during long‐course radiotherapy for rectal cancer, the testes can be exposed to direct and/or scattered radiation; (ii) men treated with radiotherapy seem at risk to develop testicular dysfunction with decreased serum testosterone levels compared with both pretreatment values and men treated with surgery alone; and (iii) a decrease in testosterone levels (<8 nmol/L) may precipitate specific symptoms caused by testosterone deficiency such as impaired physical, psychological, and sexual function after treatment. Buchli C, Martling A, Arver S, and Holm T. Testicular function after radiotherapy for rectal cancer—A review. J Sex Med 2011;8:3220–3226.
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•The first randomized trial comparing short-course radiotherapywith photons or protons in primary treatment of locally advanced rectal cancer.•Twenty patients successfully treated ...during the first year.•Excellent dosimetric quality of proton treatment plans.•Significantly less irradiation of pelvic OAR with proton beam therapy.
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.
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