Radiation: The fundamentals

Radiation Therapies
Written By Sydney Oesch

Episode Notes

  1. Radiation biology 

    1. Compton process: high energy photons from the ionizing radiation waves collide with tissue, ejecting electrons from the atoms and generating ions. Electrons mediate tissue response via indirect and direct effects

      1. Indirect effects (75%): electrons interact with water atoms > hydroxyl radicals. Hydroxyl radicals create oxidative stress and DNA damage

      2. Direct effects (25%): scattered electrons directly interact with DNA, creating damage

      3. DNA damage > double stranded DNA breaks > cell death

      4. Ionizing radiation waves are high frequency, short wavelengths

      5. Photon: an energy packet within ionizing radiation waves

    2. Cell response to DNA damage

      1. Repair: Double-strand repair accomplished via homologous recombination (HR - more reliable) or nonhomologous end joining (NHEJ - more error-prone)

      2. Mitotic catastrophe: inaccurate repair leaves cells without the ability to survive at the time of mitosis; when cells attempt to divide, they die

        1. Tissue effects: necrosis and inflammation

        2. Impact: radiation effects occur beyond the time of radiation administration; cell death continues to occur until cells go through their next attempted cell division

    3. Fractionation: splitting total planned radiation dose into several smaller doses (fractions)

      1. Fractionating radiation doses takes advantage of log cell kill and improves therapeutic ratio

        1. Log cell kill model: similar to chemotherapy, each dose/fraction of radiation kills a fixed percentage of cells

        2. Therapeutic ratio: ratio of the amount of radiation needed to cause desirable effect/sufficient cell kill (tumor control probability) compared to the toxic effects of radiation (normal tissue complication probability)

      2. Benefits: improved therapeutic ratio

      3. Drawbacks: requires a higher overall dose to reach the same amount of cell kill

    4. The “4 R’s” of radiobiology: these describe factors which impact tumor sensitivity to ionizing radiation

      1. Repair: repair of DNA damage occurs differently/at a different pace in different cell types. Normal tissues have more intact DNA repair mechanisms and are better able to repair radiation induced damage than cancer cells.

        1. Fractionation allows normal cells to repair in between doses while the cancer cells don’t have time to fully repair before being hit with another dose/fraction

      2. Repopulation: repopulation of tumor cells between fractions - this can decrease efficacy of our delivered radiation.

        1. Repopulation is accelerated after radiation delivery; this is a response to cell stress

        2. Avoiding treatment breaks and delays is essential to minimizing tumor cell repopulation between fractions

      3. Reassortment/redistribution: radiation is more effective (cells are more radiosensitive) in G2 and M phase, more resistant in S phase.  Individual cells within a tissue will be in different phases of the cell cycle; ideally, with subsequent fractions, we “catch” the cells that were previously in a radioresistant phase. 

      4. Reoxygenation: hypoxia makes cells more resistant to radiation; hypoxic cells require 3x the radiation dose to be killed. As tumor cells die, the remaining cells become more oxygenated (due to less competition for nutrients) and thus become more sensitive to radiation with the next fraction

    5. Radiosensitizing chemotherapy: 

      1. Radiosensitizing chemotherapies (example: cisplatin) tend to arrest cells in mitosis, making them more sensitive to ionizing radiation

      2. Chemotherapy and radiation also work in different ways, so combined cell kill from two modalities can help prevent the development of resistant tumor clones

      3. Too much radiosensitization can worsen toxicities of radiation therapy by making the normal cells more radiosensitive

  2. Radiation physics

    1. Photon radiation creation/sources

      1. Linear acceleration: accounts for 95% of radiation currently used in gynecologic oncology (example: EBRT, IMRT)

        1. Linear accelerators take electronic energy (electrons) and turn it into x-ray energy (photons). Photons are electromagnetic radiation, created by the acceleration and then rapid deceleration of electrons (Bremsstrahlung reaction)

      2. Nuclear decay: accounts for 5% of radiation used in gyn oncology (example: brachytherapy, gamma knife).

        1. Most common radiation source in high dose rate brachytherapy: Iridium 192

        2. Radiation source (iridium) releases an electron (aka beta particle) from the nucleus, which eventually produces gamma ray radiation (photon). 

    2. Units of measurement

      1. 1 Gray = 1 joule/kg. This is a measure of the absorbed dose of radiation

        1. Gray is not a measure of radiation effect: different energies/types of radiation may need more/less radiation to produce the same Gray

        2. 1 Gray = 100 rads = 100 cGy

    3. Inverse square law: intensity of radiation delivered decreases proportionally to the square of the distance from the source (i.e. the farther the target is from the source, the less dose delivered)

    4. Dosing: 

      1. Conventional fractionation (dosing for most Gyn cancer): 1.8-2Gy per fraction, calculate # of fractions to reach total desired dose

    5. Target Volumes for radiation delivery

      1. Gross Target Volume (GTV): volume of the tumor which we are targeting, which we can see

      2. Clinical Target Volume (CTV): expand the GTV to include areas which are likely to harbor microscopic spread (larger than the GTV)

        1. Use of anatomy and disease specific patterns of spread help to determine the CTV

        2. Imaging with PET, CT, or MRI are useful to plan

          1. Hounsfield units on CT scan measure density of different tissues/organs, allowing for detailed planning

      3. Planning Target Volume (PTV): accounts for tissue shifting and patient movement

        1. This is the final volume used to plan or conform radiation dosing. Goal is to minimize radiaiton to normal surrounding tissues (aka organs at risk, OAR)

    6. Fluence: intensity of radiation/number of photons passing through an area

      1. Beam modifiers are useful to modify fluence; these wedges allow less photons to pass through areas where less intensity is desired; they also allow delivery of beams from multiple angles

      2. Opposing beams: beams originate from opposite sides of the patient, increasing the target tissue delivery and decreasing delivery to OAR

        1. More beams = better therapeutic ratio

  3. Types of radiation, delivery specifics

    1. EBRT 

      1. Patients usually immobilized in the same position for each fraction, daily image guidance often is used to optimize delivery

        1. Image-Guided RT uses real-time imaging to guide daily treatment delivery

      2. 3-D Conformal RT, IMRT, VMAT, and SBRT are all types of/refinements of traditional EBRT, utilizing the same radiation physics as EBRT

        1. 3-D CRT: addresses fluence to improve the therapeutic ratio (older/more traditional method): use Hounsfield units on CT to calculate dose, then adjust multiple beams to the 3D shape of the tumor.

          1. Limited by small # of total beams

          2. Still used in some scenarios, like palliative radiation for symptom control

      3. Intensity Modulated RT (IMRT): Refinement of 3-D CRT, still using Hounsfield units

        1. Can change intensity of radiation in a single beam during treatment

        2. Increased # of beams

        3. Allows for treatment multiple areas on the target volume to different dose levels

        4. Multileaf collimators: tungsten leaves which shift to match the tumor shape, protecting normal tissues/tailoring radiation to desired reas

        5. Time-C study: 2018. Compared IMRT to standard four-field RT in post-hysterectomy patients; IMRT provided improved GI and urinary toxicity profiles

      4. Volume-Modulated Arc Therapy (VMAT): advanced type of IMRT, delivers radiation in 360-degree arches

      5. Stereotactic body radiotherapy (SBRT) aka Stereotactive Ablative Radiotherapy (SABR): focused EBRT delivering fewer fractions with higher doses of focused radiation per fraction. Used for isolated disease sites like oligometastases

        1. Typically 1-5 fractions

        2. Immobilization and reproducibility of planning volumes is crucial due to high doses of radiation in each fraction

        3. SABR-COMET trial: phase II trial of SABR as primary treatment for oligometastases: compared to standard of care palliative therapy (including chemo or palliative symptom-directed radiation), standard of care + SABR to oligometastatic lesions resulting in improved OS (42% vs. 18%) at 5 years, with preserved quality of life. 

    2. Brachytherapy

      1. Brachytherapy is internal radiation delivered to the cervix or vaginal cuff using applicators

      2. Requires sedation, done in the OR or a procedural suite

      3. Examples of application devices: tandem and ovoids (Fletcher), vaginal cylinder, Syed templates with interstitial needles

      4. Radiation source

        1. Afterloader: machine which houses the radiation source, connected to the applicators via catheters. Radiation moves along the catheters into th epatient

      5. Delivery:

        1. Traditional: point A - 2cm from top of ovoids, 2cm laterally. Expected to be the point where uterine artery and ureter cross

          1. Current: volumetric-based planning target tumor volumes, point A not always utilized

          2. See figure

      6. Dose-rates: options for brachytherapy, similar efficacy, less long term complications with HDR

        1. High dose rate: two ways for cell killing

          1. One electron breaks two DNA strands

          2. Two separate electrons break individual strands

          3. Cell kill curve = linear quadratic (higher damage at higher doses)

          4. Allows for outpatient treatment

        2. Low dose rate: cell killing via single electron > double-stranded DNA breaks

          1. Requires inpatient hospitalization

Figure 1: Point A depiction, brachytherapy dosing

Source: https://www.aboutcancer.com/pointa.jpg

References

1.    Ferrigno R, Nishimoto IN, Ribeiro Dos Santos Novaes PE, et al. Comparison of low and high dose rate brachytherapy in the treatment of uterine cervix cancer. Retrospective analysis of two sequential series. Int J Radiat Oncol Biol Phys. 2005;62(4):1108-1116. doi:10.1016/J.IJROBP.2004.12.016

2.    Klopp AH, Yeung AR, Deshmukh S, et al. Patient-Reported Toxicity During Pelvic Intensity-Modulated Radiation Therapy: NRG Oncology-RTOG 1203. J Clin Oncol. 2018;36(24):2538-2544. doi:10.1200/JCO.2017.77.4273

3.    Verma J, Sulman EP, Jhingran A, et al. Dosimetric predictors of duodenal toxicity after intensity modulated radiation therapy for treatment of the para-aortic nodes in gynecologic cancer. Int J Radiat Oncol Biol Phys. 2014;88(2):357-362. doi:10.1016/J.IJROBP.2013.09.053

4.    Yeung AR, Deshmukh S, Klopp AH, et al. Intensity-Modulated Radiation Therapy Reduces Patient-Reported Chronic Toxicity Compared With Conventional Pelvic Radiation Therapy: Updated Results of a Phase III Trial. J Clin Oncol. 2022;40(27):3115-3119. doi:10.1200/JCO.21.02831

5.    Pötter R, Tanderup K, Schmid MP, et al. MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study. Lancet Oncol. 2021;22(4):538-547. doi:10.1016/S1470-2045(20)30753-1

6.    Klopp AH, Moughan J, Portelance L, et al. Hematologic Toxicity in RTOG 0418: A Phase 2 Study of Postoperative IMRT for Gynecologic Cancer. International Journal of Radiation Oncology*Biology*Physics. 2013;86(1):83-90. doi:10.1016/J.IJROBP.2013.01.017

7.    Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. Vol 38.; 2020. https://doi.org/10.

8. Radiation Oncology Concepts by Dr. McDonald, SGO ConnectEd Fellows Bootcamp



 



Sydney Oesch
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