Study Guide for Radiation and Cancer Biology

Download this study guide in printable .pdf format This exam tests your knowledge of the principles of radiation and cancer biology underlying the practice of radiation oncology. Included are questions on the general domains listed below. Exam performance will be reported to you based on an overall pass/fail grade, with specific information provided regarding quintile performance in the 10 individual domains. Because of the nature of scientific knowledge and subcategories, there may be some overlap of items across domains. Each exam will include items from every domain, but individual subtopics may not be included in every exam and the number of items per domain depends on the domain.

I. Interaction of radiation with matter	1% to 4%
II. Molecular and cellular damage and repair	13% to 17%
III. Cellular response to radiation	7% to 10%
IV. Linear energy transfer (LET) and oxygen effect	3% to 5%
V. Tumor biology and microenvironment	3% to 5%
VI. Cancer biology	19% to 23%
VII. Radiobiology of normal tissues	9% to 12%
VIII. Dose delivery	11% to 15%
IX. Combined modality therapy	11% to 15%
X. Late effects and radiation protection	6% to 9%

The ranges above are those generally in effect for the exam to be administered in 2020 and are intended only for guidance in candidate preparation. They do not necessarily represent a precise number of scorable items.

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I.	Interaction of radiation with matter Definition of ionizing radiation, free radicals, and radical damage Direct and indirect action of radiation, numbers, and types of DNA lesions Consequences of unrepaired DNA DSB
II.	Molecular and cellular damage and repair Molecular mechanisms of DNA damage Assays for measuring DNA damage and repair Single lethal hits, accumulated damage, and multiple damaged sites Molecular mechanisms of DNA repair Repair of base damage, single-strand and double-strand breaks DSB repair: Homologous recombination and non-homologous end joining Molecular mechanisms of DNA DSB damage recognition and damage signaling to initiate repair Cellular recovery Repair at the cellular level Sublethal damage repair Dose-rate effects and repair Dose-fractionation effects and repair Chromosome and chromatid damage Assays for measuring chromosome damage – Giemsa to FISH Dose-response relationships Use of peripheral blood lymphocytes in in vivo dosimetry Human genetic diseases that affect DNA repair, fragility, and radiosensitivity Stable and unstable chromatid and chromosome aberrations
III.	Cellular responses to radiation Mechanisms of cell death Mechanisms and major characteristics of pathways of radiation-induced apoptosis, necrosis, autophagy, and senescence Mitotic-linked cell death and chromosome aberrations Cell division post-radiation and time to clonogen death Cell and tissue survival assays: measurement of response In vitro clonogenic assays – effects of dose and dose rate In vivo clonogenic assays – bone marrow stem cell assays, jejunal crypt stem cell assay, skin clones, and kidney tubules Models of cell survival Random nature of cell killing and Poisson statistics Single hit, multitarget models of cell survival – survival curve descriptors Linear-quadratic models: definition of α/β ratio Calculations of cell survival with dose and dose rate Shapes of the dose-response curves for early and late responding tissues isoeffect curves and impact of changing fraction size and number on survival and LQ parameters
IV.	Linear energy transfer (LET) and oxygen effect Linear energy transfer Definition of LET and quality of radiation RBE defined RBE as a function of LET in cells and tissues Effect on RBE on change in fractionation Oxygen Effect Definition of OER Dose or dose per fraction effects OER vs LET Impact of O2 concentration Mechanisms of oxygen effect
V.	Tumor biology and microenvironment Solid tumor assay systems Concept of xenograft and syngeneic tumor models Assay of tumor response to treatment– growth delay TCD50 tumor control assay Tumor microenvironment Characteristics of tumor vasculature and microenvironment; effect of radiation on them How tumor microenvironment can regulate tumor growth and vasculature Angiogenesis and neovasculogenesis Clinical consequence and relevance of hypoxia in tumors and tumor progressions Reoxygenation after irradiation Cellular and molecular responses to hypoxia and hypoxia-induced signal transduction Cellular composition of tumors Immune microenvironment and role of inflammation
VI.	Cancer biology Cell and tissue kinetics Methods to assess cell cycle kinetics Proteins involved in cell cycle control and checkpoint initiation (e.g., CDKs, cyclins, CDK inhibitors) Phases of cell cycle and radiation sensitivity Cell cycle arrest and redistribution after irradiation Molecular signaling Main signaling pathways and critical proteins involved (e.g., PI3K/AKT, RAS/ERK, TGF-β, Wnt, Notch, NFkB) Receptors/ligand (e.g., EGFR, VEGFR, c-MET, HER2, FGFR,ALK) Kinases Definition of kinases (e.g., STKs, TKs/RTKs, DSKs) Common kinases in cancer (e.g., ATM, ATR, Chk1, Chk2, PI3K, MAPK) and corresponding phosphatases (e.g., PTEN) Molecular signaling pathways activated by IR Transcription factors involved in cancer regulation (e.g.,MYC, TP53 and associated proteins) Cell death pathways and main associated players Intrinsic vs extrinsic apoptosis (caspases) BCL-2 family member proteins (pro- vs anti-apoptotic) Mechanisms of cancer development Hallmarks of cancer and how they could affect 4/5 Rs of radiobiology Common oncogenes (e.g., HER2/neu, Ras, Myc) & tumor suppressors (Rb, p16, p53, BRCA1/BRCA2, APC, NF1) Telomeres and pathways in cancer to overcome telomere shortening (e.g., TERT promoter mutations and alternative lengthening of telomeres (ALT)) Signaling abnormalities and association with treatment response Cancer as a genetic disease Multistep nature of carcinogenesis Signaling abnormalities in carcinogenesis Prognostic and therapeutic significance of tumor characteristics Cancer genetics/genomics Types of epigenetic regulation (e.g., DNA methylation (DNMTs/TETs), histone modifications (e.g. HDACs/HATs), chromatin remodelers) Main epigenetic alterations (e.g., CpG island methylator phenotype [CIMP]) in cancer IDH1/2 mutations in glioma and AML TET2 mutations in AML Epigenetic targets in cancer (DNMTi, HDACi, IDHi, EZH2i) Omics approaches in cancer (next-gen sequencing/arrays) and newer methods (ctDNA) Biomarkers in cancer (e.g., BCR-ABL, EGFR, ALK) Molecular profiling of cancer
VII.	Radiobiology of normal tissues Clinically relevant normal tissue responses to radiation Responses in early versus late responding tissues Reirradiation Mechanisms of normal tissue radiation responses Molecular and cellular responses in slowly and rapidly proliferating tissues Mechanisms underlying clinical symptoms Tissue kinetics Total body irradiation Prodromal radiation syndrome Acute radiation syndromes Mean lethal dose and dose/time responses Immunological effects Assessment and treatment of radiation accidents Bone marrow transplantation
VIII.	Dose delivery Therapeutic ratio Tumor control probability (TCP) curves Normal tissue complication probability (NTCP) curves Causes of treatment failure Time, dose, and fractionation The four R’s of fractionation Radiobiological rationale behind dose fractionation Effect of tissue/tumor type on the response to dose fractionation (α/β ratios) Quantitation of multifraction survival curves BED and isoeffect dose calculations Hypofractionation Brachytherapy Dose-rate effects (HDR and LDR) Choice of isotopes Radiolabeled antibodies and other ligands Radiobiological aspects of different radiation modalities Protons, high LET sources Stereotactic radiosurgery/radiotherapy, IMRT, IORT, and systemic radionuclides Dose distributions and dose heterogeneity
IX.	Combined modality therapy Chemotherapeutic agents and radiation therapy Classes of chemotherapy agents Mechanisms of action Oxygen effect on radiation therapy and chemotherapy Main drug resistance mechanisms (e.g., MDR genes) Interactions/synergism of chemotherapy with radiation therapy Targeted therapeutic agents Radiosensitizers, bioreductive drugs, and radioprotectors Definition of therapeutic window Tumor radiosensitizers (e.g., oxygen) and mimics (e.g., nitromidazole) Normal tissue radioprotectors (e.g., amifostine) Biological response modifiers (e.g., IL-2 and IFN) DNA repair inhibitors (e.g., PARPi, ATMi, ATRi, Chk1/2i) Immune therapeutics Types of immunotherapy treatments in oncology Monoclonal antibodies (MABs) Checkpoint inhibitors Cytokines Vaccines Adoptive cell transfer types (chimeric antigen receptors [CARs], tumor infiltrating lymphocytes [TILs], and T cell receptors [TCRs]) Combination of immune therapies and radiation Recently published trials (e.g., PACIFIC, KEYNOTE) Known predictors of response/biomarkers Hyperthermia
X.	Late effects and radiation protection Radiation carcinogenesis Dose response for radiation-induced cancers Importance of age at exposure, time since exposure, sex, and tissue Second tumors in radiation therapy patients Risk estimates in humans Heritable effects of radiation Relative vs absolute mutation risk Doubling dose Heritable effects in humans Risk estimates for hereditable effects Radiation effects in the developing embryo Dependence of abnormalities and death on dose and gestational stage Microcephaly, intellectual disabilities Radiation protection Stochastic effects and tissue reactions Tissue and radiation weighting factors Equivalent dose, effective dose, committed dose Dose limits for occupational and public exposure

References: References are intended as resource for exam takers and will form the sources for the majority of individual items in the exam. Individual items may be sourced from references not cited in this study guide. Primary references are intended to be the source of the majority of exam items. Secondary references are for individual smaller categories of items. Primary References:

• • Hall, EJ.; Giaccia, AJ., Radiobiology for the Radiologist, 8^th Ed., 2018, Lippincott Williams & Wilkins, Phila., Pa

• • Joiner, MC and van der Kogel, AJ, Basic Clinical Radiobiology, 5^th Edition, 2018, CRC Press

Secondary References:

• • Eriksson, D. and T. Stigbrand, Radiation-induced cell death mechanisms. Tumour Biol, 2010. 31(4):p. 363-72.

• • Good, J.S. and K.J. Harrington, The hallmarks of cancer and the radiation oncologist: updating the 5Rs of radiobiology. Clin Oncol (R Coll Radiol), 2013. 25(10): p. 569-77.

• • Barker, H.E., et al., The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer, 2015. 15(7): p. 409-25.

• • Bristow, R.G. and R.P. Hill, Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer. 2008 Mar;8 (3):180-92.

• • Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. Cell, 2011. 144(5): p. 646-74.

• • Whitfield, M. L., L. K. George, G. D. Grant and C. M. Perou (2006). “Common markers of proliferation.” Nat Rev Cancer 6(2): 99-106.

• • Schaue, D. and W. H. McBride (2015). “Opportunities and challenges of radiotherapy for treating cancer.” Nat Rev Clin Oncol 12(9): 527-540.

• • Pajonk, F., E. Vlashi and W. H. McBride (2010). “Radiation resistance of cancer stem cells: the 4 R’s of radiobiology revisited.” Stem Cells 28(4): 639-648.

• • Otto, T. and P. Sicinski (2017). “Cell cycle proteins as promising targets in cancer therapy.” Nat Rev Cancer 17(2): 93-115.

• • Huang, M., A. Shen, J. Ding and M. Geng (2014). “Molecularly targeted cancer therapy: some lessons from the past decade.” Trends Pharmacol Sci 35(1): 41-50.

• • Demaria, S., E.B. Golden, and S.C. Formenti, Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA Oncol, 2015. 1(9): p. 1325-32.

• • Weinberg, RA., The Biology of Cancer, 2^nd Edition, 2013, Garland Science, New York, NY

NOTE: This study guide is subject to future revision as feedback is received on both content and clarity.