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Quality assurance remains a neglected component of many trials, particularly for technical interventions, such as surgery and radiotherapy, for which quality of treatment is an important component in defining outcomes. We aimed to evaluate evidence for the processes used in radiotherapy quality assurance of clinical trials. A systematic review was undertaken focusing on use of a pre-trial outlining benchmark case and subsequent on-trial individual case reviews of outlining for recruited patients. These pre-trial and on-trial checks are used to ensure consistency and standardisation of treatment for each patient recruited to the trial by confirming protocol compliance. Non-adherence to the trial protocol has been shown to have a negative effect on trial outcomes. 29 studies published between January, 2000, and December, 2022, were identified that reported on either outlining benchmark case results or outlining individual case review results, or both. The trials identified varied in their use of radiotherapy quality assurance practices and reporting of outcomes was inconsistent. Deviations from trial protocols were frequent, particularly regarding outlining. Studies correlating benchmark case results with on-trial individual case reviews provided mixed results, meaning firm conclusions could not be drawn regarding the influence of the pre-trial benchmark case on subsequent on-trial performance. The optimal radiotherapy quality assurance processes were unclear, and there was little evidence available. Improved reporting of outcomes from radiotherapy quality assurance programmes is needed to develop an evidence base for the optimal approach to radiotherapy quality assurance in trials.

Among patients with early-stage Hodgkin's lymphoma who have negative PET findings after three cycles of chemotherapy, radiotherapy produces a 3.8-percentage-point improvement in 3-year progression-free survival. However, 90% of patients are cured by chemotherapy alone. Long-term survival in early-stage Hodgkin’s lymphoma was first made possible by the introduction of the mantle 1 and inverted Y 2 fields of radiotherapy in the 1960s. The addition of adjuvant mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)–like chemotherapies improved progression-free survival rates, 3 but these chemotherapies were associated with severe emesis, 4 gonadal dysfunction, 5 , 6 and in rare cases, secondary leukemia. 7 Evidence of late toxic effects of mantle-field radiotherapy, such as hypothyroidism, 8 second cancers (especially of the breast 9 and lung 10 ), and cardiovascular disease, 11 , 12 also emerged. Thus, it was increasingly apparent that cure was bought at a high price and that less damaging . . .

Follicular lymphoma has been shown to be highly radiosensitive with responses to doses as low as 4 Gy in two fractions. This trial was designed to explore the dose response for follicular lymphoma comparing 4 Gy in two fractions with 24 Gy in 12 fractions FORT is a prospective randomised, unblinded, phase 3 non-inferiority study comparing radiotherapy given as 4 Gy in two fractions with a standard dose of 24 Gy in 12 fractions. Entry criteria included all patients aged over 18 years, having local radiotherapy for radical or palliative local control, with follicular lymphoma or marginal zone lymphoma, who had received no previous treatment for at least 1 month before. The primary outcome was time to local progression analysed on an intention-to-treat basis. Randomisation was centralised through the Cancer Research UK and University College London Cancer Trials Centre. Radiotherapy target sites were randomised (1:1) with minimisation stratified by histology (follicular lymphoma vs marginal zone lymphoma), treatment intent (palliative or curative) and centre. This trial is registered with ClinicalTrials.gov number, NCT00310167. 299 sites were randomly assigned to 24 Gy and 315 sites to 4 Gy between April 7, 2006, and June 8, 2011, at 43 centres in the UK. After a median follow-up of 26 months (range 0·39–75·4), 91 local progressions had been recorded (21 in the 24 Gy group and 70 in the 4 Gy group). Time to local progression with 4 Gy was not non-inferior to 24 Gy (hazard ratio 3·42, 95% CI 2·09–5·55, p<0·0001). Eight (3%) of 282 patients in the 24 Gy group and four (1%) of 300 in the 4 Gy group had acute grade 3–4 toxic effects. Four (1%) patients in the 24 Gy group and four (1%) patients in the 4 Gy group had late toxic effects. Mucositis was the most common event in the 24 Gy group (two patients with acute mucositis and two with late mucositis; all grade 3) and was not reported in the 4 Gy group. The most common acute effect was pain at the site of irradiation (two patients in the 4 Gy group, one patient in the 24 Gy group; all grade 3), and the most common late effect was fatigue (two patients in the 4 Gy group, one patient in the 24 Gy group; all grade 3). 24 Gy in 12 fractions is the more effective radiation schedule for indolent lymphoma and should be regarded as the standard of care. However, 4 Gy remains a useful alternative for palliative treatment. Cancer Research UK.

Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56–0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52–0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3–4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3–4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3–4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. Algeta ASA and Bayer HealthCare Pharmaceuticals.

The optimal radiotherapy dose for indolent non-Hodgkin lymphoma is uncertain. We aimed to compare 24 Gy in 12 fractions (representing the standard of care) with 4 Gy in two fractions (low-dose radiation). FoRT (Follicular Radiotherapy Trial) is a randomised, multicentre, phase 3, non-inferiority trial at 43 study centres in the UK. We enrolled patients (aged >18 years) with indolent non-Hodgkin lymphoma who had histological confirmation of follicular lymphoma or marginal zone lymphoma requiring radical or palliative radiotherapy. No limit on performance status was stipulated, and previous chemotherapy or radiotherapy to another site was permitted. Radiotherapy target sites were randomly allocated (1:1) either 24 Gy in 12 fractions or 4 Gy in two fractions using minimisation and stratified by histology, treatment intent, and study centre. Randomisation was centralised through the Cancer Research UK and University College London Cancer Trials Centre. Patients, treating clinicians, and investigators were not masked to random assignments. The primary endpoint was time to local progression in the irradiated volume based on clinical and radiological evaluation and analysed on an intention-to-treat basis. The non-inferiority threshold aimed to exclude the chance that 4 Gy was more than 10% inferior to 24 Gy in terms of local control at 2 years (HR 1·37). Safety (in terms of adverse events) was analysed in patients who received any radiotherapy and who returned an adverse event form. FoRT is registered with ClinicalTrials.gov, NCT00310167, and the ISRCTN Registry, ISRCTN65687530, and this report represents the long-term follow-up. Between April 7, 2006, and June 8, 2011, 614 target sites in 548 patients were randomly assigned either 24 Gy in 12 fractions (n=299) or 4 Gy in two fractions (n=315). At a median follow-up of 73·8 months (IQR 61·9–88·0), 117 local progression events were recorded, 27 in the 24 Gy group and 90 in the 4 Gy group. The 2-year local progression-free rate was 94·1% (95% CI 90·6–96·4) after 24 Gy and 79·8% (74·8–83·9) after 4 Gy; corresponding rates at 5 years were 89·9% (85·5–93·1) after 24 Gy and 70·4% (64·7–75·4) after 4 Gy (hazard ratio 3·46, 95% CI 2·25–5·33; p<0·0001). The difference at 2 years remains outside the non-inferiority margin of 10% at −13·0% (95% CI −21·7 to −6·9). The most common events at week 12 were alopecia (19 [7%] of 287 sites with 24 Gy vs six [2%] of 301 sites with 4 Gy), dry mouth (11 [4%] vs five [2%]), fatigue (seven [2%] vs five [2%]), mucositis (seven [2%] vs three [1%]), and pain (seven [2%] vs two [1%]). No treatment-related deaths were reported. Our findings at 5 years show that the optimal radiotherapy dose for indolent lymphoma is 24 Gy in 12 fractions when durable local control is the aim of treatment. Cancer Research UK.

Re-irradiation can be considered for local recurrence or new tumours adjacent to a previously irradiated site to achieve durable local control for patients with cancer who have otherwise few therapeutic options. With the use of new radiotherapy techniques, which allow for conformal treatment plans, image guidance, and short fractionation schemes, the use of re-irradiation for different sites is increasing in clinical settings. Yet, prospective evidence on re-irradiation is scarce and our understanding of the underlying radiobiology is poor. Our consensus on re-irradiation aims to assist in re-irradiation decision making, and to standardise the classification of different forms of re-irradiation and reporting. The consensus has been endorsed by the European Society for Radiotherapy and Oncology and the European Organisation for Research and Treatment of Cancer. The use of this classification in daily clinical practice and research will facilitate accurate understanding of the clinical implications of re-irradiation and allow for cross-study comparisons. Data gathered in a uniform manner could be used in the future to make recommendations for re-irradiation on the basis of clinical evidence. The consensus document is based on an adapted Delphi process and a systematic review of the literature was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Radical treatment of many solid tumours has moved from surgery to multimodal organ preservation strategies combining systemic and local treatments. Trimodality bladder-preserving treatment (TMT) comprises maximal transurethral resection of the bladder tumour followed by radiotherapy and concurrent radiosensitizing treatment, thereby sparing the urinary bladder. From the patient’s perspective, the choice of maintaining quality of life without a negative effect on the chances of cure and long-term survival is attractive. In muscle-invasive bladder cancer (MIBC), the evidence shows comparable clinical outcomes between patients undergoing radical cystectomy and TMT. Despite this evidence, many patients continue to be offered radical surgery as the standard-of-care treatment. Improvements in radiotherapy techniques with adaptive radiotherapy and advances in imaging translate to increases in the accuracy of treatment delivery and reductions in long-term toxicities. With the advent of novel biomarkers promising improved prediction of treatment response, stratification of patients for different treatments on the basis of tumour biology could soon be a reality. The future of oncological treatment lies in personalized medicine with the combination of technological and biological advances leading to truly bespoke management for patients with MIBC.

Two radiotherapy fractionation schedules are used to treat locally advanced bladder cancer: 64 Gy in 32 fractions over 6·5 weeks and a hypofractionated schedule of 55 Gy in 20 fractions over 4 weeks. Long-term outcomes of these schedules in several cohort studies and case series suggest that response, survival, and toxicity are similar, but no direct comparison has been published. The present study aimed to assess the non-inferiority of 55 Gy in 20 fractions to 64 Gy in 32 fractions in terms of invasive locoregional control and late toxicity in patients with locally advanced bladder cancer. We did a meta-analysis of individual patient data from patients (age ≥18 years) with locally advanced bladder cancer (T1G3 [high-grade non-muscle invasive] or T2–T4, N0M0) enrolled in two multicentre, randomised, controlled, phase 3 trials done in the UK: BC2001 (NCT00024349; assessing addition of chemotherapy to radiotherapy) and BCON (NCT00033436; assessing hypoxia-modifying therapy combined with radiotherapy). In each trial, the fractionation schedule was chosen according to local standard practice. Co-primary endpoints were invasive locoregional control (non-inferiority margin hazard ratio [HR]=1·25); and late bladder or rectum toxicity, assessed with the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic tool (non-inferiority margin for absolute risk difference [RD]=10%). If non-inferiority was met for invasive locoregional control, superiority could be considered if the 95% CI for the treatment effect excluded the null effect (HR=1). One-stage individual patient data meta-analysis models for the time-to-event and binary outcomes were used, accounting for trial differences, within-centre correlation, randomised treatment received, baseline variable imbalances, and potential confounding from relevant prognostic factors. 782 patients with known fractionation schedules (456 from the BC2001 trial and 326 from the BCON trial; 376 (48%) received 64 Gy in 32 fractions and 406 (52%) received 55 Gy in 20 fractions) were included in our meta-analysis. Median follow-up was 120 months (IQR 99–159). Patients who received 55 Gy in 20 fractions had a lower risk of invasive locoregional recurrence than those who received 64 Gy in 32 fractions (adjusted HR 0·71 [95% CI 0·52–0·96]). Both schedules had similar toxicity profiles (adjusted RD −3·37% [95% CI −11·85 to 5·10]). A hypofractionated schedule of 55 Gy in 20 fractions is non-inferior to 64 Gy in 32 fractions with regard to both invasive locoregional control and toxicity, and is superior with regard to invasive locoregional control. 55 Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer. Cancer Research UK.

Key Points Brachytherapy and brachytherapy boost with low-dose-rate brachytherapy (LDR-BT) or high-dose-rate (HDR)-BT can be used as first-line therapies in the management of prostate cancer patients of all National Comprehensive Cancer Network (NCCN)-defined risk groups LDR-BT, consisting of a single implant, typically uses 125 I or 103 Pd; by contrast, HDR-BT consists of 1–3 implants and uses 192 Ir Benefits of HDR-BT over LDR-BT include the ability to use the same source for other cancers, lower operator dependence, and fewer acute irritative symptoms Benefits of LDR-BT include more favourable scheduling logistics, lower initial capital equipment costs, non-requirement of a shielded room, completion in a single implant, and more robust data from clinical trials Outcomes of HDR-BT and LDR-BT are similar to those of other treatment options, including external beam radiotherapy (EBRT) and surgery, and brachytherapy can also be used in combination with EBRT in intermediate-risk and high-risk disease Severe toxicities of HDR-BT and LDR-BT are rare, although the rate of urethral stricture is increased when brachytherapy boost is performed; incontinence is not associated with any radiotherapy modality Brachytherapy offers an excellent treatment option for definitive and salvage treatment of prostate cancer, with excellent oncological outcomes, limited toxic effects, and good quality of life for patients. However, use of prostate brachytherapy has been declining. In this comprehensive Review, Zaorsky and colleagues consider the evolution of brachytherapy from its inception to contemporary practice, from historical background to current indications and contraindications, underlying radiophysics and technical aspects, cost, and clinical outcomes. Brachytherapy (BT), using low-dose-rate (LDR) permanent seed implantation or high-dose-rate (HDR) temporary source implantation, is an acceptable treatment option for select patients with prostate cancer of any risk group. The benefits of HDR-BT over LDR-BT include the ability to use the same source for other cancers, lower operator dependence, and — typically — fewer acute irritative symptoms. By contrast, the benefits of LDR-BT include more favourable scheduling logistics, lower initial capital equipment costs, no need for a shielded room, completion in a single implant, and more robust data from clinical trials. Prospective reports comparing HDR-BT and LDR-BT to each other or to other treatment options (such as external beam radiotherapy (EBRT) or surgery) suggest similar outcomes. The 5-year freedom from biochemical failure rates for patients with low-risk, intermediate-risk, and high-risk disease are >85%, 69–97%, and 63–80%, respectively. Brachytherapy with EBRT (versus brachytherapy alone) is an appropriate approach in select patients with intermediate-risk and high-risk disease. The 10-year rates of overall survival, distant metastasis, and cancer-specific mortality are >85%, <10%, and <5%, respectively. Grade 3–4 toxicities associated with HDR-BT and LDR-BT are rare, at <4% in most series, and quality of life is improved in patients who receive brachytherapy compared with those who undergo surgery.

Correspondence to: R J Davies justindavies2000@yahoo.com What you need to know Long term use of aspirin may prevent colorectal cancer in people with Lynch syndrome, a group with a high risk of colorectal cancer Treatment options for early rectal cancer include endoscopic and surgical treatments A shorter duration of adjuvant chemotherapy for three months can be effective and with lower side effects compared with the standard six months for people with lymph node-positive colorectal cancer Colonic stenting is now an option for treatment with curative intent of acute left sided large bowel obstruction Low anterior resection syndrome (LARS) is a common long term side effect for people who have undergone sphincter-preserving surgery for colorectal cancer Colorectal cancer (cancer of the colon, rectum, or bowel) is the fourth most common cancer in the UK, with over 42 000 new cases diagnosed each year.1 Survival rates have improved, with a five year survival rate of almost 60% now.2 This article summarises recent recommendations from the update of the National Institute for Health and Care Excellence (NICE) guideline for the diagnosis and management of colorectal cancer.3 The update focuses on the management of colorectal cancer, reflecting new research evidence in this area. What’s new in this guidance Aspirin is recommended for the prevention of colorectal cancer in people with Lynch syndrome Three months of adjuvant chemotherapy is recommended as an alternative to six months for people with stage III colon cancer (pT1-4, pN1-2, M0) or stage III rectal cancer (pT1-4, pN1-2, M0) treated with short course radiotherapy or no preoperative treatment Preoperative radiotherapy or chemoradiotherapy is recommended for people with rectal cancer that is cT1-T2, cN1-N2, M0 or cT3-T4, any cN, M0 Treatment options are recommended for metastatic colorectal cancer in the lung, liver, or peritoneum Minimum case volumes are set for surgeons and institutions treating patients with rectal cancer Recognition and assessment of low anterior resection syndrome (LARS) is recommended in people with associated symptoms Recommendations NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. Transanal excision* Endoscopic submucosal dissection Total mesorectal excision Type of procedure Endoscopic/surgery Endoscopic Surgery Minimally invasive procedure Yes Yes Possible Resection of bowel (may have more impact on sexual and bowel function) No No Yes Stoma needed (a permanent or temporary opening in the abdomen for waste to pass through) No No Possible General anaesthetic needed (and the possibility of associated complications) Yes No, conscious sedation Yes Full thickness excision possible (better chance of removing cancerous cells and more accurate prediction of lymph node involvement) Yes No Yes Removal of lymph nodes (more accurate staging of the cancer so better chance of cure) No No Yes Conversion to more invasive surgery needed if complication Possible Possible Possible Further surgery needed depending on histology Possible Possible Usually no Usual hospital stay 1–2 days 1–2 days 5–7 days External scarring No No Yes Possible complications (in alphabetical order): [Based on very low to low quality evidence and the experience and opinion of the GC] Hospital and surgeon case volumes for people with rectal cancer Hospitals performing major resection for rectal cancer should perform at least 10 of these operations each year.