Stereotactic body radiotherapy for moderately central and ultra-central oligometastatic disease: initial outcomes

Background: Delivery of SBRT to central thoracic tumours within 2 cm of the proximal bronchial tree (PBT), and especially ultra-central tumours which directly abut the PBT, has been controversial due to concerns about high risk of toxicity and treatment-related death when delivering high doses close to critical mediastinal structures. We present dosimetric and clinical outcomes from a group of oligometastatic patients treated with a risk-adapted SBRT approach. Methods: Between September 2015 and October 2018, 27 patients with 28 central thoracic oligometastases (6 moderately central, 22 ultra-central) were treated with 60 Gy in 8 fractions under online CBCT guidance. PTV dose was compromised where necessary to meet mandatory OAR constraints. Patients were followed up for toxicity and disease status. Results: Mandatory OAR constraints were met in all cases; this required PTV coverage compromise in 23 cases, with V100% reduced to <70% in 11 cases. No acute or late toxicities of Grade ≥ 3 were reported. One and 2 year in-field control rates were 95.2% and 85.7% respectively, progression-free survival rates were 42.8% and 23.4% respectively, and overall survival rates were 82.7% and 69.5% respectively. No significant differences were seen in control or survival rates by extent of PTV underdosage or between moderately and ultra-central cases. Conclusion: It appears that compromising PTV coverage to meet OAR constraints allows safe and effective delivery of SBRT to moderately and ultra-central tumours, with low toxicity rates and high in-field control rates. This treatment can be delivered on standard linear accelerators with widely available imaging technology

An inflammation based score can optimize the selection of patients with advanced cancer considered for early phase clinical trials.

Background: Adequate organ function and good performance status (PS) are common eligibility criteria for phase I trials. As inflammation is pathogenic and prognostic in cancer we investigated the prognostic performance of inflammation-based indices including the neutrophil (NLR) and platelet to lymphocyte ratio (PLR). Methods: We studied inflammatory scores in 118 unselected referrals. NLR normalization was recalculated at disease reassessment. Each variable was assessed for progression-free (PFS) and overall survival (OS) on uni- and multivariate analyses and tested for 90 days survival (90DS) prediction using receiving operator curves (ROC). Results: We included 118 patients with median OS 4.4 months, 23% PS>1. LDH 65450 and NLR 655 were multivariate predictors of OS (p<0.001). NLR normalization predicted for longer OS (p<0.001) and PFS (p<0.05). PS and NLR ranked as most accurate predictors of both 90DS with area under ROC values of 0.66 and 0.64, and OS with c-score of 0.69 and 0.60. The combination of NLR+PS increased prognostic accuracy to 0.72. The NLR was externally validated in a cohort of 126 subjects. Conclusions: We identified the NLR as a validated and objective index to improve patient selection for experimental therapies, with its normalization following treatment predicting for a survival benefit of 7 months. Prospective validation of the NLR is warranted. Copyright: \ua9 2014 Pinato et al

NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer

We hypothesise that the NRF2 transcription factor would act a biomarker of poor prognosis in colorectal cancer. We derived and validated an mRNA based metagene signature of NRF2 signalling and validated it in 1360 patients from 4 different datasets as an independent biomarker of poor prognosis. This is a novel insight into the molecular signalling of colorectal cancer.Background: NRF2 over activity confers poor prognosis in some cancers but its prognostic role in colorectal cancer (CRC) is unknown. As a transcription factor, we hypothesise a signature of NRF2 regulated genes could act as a prognostic biomarker in CRC and reveal novel biological insights.Methods: Using known NRF2 regulated genes, differentially expressed in CRC, we defined a signature of NRF2 pathway activity using principal component analysis and Cox proportional hazard models and tested it in four independent mRNA datasets, profiled on three different mRNA platforms.Results: 36 genes comprised the final NRF2 signature. 1360 patients were included in the validation. High NRF2 was associated with worse disease free survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR=1.55, 95% C.I 1.2–2.004, p = 0.0008; GSE39582 HR=1.24, 95% C.I 1.086–1.416, p = 0.001; GSE87211 HR=1.431, 95% C.I 1.06–1.93, p = 0.056; MRC FOCUS trial HR=1.14, 95% C.I 1.04–1.26, p = 0.008). In multivariate analyses, NRF2 remained significant when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and BRAF V600E mutation and sidedness in stage IV disease. NRF2 activity was particularly enriched in Consensus Molecular Subtype (CMS) 4.Conclusion: For the first time, NRF2 is shown to be a consistent, robust prognostic biomarker across all stages of colorectal cancer with additional clinical value to current known prognostic biomarkers. High NRF2 signalling in CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, suggesting avenues of further study

Patient characteristics.

<p>Training and Validation Cohorts.</p

Study flow diagram illustrating patient disposition in the training and validation set.

<p>Study flow diagram illustrating patient disposition in the training and validation set.</p

The relationship between clinicopathological factors and baseline inflammatory scores (NLR, PLR) in patients with advanced solid tumours considered for experimental treatments (Training Set).

<p>Marks an association reaching statistical significance (p<0.05).</p

Univariate and multivariate analysis of prognostic factors of overall and progression free survival (Training Set).

<p>Abbreviations: LDH, Lactate dehydrogenase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio: Delta NLR: NLR changes following 2 cycles of treatment as previously categorized by Kao et al. 2010 (Ref. 23). Associations reaching statistical significance (p<0.05) are marked with an asterisk (*). Categorization of LDH, haemoglobin and albumin was carried out using clinically employed cutoff values (Arkenau et al. 2008, Ref. 8). To avoid colinearity bias, the independent effect of NLR and Delta NLR was tested in two independent Cox models.</p

Integration of the NLR with ECOG PS in the prediction of OS (Training and Validation Set).

<p>Chi-square test of equality of survival distributions for the different NLR categories.</p><p>^# Patients with PS 2 and 3 were considered together due to the small number of patients with PS = 3 (n = 9),</p><p>^## Patients were dichotomized as “favourable PS” (ie. 0–1) versus “poor PS” (ie. 2–3) due to limited sample size.</p><p>Marks an association reaching statistical significance (p<0.05).</p

Kaplan Meier curve analysis showing that NLR≥5 predicts for poor OS in the training (Panel A) and in the validation set (Panel B).

<p>NLR normalization calculated at disease reassessment predicts for better OS (<b>Panel C</b>) and PFS (<b>Panel D</b>). Receiver operator curve for comparison of PS, baseline NLR and PLR for predicting 90 day survival (<b>Panel E</b>).</p