In men with localized prostate cancer, dose-escalated conformal radiotherapy (CFRT) improves efficacy outcomes at the cost of increased toxicity. We present a detailed analysis to provide further ...information about the incidence and prevalence of late gastrointestinal side effects.
The UK Medical Research Council RT01 trial included 843 men with localized prostate cancer, who were treated for 6 months with neoadjuvant radiotherapy and were randomly assigned to either 64-Gy or 74-Gy CFRT. Toxicity was evaluated before CFRT and during long-term follow-up using Radiation Therapy Oncology Group (RTOG) grading, the Late Effects on Normal Tissue: Subjective, Objective, Management (LENT/SOM) scale, and Royal Marsden Hospital assessment scores. Patients regularly completed Functional Assessment of Cancer Therapy--Prostate (FACT-P) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) questionnaires.
In the dose-escalated group, the hazard ratio (HR) for rectal bleeding (LENT/SOM grade ≥2) was 1.55 (95% CI, 1.17–2.04); for diarrhea (LENT/SOM grade ≥2), the HR was 1.79 (95% CI, 1.10–2.94); and for proctitis (RTOG grade ≥2), the HR was 1.64 (95% CI, 1.20–2.25). Compared to baseline scores, the prevalence of moderate and severe toxicities generally increased up to 3 years and than lessened. At 5 years, the cumulative incidence of patient-reported severe bowel problems was 6% vs. 8% (standard vs. escalated, respectively) and severe distress was 4% vs. 5%, respectively.
There is a statistically significant increased risk of various adverse gastrointestinal events with dose-escalated CFRT. This remains at clinically acceptable levels, and overall prevalence ultimately decreases with duration of follow-up.
Summary Background In men with localised prostate cancer, conformal radiotherapy (CFRT) could deliver higher doses of radiation than does standard-dose conventional radical external-beam ...radiotherapy, and could improve long-term efficacy, potentially at the cost of increased toxicity. We aimed to present the first analyses of effectiveness from the MRC RT01 randomised controlled trial. Methods The MRC RT01 trial included 843 men with localised prostate cancer who were randomly assigned to standard-dose CFRT or escalated-dose CFRT, both administered with neoadjuvant androgen suppression. Primary endpoints were biochemical-progression-free survival (bPFS), freedom from local progression, metastases-free survival, overall survival, and late toxicity scores. The toxicity scores were measured with questionnaires for physicians and patients that included the Radiation Therapy Oncology Group (RTOG), the Late Effects on Normal Tissue: Subjective/Objective/Management (LENT/SOM) scales, and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) scales. Analysis was done by intention to treat. This trial is registered at the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN47772397. Findings Between January, 1998, and December, 2002, 843 men were randomly assigned to escalated-dose CFRT (n=422) or standard-dose CFRT (n=421). In the escalated group, the hazard ratio (HR) for bPFS was 0·67 (95% CI 0·53–0·85, p=0·0007). We noted 71% bPFS (108 cumulative events) and 60% bPFS (149 cumulative events) by 5 years in the escalated and standard groups, respectively. HR for clinical progression-free survival was 0·69 (0·47–1·02; p=0·064); local control was 0·65 (0·36–1·18; p=0·16); freedom from salvage androgen suppression was 0·78 (0·57–1·07; p=0·12); and metastases-free survival was 0·74 (0·47–1·18; p=0·21). HR for late bowel toxicity in the escalated group was 1·47 (1·12–1·92) according to the RTOG (grade ≥2) scale; 1·44 (1·16–1·80) according to the LENT/SOM (grade ≥2) scales; and 1·28 (1·03–1·60) according to the UCLA PCI (score ≥30) scale. 33% of the escalated and 24% of the standard group reported late bowel toxicity within 5 years of starting treatment. HR for late bladder toxicity according to the RTOG (grade ≥2) scale was 1·36 (0·90–2·06), but this finding was not supported by the LENT/SOM (grade ≥2) scales (HR 1·07 0·90–1·29), nor the UCLA PCI (score ≥30) scale (HR 1·05 0·81–1·36). Interpretation Escalated-dose CFRT with neoadjuvant androgen suppression seems clinically worthwhile in terms of bPFS, progression-free survival, and decreased use of salvage androgen suppression. This additional efficacy is offset by an increased incidence of longer term adverse events.
To determine, in a randomized clinical trial, whether high-dose therapy (HDT) followed by autologous stem-cell transplantation is more effective than standard treatment with regard to ...progression-free survival (PFS) and overall survival (OS) in patients with relapsed follicular non-Hodgkin's lymphoma; and to assess the additional value of B-cell purging of the stem-cell graft with regards to PFS and OS.
Patients received three cycles of chemotherapy. Responding patients with limited bone marrow infiltration were eligible for random assignment to three further cycles of chemotherapy (C), unpurged HDT (U), or purged HDT (P).
Between August 1993 and April 1997, 140 patients were registered from 36 centers internationally, and 89 were randomly assigned. Reasons for not randomizing included patient refusal, early progression, or death on induction therapy. With a 69-month median follow-up, the log-rank P value for PFS and OS were.0037 and.079, respectively. For PFS, the hazard ratios (95% CIs) for U versus C, P versus C, and P versus U were 0.33 (0.16 to 0.70), 0.38 (0.19 to 0.79), and 1.02 (0.51 to 2.05), respectively. The hazard ratio (95% CI) for C versus U + P was 0.30 (0.15 to 0.61). Hazard ratios (95% CIs) for OS were 0.43 (0.18 to 1.06), 0.43 (0.18 to 1.02), and 0.72 (0.32 to 1.63). For C versus U + P, the hazard ratio (95% CI) was 0.40 (0.18 to 0.89). Kaplan-Meier estimates (95% CIs) of 2-year PFS for C, U, and P were 26% (8% to 44%), 58% (37% to 79%), and 55% (34% to 75%), respectively. OS at 4 years for C, U, and P are 46% (25% to 67%), 71% (52% to 91%), and 77% (60% to 95%) respectively.
HDT significantly improves PFS and OS. There is no clear evidence of benefit through purging.
Summary Background Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes. Few associations have been tested in ...independent validation studies. This prospective study aimed to validate reported associations between genotype and radiation toxicity in a large independent dataset. Methods 92 (of 98 attempted) SNPs in 46 genes were successfully genotyped in 1613 patients: 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial (ISRCTN21474421, n=942) or in a prospective study of breast toxicity at the Christie Hospital, Manchester, UK (n=34). A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial (ISRCTN47772397, n=224) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHiP) trial (ISRCTN97182923, n=413). Late toxicity was assessed 2 years after radiotherapy with a validated photographic technique (patients with breast cancer only), clinical assessment, and patient questionnaires. Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses. At a type I error rate adjusted for multiple testing, this study had 99% power to detect a SNP, with minor allele frequency of 0·35, associated with a per allele odds ratio of 2·2. Findings None of the previously reported associations were confirmed by this study, after adjustment for multiple comparisons. The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance. Interpretation We did not replicate previously reported late toxicity associations, suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinically relevant effect. Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and methodological challenges addressed. Funding Cancer Research UK, The Royal College of Radiologists, Addenbrooke's Charitable Trust, Breast Cancer Campaign, Cambridge National Institute of Health Research (NIHR) Biomedical Research Centre, Experimental Cancer Medicine Centre, East Midlands Innovation, the National Cancer Institute, Joseph Mitchell Trust, Royal Marsden NHS Foundation Trust, Institute of Cancer Research NIHR Biomedical Research Centre for Cancer.
Innovations in treatments, imaging and molecular characterisation have improved outcomes for people with advanced prostate cancer; however, many aspects of clinical management are devoid of ...high-level evidence. At the Advanced Prostate Cancer Consensus Conference (APCCC) 2019, many of these topics were addressed, and consensus was not always reached. The results from clinical trials will most reliably plus the gaps.
An invited panel of 57 experts voted on 123 multiple-choice questions on clinical management at APCCC 2019. No consensus was reached on 88 (71.5%) questions defined as <75% of panellists voting for the same answer option. We reviewed clinicaltrials.gov to identify relevant ongoing phase III trials in these areas of non-consensus.
A number of ongoing phase III trials were identified that are relevant to these non-consensus issues. However, many non-consensus issues appear not to be addressed by current clinical trials. Of note, no phase III but only phase II trials were identified, investigating side effects of hormonal treatments and their management.
Lack of consensus almost invariably indicates gaps in existing evidence. The high percentage of questions lacking consensus at APCCC 2019 highlights the complexity of advanced prostate cancer care and the need for robust, clinically relevant trials that can fill current gaps with high-level evidence. Our review of these areas of non-consensus and ongoing trials provides a useful summary, indicating areas in which future consensus may soon be reached. This review may facilitate academic investigators to identify and prioritise topics for future research.
•APCCC (Advanced Prostate Cancer Consensus Conference) addresses knowledge gaps.•At APCCC 2019, many topics did not reach a consensus.•This article reviews ongoing trials and identifies outstanding gaps in knowledge.•The need for robust, clinically relevant trials that can fill gaps is highlighted.•This review may facilitate academic investigators to prioritise research topics.
Despite the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) encouraging the use of risk-based monitoring for trials in 2013, there remains a lack of evidence-based ...guidelines on how to monitor. We surveyed the academic United Kingdom Clinical Research Collaboration (UKCRC) registered clinical trials units (CTUs) to find out their policy on monitoring of phase III randomised clinical trials of an investigational medicinal product (CTIMPs).
An online survey of monitoring policy with sections on the CTU, central monitoring and on-site monitoring was sent to all 50 UKCRC registered CTUs in November 2018. Descriptive data analysis and tabulations are reported using the total number answering each question.
A total of 43/50 (86%) of CTUs responded with 38 conducting phase III randomised CTIMP trials. Of these 38 CTUs, 34 finished the survey. Most CTUs (36/37, 97%) use a central monitoring process to guide, target or supplement site visits. More than half (19/36, 53%) of CTUs do not use an automated monitoring report when centrally monitoring trials and all units use trial team knowledge to make a final decision on whether an on-site visit is required. A total of 31/34 (91%) CTUs used triggers to decide whether or not to conduct an on-site monitoring visit. On-site, a mixture of source data verification and checking of processes was carried out. The CTUs overwhelmingly (27/34, 79%) selected optimising central monitoring as their most pressing concern.
The survey showed a wide variation in phase III randomised CTIMP trial monitoring practices by academic clinical trials units within a single research-active country. We urgently need to develop evidence-based regulator-agreed guidance for CTUs on best practice for both central and on-site monitoring and to develop tools for all CTUs to use.
Researchers are increasingly seeking to use routinely collected data to support clinical trials. This approach has the potential to transform the way clinical trials are conducted in the future. The ...availability of routinely collected data for research, whether healthcare or administrative, has increased, and infrastructure funding has enabled much of this. However, challenges remain at all stages of a trial life cycle. This study, COMORANT-UK, aimed to systematically identify, with key stakeholders across the UK, the ongoing challenges related to trials that seek to use routinely collected data.
This three-step Delphi method consisted of two rounds of anonymous web-based surveys and a virtual consensus meeting. Stakeholders included trialists, data infrastructures, funders of trials, regulators, data providers and the public. Stakeholders identified research questions or challenges that they considered were of particular importance and then selected their top 10 in the second survey. The ranked questions were taken forward to the consensus meeting for discussion with representatives invited from the stakeholder groups.
In the first survey, 66 respondents yielded over 260 questions or challenges. These were thematically grouped and merged into a list of 40 unique questions. Eighty-eight stakeholders then ranked their top ten from the 40 questions in the second survey. The most common 14 questions were brought to the virtual consensus meeting in which stakeholders agreed a top list of seven questions. We report these seven questions which are within the following domains: trial design, Patient and Public Involvement, trial set-up, trial open and trial data. These questions address both evidence gaps (requiring further methodological research) and implementation gaps (requiring training and/or service re-organisation).
This prioritised list of seven questions should inform the direction of future research in this area and should direct efforts to ensure that the benefits in major infrastructure for routinely collected data are achieved and translated. Without this and future work to address these questions, the potential societal benefits of using routinely collected data to help answer important clinical questions will not be realised.
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