Timing of high-dose rate brachytherapy with external beam radiotherapy in intermediate and high-risk localized prostate cancer (THEPCA) patients and its effects on toxicity and quality of life: Results of a randomized feasibility trial

Background: Advances in brachytherapy, external beam radiotherapy (EBRT) and image-guided radiotherapy have revolutionized radiotherapy delivery. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities remain a significant issue. Currently there is no European consensus on the timing of high-dose rate (HDR) brachytherapy in relation to EBRT. Schedules of HDR boost before or after EBRT vary significantly between institutions.The incidence of GI and GU toxicities was assessed in patients receiving HDR brachytherapy before and after EBRT. Methods: Men with Intermediate/high risk localized prostate cancer were randomized to Arm A (HDR brachytherapy before EBRT) or Arm B (HDR brachytherapy after EBRT). Both arms received a HDR boost of 15Gy and 46Gy in 23 fractions of EBRT. All patients received neoadjuvant and adjuvant hormone therapy for up to 2 years. Patients were followed quarterly up to a year. CTCAE scores for GU and GI toxicities were taken. IPSS, IEFL and FACT-P scores were collected. Fisher’s exact test was used to analyze the association between GU and GI toxicities. The T-test compared the mean differences in IPSS total scores at each follow-up. Analysis of variance evaluated the difference at follow up. Post-hoc testing and Bonferroni correction was applied. Results: 100 patients were randomized between 2015 and 2017. Data for 88 patients was available at cutoff. Mean age was 69 years (SD: 4.6). Age, Gleason score, TNM and clinical staging were similar in each arm. Mean IPSS Score was similar between both arms at baseline Arm A (6.52) & Arm B (6.57). 12 months follow up showed mild worsening of symptoms in both arms, but no significant difference noticed between Arm A (8.02) & Arm B (8.14) p=0.55. At 12 months, Grade 1 and 2 GU toxicities were more frequent in Arm A (22.88% & 5.28%, p=0.669) compared to Arm B (19.36% and 2.64%, p=0.485). Grade 1 GI toxicity was more common in Arm B (23.76%) than Arm A (21.2%), p=0.396. Grade 2 GI toxicities were more common in Arm A 5.28% vs 3.52%, p=0.739. Baseline mean IIEF scores were 10.9 and 10.53 in Arm A and B respectively. At 12 months this was 6.6 in Arm A and 7.11 in Arm B, but not statistically significant. FACT-P scores were not different in either arm, with good QOL scores maintained throughout. Mean score at baseline (125.18) was observed to be similar at 12 months follow up at (126.10). The PTV, CTV & OAR dose were compared and no significant differences were found. Conclusions: There were no significant differences in GI and GU related toxicities up to a year between patients receiving HDR brachytherapy before or after EBRT. There were no grade 3 or 4 toxicities. Treatment was well tolerated in both arms with good QOL scores. Longer follow up and a phase III multicenter RCT would be needed to validate findings. Clinical trial information: NCT02618161

Prognostic factors for survival and ambulatory status at 8 weeks with metastatic spinal cord compression in the SCORAD randomised trial

BACKGROUND: Metastatic spinal cord compression (MSCC) carries a poor prognosis and management is based on the likelihood of maintaining mobility and predicted survival. PATIENTS AND METHOD: SCORAD is a randomised trial of 686 patients comparing a single dose of 8Gy radiotherapy with 20Gy in 5 fractions. Data was split into a training set (412, 60%) and a validation set (274, 40%). A multivariable Cox regression for overall survival (OS) and a logistic regression for ambulatory status at 8 weeks were performed in the training set using baseline factors and a backward selection regression to identify a parsimonious model with p≤0.10. Receiver Operating Characteristic (ROC) analysis evaluated model prognostic performance in the validation set. Validation of the final survival model was performed in a separate registry dataset (n=348). RESULTS: The survival Cox model identified male gender, lung, gastrointestinal, and other types of cancer, compression at C1-T12, presence of non-skeletal metastases and poor ambulatory status all significantly associated with worse OS (all p<0.05). The ROC AUC for the selected model was 75% (95%CI: 69 to 81) in the SCORAD validation set and 68% (95%CI: 62 to 74) in the external validation registry data. The logistic model for ambulatory outcome identified primary tumour breast or prostate, ambulatory status grade 1 or 2, bladder function normal and prior chemotherapy all significantly associated with increased odds of ambulation at 8 weeks (all p<0.05). The ROC AUC for the selected model was 72.3% (95% CI 62.6-82.0) in the validation set. CONCLUSIONS: Primary breast or prostate cancer, and good ambulatory status at presentation, are favourable prognostic factors for both survival and ambulation after treatment

Association of Molecular Subtypes With Differential Outcome to Apalutamide Treatment in Nonmetastatic Castration-Resistant Prostate Cancer.

There is a need to identify prognostic biomarkers to guide treatment intensification in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). To examine whether molecular subtypes predict response to apalutamide, using archived primary tumor samples from the randomized, double-blind, phase 3 SPARTAN trial. In this cohort study, gene expression data from 233 archived samples from patients with nmCRPC enrolled in the SPARTAN trial were generated using a human exon microarray. The present analysis was conducted from May 10, 2018, to October 15, 2020. Patients were randomized (2:1) to apalutamide, 240 mg/d, with androgen deprivation therapy (apalutamide+ADT) or placebo+ADT. Patients were stratified into high-risk and low-risk categories for developing metastases based on genomic classifier (GC) scores for high (GC >0.6) and low to average (GC≤0.6) and into basal and luminal subtypes; associations between these molecular subtypes and metastasis-free survival (MFS), overall survival (OS), and progression-free survival 2 (PFS2) were evaluated using Cox proportional hazards regression and Kaplan-Meier analysis. Median age of the 233 included patients was 73 (range, 49-91) years. A total of 116 of 233 patients (50%) in the SPARTAN biomarker subset had high GC scores. Although all patients receiving apalutamide+ADT had improved outcomes, having high GC scores was associated with the greatest improvement in MFS (hazard ratio [HR], 0.21; 95% CI, 0.11-0.40; P  The findings of this study suggest that the GC score and basal-luminal subtype derived from archived tumor specimens may be biomarkers of response to apalutamide+ADT in the nmCRPC setting. Although overall, the addition of apalutamide to ADT was beneficial, higher-risk and luminal subtypes appeared to benefit most. Obtaining GC scores may be useful for identifying patients for early treatment intensification with apalutamide, and basal-luminal subtyping may be a beneficial approach for patient selection for further treatment intensification in trials combining novel therapies with apalutamide

Minimum information about a single amplified genome (MISAG) and a metagenome-assembled genome (MIMAG) of bacteria and archaea

We present two standards developed by the Genomic Standards Consortium (GSC) for reporting bacterial and archaeal genome sequences. Both are extensions of the Minimum Information about Any (x) Sequence (MIxS). The standards are the Minimum Information about a Single Amplified Genome (MISAG) and the Minimum Information about a Metagenome-Assembled Genome (MIMAG), including, but not limited to, assembly quality, and estimates of genome completeness and contamination. These standards can be used in combination with other GSC checklists, including the Minimum Information about a Genome Sequence (MIGS), Minimum Information about a Metagenomic Sequence (MIMS), and Minimum Information about a Marker Gene Sequence (MIMARKS). Community-wide adoption of MISAG and MIMAG will facilitate more robust comparative genomic analyses of bacterial and archaeal diversity

Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study

Background: FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. Methods: The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. Findings: Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6-23·9), an objective response was observed in 64 (30% [95% CI 24-36]) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 [12%]), palmar-plantar erythrodysaesthesia syndrome (12 [6%]), and hyperphosphataemia (11 [5%]). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths. Interpretation: RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.</p

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

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