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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. 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. 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). 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. Swedish Research Council, Swedish Cancer Society, Stockholm Cancer Society, and the Regional Agreement on Medical Training and Clinical Research in Stockholm.

The TME trial investigated the value of preoperative short-term radiotherapy in combination with total mesorectal excision (TME). Long-term results are reported after a median follow-up of 12 years. Between Jan 12, 1996, and Dec 31, 1999, 1861 patients with resectable rectal cancer without evidence of distant disease were randomly assigned to TME preceded by 5 × 5 Gy radiotherapy or TME alone (ratio 1:1). Randomisation was based on permuted blocks of six with stratification according to centre and expected type of surgery. The primary endpoint was local recurrence, analysed for all eligible patients who underwent a macroscopically complete local resection. 10-year cumulative incidence of local recurrence was 5% in the group assigned to radiotherapy and surgery and 11% in the surgery-alone group (p<0·0001). The effect of radiotherapy became stronger as the distance from the anal verge increased. However, when patients with a positive circumferential resection margin were excluded, the relation between distance from the anal verge and the effect of radiotherapy disappeared. Patients assigned to radiotherapy had a lower overall recurrence and when operated with a negative circumferential resection margin, cancer-specific survival was higher. Overall survival did not differ between groups. For patients with TNM stage III cancer with a negative circumferential resection margin, 10-year survival was 50% in the preoperative radiotherapy group versus 40% in the surgery-alone group (p=0·032). For all eligible patients, preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone without an overall survival benefit. For patients with a negative resection margin, the effect of radiotherapy was irrespective of the distance from the anal verge and led to an improved cancer-specific survival, which was nullified by an increase in other causes of death, resulting in an equal overall survival. Nevertheless, preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and TNM stage III. Future staging techniques should offer possibilities to select patient groups for which the balance between benefits and side-effects will result in sufficiently large gains. The Dutch Cancer Society, the Dutch National Health Council, and the Swedish Cancer Society.

Laparoscopic surgery as an alternative to open surgery in patients with rectal cancer has not yet been shown to be oncologically safe. The aim in the COlorectal cancer Laparoscopic or Open Resection (COLOR II) trial was to compare laparoscopic and open surgery in patients with rectal cancer. A non-inferiority phase 3 trial was undertaken at 30 centres and hospitals in eight countries. Patients (aged ≥18 years) with rectal cancer within 15 cm from the anal verge without evidence of distant metastases were randomly assigned to either laparoscopic or open surgery in a 2:1 ratio, stratified by centre, location of tumour, and preoperative radiotherapy. The study was not masked. Secondary (short-term) outcomes—including operative findings, complications, mortality, and results at pathological examination—are reported here. Analysis was by modified intention to treat, excluding those patients with post-randomisation exclusion criteria and for whom data were not available. This study is registered with ClinicalTrials.gov, number NCT00297791. The study was undertaken between Jan 20, 2004, and May 4, 2010. 1103 patients were randomly assigned to the laparoscopic (n=739) and open surgery groups (n=364), and 1044 were eligible for analyses (699 and 345, respectively). Patients in the laparoscopic surgery group lost less blood than did those in the open surgery group (median 200 mL [IQR 100–400] vs 400 mL [200–700], p<0·0001); however, laparoscopic procedures took longer (240 min [184–300] vs 188 min [150–240]; p<0·0001). In the laparoscopic surgery group, bowel function returned sooner (2·0 days [1·0–3·0] vs 3·0 days [2·0–4·0]; p<0·0001) and hospital stay was shorter (8·0 days [6·0–13·0] vs 9·0 days [7·0–14·0]; p=0·036). Macroscopically, completeness of the resection was not different between groups (589 [88%] of 666 vs 303 [92%] of 331; p=0·250). Positive circumferential resection margin (<2 mm) was noted in 56 (10%) of 588 patients in the laparoscopic surgery group and 30 (10%) of 300 in the open surgery group (p=0·850). Median tumour distance to distal resection margin did not differ significantly between the groups (3·0 cm [IQR 2·0–4·8] vs 3·0 cm [1·8–5·0], respectively; p=0·676). In the laparoscopic and open surgery groups, morbidity (278 [40%] of 697 vs 128 [37%] of 345, respectively; p=0·424) and mortality (eight [1%] of 699 vs six [2%] of 345, respectively; p=0·409) within 28 days after surgery were similar. In selected patients with rectal cancer treated by skilled surgeons, laparoscopic surgery resulted in similar safety, resection margins, and completeness of resection to that of open surgery, and recovery was improved after laparoscopic surgery. Results for the primary endpoint—locoregional recurrence—are expected by the end of 2013. Ethicon Endo-Surgery Europe, Swedish Cancer Foundation, West Gothia Region, Sahlgrenska University Hospital.

Preoperative or postoperative radiotherapy reduces the risk of local recurrence in patients with operable rectal cancer. However, improvements in surgery and histopathological assessment mean that the role of radiotherapy needs to be reassessed. We compared short-course preoperative radiotherapy versus initial surgery with selective postoperative chemoradiotherapy. We undertook a randomised trial in 80 centres in four countries. 1350 patients with operable adenocarcinoma of the rectum were randomly assigned, by a minimisation procedure, to short-course preoperative radiotherapy (25 Gy in five fractions; n=674) or to initial surgery with selective postoperative chemoradiotherapy (45 Gy in 25 fractions with concurrent 5-fluorouracil) restricted to patients with involvement of the circumferential resection margin (n=676). The primary outcome measure was local recurrence. Analysis was by intention to treat. This study is registered, number ISRCTN 28785842. At the time of analysis, which included all participants, 330 patients had died (157 preoperative radiotherapy group vs 173 selective postoperative chemoradiotherapy), and median follow-up of surviving patients was 4 years. 99 patients had developed local recurrence (27 preoperative radiotherapy vs 72 selective postoperative chemoradiotherapy). We noted a reduction of 61% in the relative risk of local recurrence for patients receiving preoperative radiotherapy (hazard ratio [HR] 0·39, 95% CI 0·27–0·58, p<0·0001), and an absolute difference at 3 years of 6·2% (95% CI 5·3–7·1) (4·4% preoperative radiotherapy vs 10·6% selective postoperative chemoradiotherapy). We recorded a relative improvement in disease-free survival of 24% for patients receiving preoperative radiotherapy (HR 0·76, 95% CI 0·62–0·94, p=0·013), and an absolute difference at 3 years of 6·0% (95% CI 5·3–6·8) (77·5% vs 71·5%). Overall survival did not differ between the groups (HR 0·91, 95% CI 0·73–1·13, p=0·40). Taken with results from other randomised trials, our findings provide convincing and consistent evidence that short-course preoperative radiotherapy is an effective treatment for patients with operable rectal cancer. Medical Research Council (UK) and the National Cancer Institute of Canada.

BackgroundIn locally advanced rectal cancer (LARC), preoperative short-course radiotherapy (SCRT) with delayed surgery has been shown to be as effective as long-course chemoradiotherapy, with only modest benefits. This study aimed to evaluate the efficacy and safety of preoperative SCRT combined with subsequent CAPOX (capecitabine and oxaliplatin) and the anti-PD-1 antibody camrelizumab in patients with LARC.MethodsThis was a prospective, single-arm, phase II trial. Treatment-naïve patients with histologically confirmed T3-4N0M0 or T1-4N+M0 rectal adenocarcinoma received 5×5 Gy SCRT with two subsequent 21-day cycles of CAPOX plus camrelizumab after 1 week, followed by radical surgery after 1 week. The primary endpoint was pathological complete response (pCR) rate. Biomarker analysis was performed to identify a potential predictor of pCR to treatment.ResultsFrom November 7, 2019 to September 14, 2020, 30 patients were enrolled, and 27 patients received at least one dose of CAPOX plus camrelizumab. Surgery was performed in 27 (100%) patients. The pCR (ypT0N0) rate was 48.1% (13/27), including 46.2% (12/26) for proficient mismatch repair (MMR) tumors and 100% (1/1) for deficient MMR tumors. Immune-related adverse events were all grade 1–2, with the most common being reactive cutaneous capillary endothelial proliferation (81.5%). No grade 4/5 adverse events occurred. Biomarker analysis showed patients without FGFR1–3 deletions had a better tendency for pCR.ConclusionsSCRT combined with subsequent CAPOX plus camrelizumab followed by delayed surgery showed a favorable pCR rate with good tolerance in patients with LARC, especially in the proficient MMR setting. A randomized controlled trial is ongoing to confirm these results.Trial registration numberClinicalTrials.gov identifier: NCT04231552.

This randomized trial compared preoperative with postoperative chemoradiotherapy for locally advanced rectal cancer. Overall survival was similar in the two groups, but patients assigned to preoperative chemoradiotherapy had lower rates of local recurrence and fewer long-term toxic effects than patients in the postoperative group. In this trial of nearly 800 patients, those assigned to preoperative chemoradiotherapy had lower rates of local recurrence and fewer toxic effects. Adjuvant radiotherapy with or without chemotherapy has been used widely to improve outcomes in patients with rectal cancer. For locally advanced disease, postoperative chemoradiotherapy significantly improves both local control and overall survival as compared with surgery alone or surgery plus irradiation. 1 , 2 This information prompted a National Institutes of Health consensus conference, convened in 1990, to recommend postoperative adjuvant chemoradiotherapy as standard treatment for patients with rectal cancer classified as tumor–node–metastasis (TNM) stage II (i.e., a tumor penetrating the rectal wall, without regional lymph-node involvement) or stage III (i.e., any tumor with regional lymph-node involvement). 3 Several randomized studies have found . . .

Preoperative radiotherapy is standard in the treatment of rectal cancer. This study showed that the addition of fluorouracil-based chemotherapy to preoperative radiotherapy had no significant effect on the survival of patients with resectable rectal cancer. Chemotherapy, however, did improve local control of the cancer. The addition of fluorouracil-based chemotherapy to preoperative radiotherapy had no significant effect on the survival of patients with resectable rectal cancer. Until the late 1980s, there was a high risk of local and distant recurrences after resection of rectal cancer. 1 – 3 Preoperative radiotherapy, with the aim of improving local control, has been extensively evaluated. The following two schedules of treatment have been explored: short-term treatment that delivers 25 Gy in 5 fractions during 1 week, followed immediately by surgery, and conventional schedules that deliver 40 to 50 Gy in 20 to 25 fractions during 4 to 5 weeks, followed by surgery 3 to 6 weeks later. Regardless of the protocol, preoperative radiotherapy decreases local recurrence rates by 50 to 60% as . . .

Background and purpose Short-course radiotherapy (SCRT) and long-course radiotherapy (LCRT) are the primary neoadjuvant radiotherapy schedules for locally advanced rectal cancer. Recent research has questioned the efficacy of SCRT. This study presents an updated analysis of our previous research, extending the follow-up to evaluate 5-year outcomes by comparing the long-term results of these two strategies. Materials and methods This randomized controlled trial compared SCRT and LCRT in locally advanced middle or high rectal adenocarcinoma. The SCRT group received 25 Gy/5 fractions over 1 week plus CAPOX, while the LCRT group received 50–50.4 Gy/25–28 fractions over 5–5.5 weeks plus capecitabine. All patients received consolidation chemotherapy and then underwent delayed surgery after 8 weeks or more post-radiotherapy. The endpoints of this updated analysis include overall survival (OS),disease-free survival (DFS), locoregional recurrence (LR) and distant metastasis (DM). Results Ninety-nine cases (45 LCRT, 54 SCRT) were followed for a median of 4.7 years. Five-year OS rates were 77.3% for LCRT vs. 65.6% for SCRT group ( P  = 0.4). The 5-year DFS rates were 69.6% for LCRT vs. 54.9% for SCRT ( P  = 0.07). Cox regression indicated no prominent difference between the two groups regarding OS, LR, or DM. Subgroup analysis demonstrated a significantly better DFS with LCRT compared to SCRT in male patients ([HR] = 2.48, 95%CI: 1.04–5.93, P  = 0.03), patients under the age of 60 (HR = 3.19, 95%CI: 1.03–9.92, P  = 0.04), and cT4 patients (HR not calculated: no events in LCRT group, P  = 0.004). Conclusion DFS showed a trend in favor of the LCRT group, with LCRT being significantly superior among men, patients under 60, and cT4 stage. Despite being intensified, SCRT failed to achieve long-term outcomes comparable to LCRT. Further research is needed to compare these two approaches in the context of total neoadjuvant treatment. Trial registration data IRCT2017110424266N3 (Registration date: 2017–11-12).  https://irct.behdasht.gov.ir/trial/20526 .

Background Excellent dosimetric characteristics were demonstrated for volumetric modulated arc therapy (VMAT) in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). In a single-center retrospective analysis, we tested whether these advantages may translate into significant clinical benefits. We compared VMAT to conventional 3D conformal radiotherapy (3DCRT) in patients, homogeneously treated according to the control arm of the CAO/ARO/AIO-04 trial. Methods CRT consisted of pelvic irradiation with 50.4/1.8Gy by VMAT ( n  = 81) or 3DCRT ( n  = 107) and two cycles of 5-fluorouracil. Standardized total mesorectal excision surgery was performed within 4–6 weeks. The tumor regression grading (TRG) was assessed by the Dworak score. Acute and late toxicity were evaluated via the Common Terminology Criteria for Adverse Events and the Late effects of normal tissues scale, respectively. Side effects greater than or equal to grade 3 were considered high-grade. Results Median follow-up was 18.3 months in the VMAT group and 61.5 months in the 3DCRT group with no differences in TRG between them ( p  = 0.1727). VMAT treatment substantially reduced high-grade acute and late toxicity, with 5 % versus 20 % ( p  = 0.0081) and 6 % vs. 22 % ( p  = 0.0039), respectively. With regard to specific organs, differences were found in skin reaction ( p  = 0.019) and proctitis ( p  = 0.0153). Conclusions VMAT treatment in preoperative CRT for LARC showed the potential to substantially reduce high-grade acute and late toxicity. Importantly, we could demonstrate that VMAT irradiation did not impair short-term oncological results. We conclude, that the reduced toxicity after VMAT irradiation may pave the way for more efficient systemic therapies, and hopefully improved patient survival in the multimodal treatment of LARC.