Gaorav P. Gupta and Barry S. Rosenstein
• Ionizing Radiation (IR): Photons that have adequate energy to eject orbital electrons from target molecules
• X-rays: Energized photons, as produced from electrical current in linear accelerators (LINACs)
• γ-rays: Energized photons that are emitted from the decay of radioactive isotopes
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).
• 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