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Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials.

ABSTRACT: There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action, and address immunomodulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient-derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies; for example, regrowth delay measures bulk tumor killing, whereas local tumor control assesses effects on CSCs. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radiochemotherapy for most tumors. Radiation models are compatible with but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapeutic agent may be different from its interaction with radiation and/or radiochemotherapy. This provides an opportunity to expand the use of molecular-targeted agents. Clin Cancer Res; 22(13); 3138-47. ©2016 AACR.

SUBMITTER: Coleman CN

PROVIDER: S-EPMC4930691 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials.

Coleman C Norman CN Higgins Geoff S GS Brown J Martin JM Baumann Michael M Kirsch David G DG Willers Henning H Prasanna Pataje G S PG Dewhirst Mark W MW Bernhard Eric J EJ Ahmed Mansoor M MM

Clinical cancer research : an official journal of the American Association for Cancer Research 20160506 13

There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more phys ...[more]

PMID: 27154913

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Project description:BackgroundManagement of prostate cancer after surgery is controversial. Past studies on adjuvant radiotherapy (aRT) for higher-risk features have had conflicting results. Through the collaborative conversations of the global radiation oncology Twitter-based journal club (#RadOnc #JC), we explored this complex topic to share recent advances, better understand what the global radiation oncology community felt was important and inspire next steps.MethodsWe selected the recent publication of a landmark international randomized controlled trial (RCT) comparing immediate and salvage radiotherapy for prostate cancer, RADICALS-RT, for discussion over the weekend of January 16 to 17, 2021. Coordination included open access to the article and an asynchronous portion to decrease barriers to participation, cooperation of study authors (CP, MS) who participated to share deeper insights including a live hour, and curation of related resources and tweet content through a blog post and Wakelet journal club summary.Discussion of resultsOur conversations created 2,370,104 impressions over 599 tweets with 51 participants spanning 11 countries and 5 continents. A quarter of the participants were from the US (13/51) followed by 10% from the UK (5/51). Clinical or Radiation Oncologists comprised 59% of active participants (16/27) with 62% (18/29) reporting giving aRT within the last 5 years. Discussion was interdisciplinary with three urologists (11%), three trainees (11%), and two physiotherapists (7%). Four months after the journal club its article Altmetric score had increased by 7% (214 to 229). Thematic analysis of tweet content suggested participants wanted clarification on definitions of adjuvant (aRT) and salvage radiotherapy (sRT) including indications, timing, and decision-making tools including guidelines; more interdisciplinary and cross-sectoral collaboration including with patients for study design including survivorship and meaningful outcomes; more effective knowledge translation including faster clinical trials; and more data including mature results of current trials, particular high-risk features (Gleason Group 4+, pT4b+, and margin-positive disease), implications of newer technologies such as PSMA-PET and genomic classifiers, and better explanations for practice pattern variations including underutilization of radiotherapy. This was further explored in the context of relevant literature.ConclusionTogether, this global collaborative review on the postoperative management of prostate cancer suggested a stronger signal for the uptake of early salvage radiation treatment with careful PSA monitoring, more sensitive PSA triggers, and expected access to radiotherapy. Questions still remain on potential exceptions and barriers to use. These require better decision-making tools for all practice settings, consideration of newer technologies, more pragmatic trials, and better use of social media for knowledge translation.

Dataset Information

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials.

Publications

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials.

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