Radiation Oncology



Radiation Oncology





BASIC RADIATION BIOLOGY AND PHYSICS

Gaorav P. Gupta

Barry S. Rosenstein



Photon Interactions With Biologic Material



  • Direct effects (minor for x-rays): DNA molecules themselves are the direct targets of ionization, which ultimately trigger a chemical or biologic change


  • Indirect effects (major for x-rays): Radiation ionizes other molecules in the cell (most frequently water) to produce free radicals that diffuse to & cause damage to DNA


  • Double strand breaks (DSBs) in DNA are thought to be the critical determinant of cellular response, although many other types of molecular damage are also induced


Cellular Response to IR



  • Mitotic death: Cell death due to chromosome missegregation during mitosis


  • Apoptosis: Programmed cell death, in this case induced by IR


  • Alternative mechanisms of IR-induced lethality include senescence & autophagy


  • Cells that undergo apoptotic death in response to IR (ie, lymphoid cells, acinar cells of the salivary glands) are typically more radiosensitive


Repair of DNA DSBs



  • Correlation between rate of death & the induction of putative “lethal” chromosomal aberrations (eg, dicentrics, rings, etc.)


  • Sublethal DSB repair occurs through nonhomologous end joining (NHEJ) or homologous recombination (HR). Defects in these pathways promote radiosensitivity.


Radiosensitivity & Cell Cycle



  • Cells vary in radiosensitivity across the cell cycle: Generally more sensitive in M & G2 phases & most resistant in late S phase


Synergy of Oxygen With Radiotherapy



  • Oxygen enhances DNA damage induced by free radicals, thereby facilitating the indirect action of IR


  • Biologically equivalent dose can vary by a factor of 2-3 depending upon the presence or absence of oxygen (referred to as the oxygen enhancement ratio)


  • Poorly oxygenated postoperative beds frequently require higher doses of RT than preoperative RT (eg, soft tissue sarcoma)


Understanding Radiation Response: The 4 Rs of Radiobiology



  • Repair of sublethal damage


  • Reassortment of cells w/in the cell cycle


  • Repopulation of cells during the course of radiotherapy


  • Reoxygenation of hypoxic cells


Basis for Conventional Dose Fractionation



  • Spares nl tissues by allowing for repair of sublethal damage & cellular repopulation between fractions


  • Augments tumor control by allowing for reoxygenation of hypoxic regions w/in the tumor & reassortment of cells into more radiosensitive portions of the cell cycle


Potential Benefits of Hypofractionated Radiotherapy



  • Radioresistant histologies (eg, melanoma, renal cell carcinoma, etc.) may not respond effectively to conventionally fractionated radiation doses (ie, 1.8-2 Gy)


  • Image-guided intensity-modulated RT (IMRT) has enabled radiation dose escalation, w/improved anatomical targeting of radiotherapy, & relative sparing of nearby nl tissues


  • Large radiation doses (ie, >8 Gy) may be a/w additional mechanisms of cancer cell death, including effects on the tumor-associated stroma (eg, endothelial cells)


  • Late effects on nl tissues of these higher radiation doses remain a concern



Chemical Modifiers of Radiation Response



  • Radioprotectors & radiosensitizers are chemical agents that modify the cellular response to IR


  • Radioprotectors are often scavengers of IR-induced free radicals. The most well studied is amifostine, which reduces xerostomia in head & neck cancer pts. However, its use has been limited due to concerns of diminished antitumor effects.


  • Radiosensitizers are actively being studied & may act by targeting the hypoxic cells or radioresistant clonogens w/in a tumor


Chemotherapy & Radiotherapy



  • Chemotherapy is frequently used sequentially or concurrently w/radiotherapy to maximize therapeutic benefit, although also a/w ↑ overall toxicity.


  • Drugs that show significant synergy w/RT: Dacarbazine, cisplatin, bleomycin, dactinomycin, Doxorubicin, mitomycin C, 5-FU, capecitabine, Gemcitabine, bevacizumab, cetuximab, PARP inhibitors


  • Mechanisms for synergy vary widely: Include cell cycle effects, hypoxic cell sensitization, & modulation of the DNA damage response


Acute Normal Tissue Effects



  • Due to cell killing of nl tissues (eg, dermatitis, esophagitis, & diarrhea), or by radiation-induced inflammatory cytokines (eg, nausea, vomiting, & fatigue)


  • Testes: 0.1-0.15 Gy leads to temporary sterility. Doses of 6-8 Gy can lead to permanent sterility. Such doses have min. effect on testosterone production.


  • Ovaries: Very sensitive to IR. Doses of 6-12 Gy result in sterilization of 50% of pts. There is age dependence, w/lower doses needed to induce sterility in older pts. Sterility is a/w ovarian hormonal failure, resulting in premature menopause.


Late Normal Tissue Effects



  • Occur after a delay of mos to y, & can result from a combination of vascular damage and/or loss of parenchymal cells in the affected organ


  • Specific dose-volume relationships have been linked to the risk of late organ toxicity. Some of these data are summarized below, derived from the QUANTEC project (Int J Radiat Oncol Biol Phys 2010;76:S1-S160).








































Organ


Outcome


Fraction Size (Gy)


Dose (Gy)


Likelihood or Risk


Braina


Radionecrosis


<2.5


120


5%


Spinal cordb


Myelopathy


1.8-2


54


61


<1%


<10%


Kidneyc


Nephrotoxicity


1-2


10 (whole kidney)


5%


Heartd,e,f


Ischemic heart disease


1.8-2


30


RR ˜ 1.5-3.3


a Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S20-S27.

b Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S42-S49.



c Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S108-S115.



d Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S77-S85.



e J Am Med Assoc 1993;270:1949-1955.



f Lancet 2005;366:2087-2106.



Secondary Malignancy



  • Dose, volume, underlying genetics, & age of the pt at the time of RT are critical determinants of the risk for secondary malignancy


  • The likelihood of secondary cancer is correlated w/dose, but there is no threshold dose below which there is no additional risk of secondary malignancy


  • Latent period for radiation-induced solid tumors is generally between 10 and 60 y, although exceptions are possible. Latent period for leukemias (less common after modern RT) is shorter—w/a peak between 5 and 7 y.


  • Important to distinguish relative risk from absolute risk when considering the likelihood of secondary malignancy



EXTERNAL BEAM RADIATION THERAPY

Sewit Teckie

Ryan M. Lanning

Simon N. Powell


What is External Beam Radiation Therapy (EBRT)?



  • EBRT = therapeutic RT delivered by an external machine to treat malignancies & some benign conditions


  • EBRT is a local Rx (exceptions: TBI = total body irradiation & TSEB = total skin electron beam)


  • Contrast w/brachytherapy: RT delivered by a source inside/near the tumor





























Types of Radiation Used for EBRT


IR


Electrons


Used for superficial cancers, such as skin & SC tissues


Photons


Most commonly used in EBRT


High-energy x-rays created by a LINAC


Protons


Deposits almost all energy in the Bragg peak → min. radiation “exit dose” beyond the target tissue


Expensive & in limited supply around the country


Indications: Pediatrics, re-RT, specific histologies


Heavy ions (eg, carbon)


↑ relative biologic effectiveness (RBE) > photons/protons


Extremely limited availability worldwide. High cost.



Neutrons


RBE, greater than other forms of radiation


Extremely limited availability worldwide; clinical trials


Hoppe, R et al. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Saunders: 2010.



How Does a Patient Proceed From Consultation to Starting EBRT?



  • Consultation visit: Radiation oncologist evaluates need for RT, schedules simulation


  • Simulation: Pt undergoes a planning CT scan, ± PET or MRI, in the treatment position



    • Pt immobilized using variety of devices


    • Treatment “isocenter” (point RT beam interaction) placed on the CT scan


    • Isocenter & alignment tattoos placed on the pt


    • Images transferred to a treatment-planning computer


  • Set volumes: MD contours target volumes & nl structures on the planning CT scan; if simple 2D treatment, MD also places desired RT beams on the CT


  • Write prescription: MD prescribes a specific dose & fractionation of RT


  • Treatment planning:



    • If 2D, physics staff verifies the dose & beams, & EBRT can begin quickly


    • If 3D or more complex treatment, physics staff generates custom plan unique for each pt; can take up to 1 wk of treatment planning & QA review


  • Treatment plan reviewed & approved by MD


  • Pt set-up on treatment machine: A “dry-run” session to double-check all treatment & machine parameters


  • EBRT begins d after set-up session


Terminology of EBRT: Delivery Types



  • Conventional: 2D RT w/2 beams; used for simple treatments & lower total doses of EBRT eg, whole-brain RT, palliation for bone mets


  • 3D conformal RT (3DCRT): 3D treatment plan using more than 2 beams to conformally treat a target region eg, pelvis for rectal cancer


  • IMRT: Use of an inverse-planning algorithm to create a computer-generated 3D RT plan using multiple beam angles; optimizes treatment of target tissue while sparing critical nl tissues eg, head & neck cancers, prostate cancer. Requires contouring/delineation of both treatment volumes & nl tissues


  • Image-guided radiation therapy (IGRT): Daily or weekly 2D or 3D imaging to ensure treatment is precisely delivered; often used along w/IMRT, stereotactic radiosurgery (SRS), & stereotactic body RT (SBRT) to allow smaller margins on treatment volumes


  • 4D CT: Used to account for pt internal motion from breathing, ensuring that tumor volume is not outside of the beams during treatment eg, lung cancer, upper abdominal cancers


  • Respiratory gating: Technique used to deliver RT only when a pt’s breathing falls w/in certain phases of respiratory cycle. Used for upper abdominal tumors.


  • SRS/SBRT: Separate chapter



Dose & Fractionation



  • Units of RT dose = Gy = 1 J/kg


  • Fractions = Number of sessions over which the total RT dose is delivered


  • Dose & fractionation are determined according to multiple factors: Intrinsic tumor radiosensitivity, proximity of tumor to critical nl tissues, data from randomized trials, use of sequential or concurrent chemotherapy, pt convenience


  • Typically, RT is delivered in daily fractions over a number of wks


  • Fractionation terminology:



    • Hypofractionation = using higher RT dose per fraction, over fewer fractions eg, SBRT, radioresistant tumors such as melanoma


    • Hyperfractionation = using smaller RT dose per fraction, over more fractions eg, limited-stage SCLC




















































Common EBRT Doses and Fractionation


Site


Total Dose (Gy)


# Fractions


Breast


50-60


25-30


Prostate


78-86


43-48


Primary brain tumor


60


30


H&N definitive treatment


70


33


Early stage lung


48-60


3-4


HL


20-36


13-20


Rectal preoperative


50


28


Postoperative tumor beds


50-66


25-33


Whole brain RT (palliation)


30


10


Hoppe, R et al. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Saunders: 2010.



Side Effects of EBRT

Aug 17, 2016 | Posted by in ONCOLOGY | Comments Off on Radiation Oncology

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