Conformity analysis to demonstrate reproducibility of target volumes for Margin-Intense Stereotactic Radiotherapy for borderline-resectable pancreatic cancer.

Margin-directed neoadjuvant radiotherapy for borderline-resectable pancreatic cancer (BRPC) aims to facilitate clear surgical margins. A systematic method was developed for definition of a boost target volume prior to a formal phase-I study.Reference structures were defined by two oncologists and one radiologist, target structures were submitted by eight oncologist investigators and compared using conformity indices. Resultant risk of duodenal bleed (NTCP) was modelled.For GTV, reference volume was 2.1cm(3) and investigator mean was 6.03cm(3) (95% CI 3.92-8.13cm(3)), for boost volume 1.1cm(3) and 1.25cm(3) (1.02-1.48cm(3)). Mean Dice conformity coefficient for GTV was 0.47 (0.38-0.56), and for boost volume was significantly higher at 0.61 (0.52-0.70, p=0.01). Discordance index (DI) for GTV was 0.65 (0.56-0.75) and for boost volume was significantly lower at 0.39 (0.28-0.49, p=0.001). NTCP using reference contours was 2.95%, with mean for investigator contour plans 3.93% (3.63-4.22%). Correlations were seen between NTCP and GTV volume (p=0.02) and NTCP and DI (correlation coefficient 0.83 (0.29-0.97), p=0.01).Better conformity with reference was shown for boost volume compared with GTV. Investigator GTV volumes were larger than reference, had higher DI scores and modelled toxicity risk. A consistent method of target structure definition for margin-directed pancreatic radiotherapy is demonstrated

Superior outcomes of nodal metastases compared to visceral sites in oligometastatic colorectal cancer treated with stereotactic ablative radiotherapy

Background: Stereotactic ablative radiotherapy (SBRT) is a radical option for oligometastatic colorectal cancer (CRC) patients, but most data relate to visceral metastases. Methods: A prospective, multi-centre database of CRC patients treated with SBRT was interrogated. Inclusion criteria were ECOG PS 0–2, ≤3 sites of disease, a disease free interval of >6 months unless synchronous liver metastases. Primary endpoints were local control (LC), progression free survival (PFS) and overall survival (OS). Results: 163 patients (172 metastases) were analysed. The median FU was 16 months (IQR 12.2–22.85). The LC at 1 year was 83.8% (CI 76.4%−91.9%) with a PFS of 55% (CI 47%−64.7%) respectively. LC at 1 year was 90% (CI 83%−99%) for nodal metastases (NM), 75% (63%−90%) for visceral metastases (VM). NM had improved median PFS (9 vs 19 months) [HR 0.6, CI 0.38–0.94, p = 0.032] and median OS (32 months vs not reached) [HR 0.28, CI 0.18–0.7, p = 0.0062] than VM, regardless of whether the NM were located inside or outside the pelvis. On multivariate analysis, NM and ECOG PS 0 were significant good prognostic factors. An exploratory analysis suggests KRAS WT is also a good prognostic factor. Conclusion: Nodal site is an important prognostic determinant of SBRT that should incorporated into patient selection. We hypothesise this may have an immunoediting basis

Reply to Comment on "The UK consensus position on the treatment of pancreatic cancer during the COVID-19 pandemic".

Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/50110000028

Pre- and postoperative prognostic factors for resectable esophageal adenocarcinoma

Background: Prognostication for esophageal cancer has traditionally relied on postoperative tissue specimens. This study aimed to use a histologically homogenous cohort to investigate the relationship between clinical, pathological or radiological variables and overall survival in patients undergoing esophagectomy for adenocarcinoma. Methods: A single-centre study of patients who underwent esophagectomy for adenocarcinoma over 10 years in a tertiary centre was performed. By regression analysis, variables available preoperatively and postoperatively were studied for prognostication. The primary outcome was overall survival. Results: 254 cases were analyzed. Over a median follow-up period of 31.8 months (IQR = 42.5), overall survival was 51.5 months (95% confidence interval: 33.0–69.9). According to hazard ratios (HR) for all-cause death, adverse prognostic factors included: a higher postoperative N-stage (HR ≥ 1.29; p ≤ 0.024), histopathological tumor length ≥25 mm (HR = 2.04; p = 0.03), poorer tumor differentiation (HR ≥ 2.86; p ≤ 0.042), and R1 status (HR = 2.33; p = 0.02). A lymph node yield ≥35 was a favorable prognostic factor (HR = 0.022; p < 0.001). Demographic and radiological variables, preoperative TNM stages, postoperative T-stage, and neoadjuvant/adjuvant treatment were not associated with overall survival. Conclusions: This study identifies several postoperatively factors which are available for the prognostication and identifies factors that should not be used to exclude patients from curative surgery

An Assessment of the Effectiveness of High Definition Cameras as Remote Monitoring Tools for Dolphin Ecology Studies.

Research involving marine mammals often requires costly field programs. This paper assessed whether the benefits of using cameras outweighs the implications of having personnel performing marine mammal detection in the field. The efficacy of video and still cameras to detect Indo-Pacific bottlenose dolphins (Tursiops aduncus) in the Fremantle Harbour (Western Australia) was evaluated, with consideration on how environmental conditions affect detectability. The cameras were set on a tower in the Fremantle Port channel and videos were perused at 1.75 times the normal speed. Images from the cameras were used to estimate position of dolphins at the water’s surface. Dolphin detections ranged from 5.6 m to 463.3 m for the video camera, and from 10.8 m to 347.8 m for the still camera. Detection range showed to be satisfactory when compared to distances at which dolphins would be detected by field observers. The relative effect of environmental conditions on detectability was considered by fitting a Generalised Estimation Equations (GEEs) model with Beaufort, level of glare and their interactions as predictors and a temporal auto-correlation structure. The best fit model indicated level of glare had an effect, with more intense periods of glare corresponding to lower occurrences of observed dolphins. However this effect was not large (-0.264) and the parameter estimate was associated with a large standard error (0.113).The limited field of view was the main restraint in that cameras can be only applied to detections of animals observed rather than counts of individuals. However, the use of cameras was effective for long term monitoring of occurrence of dolphins, outweighing the costs and reducing the health and safety risks to field personal. This study showed that cameras could be effectively implemented onshore for research such as studying changes in habitat use in response to development and construction activities

A phase-I trial of pre-operative, margin intensive, stereotactic body radiation therapy for pancreatic cancer: the 'SPARC' trial protocol.

BACKGROUND: Standard therapy for borderline-resectable pancreatic cancer in the UK is surgery with adjuvant chemotherapy, but rates of resection with clear margins are unsatisfactory and overall survival remains poor. Meta-analysis of single-arm studies shows the potential of neo-adjuvant chemo-radiotherapy but the relative radio-resistance of pancreatic cancer means the efficacy of conventional dose schedules is limited. Stereotactic radiotherapy achieves sufficient accuracy and precision to enable pre-operative margin-intensive dose escalation with the goal of increasing rates of clear resection margins and local disease control. METHODS/DESIGN: SPARC is a "rolling-six" design single-arm study to establish the maximum tolerated dose for margin-intensive stereotactic radiotherapy before resection of pancreatic cancer at high risk of positive resection margins. Eligible patients will have histologically or cytologically proven pancreatic cancer defined as borderline-resectable per National Comprehensive Cancer Network criteria or operable tumour in contact with vessels increasing the risk of positive margin. Up to 24 patients will be recruited from up to 5 treating centres and a 'rolling-six' design is utilised to minimise delays and facilitate ongoing recruitment during dose-escalation. Radiotherapy will be delivered in 5 daily fractions and surgery, if appropriate, will take place 5-6 weeks after radiotherapy. The margin-intense radiotherapy concept includes a systematic method to define the target volume for a simultaneous integrated boost in the region of tumour-vessel infiltration, and up to 4 radiotherapy dose levels will be investigated. Maximum tolerated dose is defined as the highest dose at which no more than 1 of 6 patients or 0 of 3 patients experience a dose limiting toxicity. Secondary endpoints include resection rate, resection margin status, response rate, overall survival and progression free survival at 12 and 24 months. Translational work will involve exploratory analyses of the cytological and humoral immunological responses to stereotactic radiotherapy in pancreatic cancer. Radiotherapy quality assurance of target definition and radiotherapy planning is enforced with pre-trial test cases and on-trial review. Recruitment began in April 2015. DISCUSSION: This prospective multi-centre study aims to establish the maximum tolerated dose of pre-operative margin-intensified stereotactic radiotherapy in pancreatic cancer at high risk of positive resection margins with a view to subsequent definitive comparison with other neoadjuvant treatment options

Investigating the toxicity and safety of radiotherapy for pancreatic cancer

The current level of understanding of the relationship of gastrointestinal toxicity with irradiation of the stomach, duodenum, and small bowel hampers the potential of radiotherapy to contribute effectively to achieving disease control for patients diagnosed with pancreatic cancer. The work in this thesis aimed to further this understanding through compilation and examination of existing informative data, and robust analysis of this relationship within a large cohort of patients treated with radiotherapy to the pancreas, and within a new clinical trial of stereotactic radiotherapy (SBRT).A systematic literature review was undertaken and publications were identified that found dose-volume parameters for the stomach (V20Gy, V50Gy, D2cm3), duodenum (V25Gy-V55Gy) and small bowel (V40Gy, V50Gy, D2cm3) to be predictive of toxicity in pancreatic cancer. Parameters were fitted for the Lyman-Kutcher-Burman normal tissue complication probability model for the duodenum, using published cohort dose-volume histograms and the associated incidence of toxicity. Results were consistent with previous analyses, showing a dependence on exposure to high dose and small volume effect.Published small bowel dose-volume histogram data was incorporated into meta-analysis and showed that, for rectal cancer, a significant volume effect exists for all clinically relevant doses (5 Gy to 50 Gy). This was not seen in data regarding irradiation for gynaecological cancer, where a volume effect was only observed at higher doses (40 Gy and over). This difference is thought to be primarily due to the concomitant chemotherapy used in the treatment of these malignancies.Analysis of the toxicity outcomes for patients treated in the phase-II trials ARCII and SCALOP identified stomach dose-volume parameters predictive of acute gastrointestinal toxicity on multivariable analysis, alongside patient sex and the concomitant chemotherapy regimen utilised. Use of a statistical technique novel to radiotherapy dose-volume analysis was explored (canonical correlation) but was not shown to be superior to existing techniques.Pre-trial radiotherapy quality assurance for the SPARC clinical trial of pre-operative SBRT was undertaken and found evidence of over-generous clinician contouring in definition of the primary tumour target volume. This was shown to have implications for modelled risk of treatment toxicity, however contouring improved with education and feedback from peers.In conclusion, intensification of pancreatic cancer radiotherapy is likely to be safe and acceptable for patients, provided that dose to the neighbouring organs of the upper gastrointestinal tract is managed. This may be achieved through accurate target definition and optimisation of the treatment process with control of patient motion and image-guided intensity-modulated radiotherapy or SBRT. Concomitant chemotherapy is shown to be an important modifier of the radiotherapy dose-volume-toxicity relationship.</p

Investigating the toxicity and safety of radiotherapy for pancreatic cancer

The current level of understanding of the relationship of gastrointestinal toxicity with irradiation of the stomach, duodenum, and small bowel hampers the potential of radiotherapy to contribute effectively to achieving disease control for patients diagnosed with pancreatic cancer. The work in this thesis aimed to further this understanding through compilation and examination of existing informative data, and robust analysis of this relationship within a large cohort of patients treated with radiotherapy to the pancreas, and within a new clinical trial of stereotactic radiotherapy (SBRT).A systematic literature review was undertaken and publications were identified that found dose-volume parameters for the stomach (V20Gy, V50Gy, D2cm3), duodenum (V25Gy-V55Gy) and small bowel (V40Gy, V50Gy, D2cm3) to be predictive of toxicity in pancreatic cancer. Parameters were fitted for the Lyman-Kutcher-Burman normal tissue complication probability model for the duodenum, using published cohort dose-volume histograms and the associated incidence of toxicity. Results were consistent with previous analyses, showing a dependence on exposure to high dose and small volume effect.Published small bowel dose-volume histogram data was incorporated into meta-analysis and showed that, for rectal cancer, a significant volume effect exists for all clinically relevant doses (5 Gy to 50 Gy). This was not seen in data regarding irradiation for gynaecological cancer, where a volume effect was only observed at higher doses (40 Gy and over). This difference is thought to be primarily due to the concomitant chemotherapy used in the treatment of these malignancies.Analysis of the toxicity outcomes for patients treated in the phase-II trials ARCII and SCALOP identified stomach dose-volume parameters predictive of acute gastrointestinal toxicity on multivariable analysis, alongside patient sex and the concomitant chemotherapy regimen utilised. Use of a statistical technique novel to radiotherapy dose-volume analysis was explored (canonical correlation) but was not shown to be superior to existing techniques.Pre-trial radiotherapy quality assurance for the SPARC clinical trial of pre-operative SBRT was undertaken and found evidence of over-generous clinician contouring in definition of the primary tumour target volume. This was shown to have implications for modelled risk of treatment toxicity, however contouring improved with education and feedback from peers.In conclusion, intensification of pancreatic cancer radiotherapy is likely to be safe and acceptable for patients, provided that dose to the neighbouring organs of the upper gastrointestinal tract is managed. This may be achieved through accurate target definition and optimisation of the treatment process with control of patient motion and image-guided intensity-modulated radiotherapy or SBRT. Concomitant chemotherapy is shown to be an important modifier of the radiotherapy dose-volume-toxicity relationship.</p

Toxicant exposure, population genetics, and trophic associations of bottlenose dolphins (Tursiops aduncus) in the Swan River

Although Indo-Pacific bottlenose dolphins (Tursiops aduncus) are a valued component of the Swan-Canning Estuary and the Swan Canning Riverpark, little is known about the health and ecology of the small community of dolphins inhabiting the estuary. To improve the scientific basis for management, we examined the population genetics, trophic associations, and contaminant exposure of dolphins within the estuary. This Swan Canning Research Innovation Program (SCRIP) study had the following objectives: (1) detail contaminant concentrations in dolphins (as a baseline for future monitoring); (2) provide a preliminary assessment of health risk posed by contaminants to dolphins; (3) examine trophic pathway associations for Swan River bottlenose dolphin community; (4) use genetic information to examine whether bottlenose dolphins from the Swan-Canning Estuary and adjacent waters (Cockburn Sound) represent one homogenous population or (alternatively) if fine-scale population structuring occurs; and (5) put project findings into the perspective of system ecology and management implications. Tissue samples for this study were obtained through remote biopsy sampling of free-ranging dolphins and the collection of tissues during post-mortem examinations under permits and licences from the WA Department of Environment and Conservation and the Murdoch University Animal Ethics Committee

Technical report on the Bottlenose dolphin (Tursiops aduncus) unusual mortality event within the Swan Canning Riverpark, June-October 2009

This technical report reviews findings from an investigation into the mortalities of six bottlenose dolphins (Tursiops aduncus) in the Swan Canning Riverpark in 2009. The report: (a) describes the epidemiology and pathology of these mortalities; (b) presents background information on the ecology of dolphins in the Swan Canning Riverpark and factors known to affect dolphin health; and (c) discusses the potential role of chemical contaminants in the mortalities. These mortalities were investigated in context of dolphin deaths in the Swan Canning Riverpark prior to 2009 and a series of mortalities of dolphins in the Bunbury area between 2008-10, as well as marine mammal mortality events in other locations