SPARC, a phase-I trial of pre‐operative, margin intensified, stereotactic body radiation therapy for pancreatic cancer

Background and purpose: Following resection of pancreatic cancer, risk of positive margins and local recurrence remain high, especially for borderline-resectable pancreatic cancer (BRPC). We aimed to establish the maximum tolerated dose of a margin-intensified five-fraction stereotactic body radiotherapy (SBRT) regimen designed to treat the region at risk. / Materials and methods: We conducted a prospective multicentre phase-1 rolling-six dose-escalation study. BRPC patients received pre-operative SBRT, with one dose to the primary tumour and an integrated boost to the region where tumour was in contact with vasculature. Four dose-levels were proposed, with starting dose 30 Gy to primary PTV and 45 Gy to boost volume (PTV_R), in five daily fractions. Primary endpoint was maximum tolerated dose (MTD), defined as highest dose where zero of three or one of six patients experienced dose-limiting toxicity (DLT). / Results: Twelve patients were registered, eleven received SBRT. Radiotherapy was well tolerated with all treatment completed as scheduled. Dose was escalated one level up from starting dose without encountering any DLT (prescribed 32.5 Gy PTV, 47.5 Gy PTV_R). Nine serious adverse reactions or events occurred (seven CTCAE Grade 3, two Grade 4). Two patients went on to have surgical resection. Median overall survival for SBRT patients was 8.1 months. The study closed early when it was unable to recruit to schedule. / Conclusion: Toxicity of SBRT was low for the two dose-levels that were tested, but MTD was not established. Few patients subsequently underwent resection of pancreatic tumour after SBRT, and it is difficult to draw conclusions regarding the safety or toxicity of these therapies in combination

SPARC, a phase-I trial of pre‐operative, margin intensified, stereotactic body radiation therapy for pancreatic cancer

Background and purpose: Following resection of pancreatic cancer, risk of positive margins and local recurrence remain high, especially for borderline-resectable pancreatic cancer (BRPC). We aimed to establish the maximum tolerated dose of a margin-intensified five-fraction stereotactic body radiotherapy (SBRT) regimen designed to treat the region at risk. / Materials and methods: We conducted a prospective multicentre phase-1 rolling-six dose-escalation study. BRPC patients received pre-operative SBRT, with one dose to the primary tumour and an integrated boost to the region where tumour was in contact with vasculature. Four dose-levels were proposed, with starting dose 30 Gy to primary PTV and 45 Gy to boost volume (PTV_R), in five daily fractions. Primary endpoint was maximum tolerated dose (MTD), defined as highest dose where zero of three or one of six patients experienced dose-limiting toxicity (DLT). / Results: Twelve patients were registered, eleven received SBRT. Radiotherapy was well tolerated with all treatment completed as scheduled. Dose was escalated one level up from starting dose without encountering any DLT (prescribed 32.5 Gy PTV, 47.5 Gy PTV_R). Nine serious adverse reactions or events occurred (seven CTCAE Grade 3, two Grade 4). Two patients went on to have surgical resection. Median overall survival for SBRT patients was 8.1 months. The study closed early when it was unable to recruit to schedule. / Conclusion: Toxicity of SBRT was low for the two dose-levels that were tested, but MTD was not established. Few patients subsequently underwent resection of pancreatic tumour after SBRT, and it is difficult to draw conclusions regarding the safety or toxicity of these therapies in combination

Considerations for the treatment of pancreatic cancer during the COVID-19 pandemic: the UK consensus position.

Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment. In light of this, we sought consensus from UK clinicians with an interest in pancreatic cancer for management approaches that would minimise patient risk and accommodate for healthcare service restrictions. The outcomes are described here and include recommendations for treatment prioritisation, strategies to bridge to later surgical resection in resectable disease and factors that modify the risk-benefit balance for treatment in the resectable through to the metastatic settings. Priority is given to strategies that limit hospital visits, including through the use of hypofractionated precision radiotherapy and chemoradiotherapy treatment approaches

Systematic review and meta-analysis of small bowel dose–volume and acute toxicity in conventionally-fractionated rectal cancer radiotherapy

The limited radiation tolerance of the small-bowel causes toxicity for patients receiving conventionally-fractionated radiotherapy for rectal cancer. Safe radiotherapy dose-escalation will require a better understanding of such toxicity. We conducted a systematic review and meta-analysis using published datasets of small bowel dose-volume and outcomes to analyse the relationship with acute toxicity. SCOPUS, EMBASE and MEDLINE were searched to identify twelve publications reporting small-bowel dose-volumes and toxicity data or analysis. Where suitable data were available (mean absolute volume with parametric error measures), fixed-effects inverse-variance meta-analysis was used to compare cohorts of patients according to Grade ≥3 toxicity. For other data, non-parametric examinations of irradiated small-bowel dose-volume and incidence of toxicity were conducted, and a univariate logistic regression model was fitted. On fixed-effects meta-analysis of three studies (203 patients), each of the dose-volume measures V5Gy-V40Gy were significantly greater (p < 0.00001) for patients with Grade ≥3 toxicity than for those without. Absolute difference was largest for the lowest dose-volume parameter; however relative difference increases with increasing dose. On logistic regression multiple small-bowel DVH parameters were predictive of toxicity risk (V5Gy, V10Gy, V30Gy - V45Gy), with V10Gy the strongest (p = 0.004). Analysis of published clinical cohort dose-volume data provides evidence for a significant dose-volume-toxicity response effect for a wide range of clinically-relevant doses in the treatment of rectal cancer. Both low dose and high dose are shown to predict toxicity risk, which has important implications for radiotherapy planning and consideration of dose escalation for these patients

SU-D-BRA-06: Duodenal interfraction motion with abdominal compression.

To quantify the effect of abdominal compression on duodenal motion during pancreatic radiotherapy

Modelling duodenum radiotherapy toxicity using cohort dose-volume-histogram data

Background and purpose Gastro-intestinal toxicity is dose-limiting in abdominal radiotherapy and correlated with duodenum dose-volume parameters. We aimed to derive updated NTCP model parameters using published data and prospective radiotherapy quality-assured cohort data. Material and methods A systematic search identified publications providing duodenum dose-volume histogram (DVH) statistics for clinical studies of conventionally-fractionated radiotherapy. Values for the Lyman-Kutcher-Burman (LKB) NTCP model were derived through sum-squared-error minimisation and using leave-one-out cross-validation. Data were corrected for fraction size and weighted according to patient numbers, and the model refined using individual patient DVH data for two further cohorts from prospective clinical trials. Results Six studies with published DVH data were utilised, and with individual patient data included outcomes for 531 patients in total (median follow-up 16 months). Observed gastro-intestinal toxicity rates ranged from 0% to 14% (median 8%). LKB parameter values for unconstrained fit to published data were: n = 0.070, m = 0.46, TD50(1) [Gy] = 183.8, while the values for the model incorporating the individual patient data were n = 0.193, m = 0.51, TD50(1) [Gy] = 299.1. Conclusions LKB parameters derived using published data are shown to be consistent to those previously obtained using individual patient data, supporting a small volume-effect and dependence on exposure to high threshold dose

The Civil Society Viewed by Czech Presidents Václav Havel and Václav Klaus.

With a special emphasis on civil society as a different conception from state, the first part of the thesis outlines the theoretical basis of different conceptions of civil society, giving a summary of the theories of such thinkers as Hobbes, Lock, Montesquie, Rousseau and Hegel as well as their followers, in particular Tocquevill, Hayek, Popper, Habermas. In oder to provide the theoretical framework for the second part of the thesis, it gives an overview of the conceptions of civil society defined by the central European thinkers after the WW2, in particular Michnik, Otáhal, Benda, Havel. The second part of the thesis aims both to introduce and to provide a critical analysis of the approach of Václav Havel and Václav Klaus to the civil society in the Czech Republic after 1989, in particular as represented by different civil iniciatives and movements. The thesis attempts to provide a deeper understanding of the differencies in these two approaches rathen than their assessment.První část práce poukazuje na teoretické základy různých pojetí občanské společnosti. Jsou zde stručně shrnuty teorie Hobbese, Locka, Montesquieua, Rousseaua a Hegela a autorů na ně navazujících jako Tocquevilla, Hayeka, Poppera a Habermase. V těchto shrnutích je kladen důraz především na problematiku pojetí občanské společnosti jako odlišné od státu. Určitou základnou pro druhou část práce je uvedení nejdůležitějších autoru středoevropského pojetí občanské společnosti, tedy těch, kteří byli silně ovlivněni politickým vývojem ve střední a východní Evropě po druhé světové válce (Michnik, Otáhal, Benda, Havel…) Cílem druhé části je za pomocí výroků naších dvou polistopadových prezidentů, tedy Václava Havla a Václava Klause, představit a kriticky analyzovat jejich pohled na občanskou společnost v ČR po roce 1989, a to zejména na existenci různých občanských hnutí a iniciativ. Nejedná se o hodnocení těchto pojetí, ale o hlubší porozumění jejich rozdílností.Department of Civil Society StudiesKatedra studií občanské společnostiFaculty of HumanitiesFakulta humanitních studi