Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)
Radiation dose is measured in Gray (Gy), which is the energy absorbed per mass of tissue (joules/kilogram). An older, non-SI unit of dose was the rad.
1 Gy = 100 rad
Fractionation is the division of a total prescribed radiation dose into small, often daily doses. Fractionation preferentially spares normal tissue injury, thereby allowing higher total doses and increased cancer cell kill. However, extending the treatment time of radiotherapy allows for tumor repopulation, negatively impacting the chance of cure.
Standard fractionation is 1.8 or 2 Gy per day.
Hyperfractionation uses smaller individual doses to reduce normal tissue injury.
- Administered multiple times per day to avoid increasing overall treatment time (e.g., 1.2 Gy bid).
- Treatments are given at least six hours apart to allow normal tissue time to complete repair of the previous fraction.
- Used most commonly in head and neck cancers, small cell lung cancer.
Hypofractionation uses fractions larger than 2 Gy/day.
- Reduces both repopulation and overall treatment time.
- Used most commonly for metastases.
Radiation-induced cell death
When x-rays pass through tissue, energy is absorbed, resulting in the ionization of molecules and generation of free radicals. The most biologically important target of these free radicals is DNA, causing double helix breaks. DNA damage can lead to cell death by two mechanisms:
- Initiation of apoptosis through the p53-caspase pathway
- Loss of cellular reproductive capacity through chromosome abnormalities
The biological effect of radiotherapy is related to the dose given and the timing of the treatment. This balances the DNA damage caused by radiation with repair processes of the cell.
The amount of DNA damage is dose-dependent, and so greater radiation doses cause more cell death. Therefore, the volume of disease before the start of radiotherapy can affect its success, with microscopic disease requiring less dose than visible tumor. Frequently, normal tissues in close proximity to the tumor limit the total doses of radiation therapy administered.
Repair processes act to inhibit cell kill. The cell-cycle phase during which the damage occurs affects the ability of repair, with mitosis and G2 having less repair capability than G1 and S phase. Treatment combining radiation with chemotherapy or hyperthermia may enhance tumor cell kill by attacking multiple pathways of DNA damage and repair.
Some tissues and organs are more sensitive to radiation than others. This is related in part to repair capabilities, ability to repopulate, and the relationship to other cells in the tissue.
An early-responding tissue will quickly respond to radiation but will also quickly recover through repopulation. These tissues typically have high cell turnover at baseline, and repopulation can be increased to meet radiation-induced cell loss. The degree of recover y relates to the total dose (number of stem cells remaining) and length of treatment (longer treatment allows for more repopulation).
- Early-responding tissues have high cell turnover.
- Toxicity presents during or within weeks of radiation and recoversquickly.
- g., GI mucosa and bone marrow
A late-responding tissue has dormant or slowly cycling cells that are better able to repair radiation-induced DNA damage. however, the tissue does not have a large reser ve of stem cells able to regenerate the tissue after cell loss occurs. Thus, the effects of radiation arise after radiation is complete, but they are permanent. The degree of permanent injury relates to both fraction size and total dose (number of cells surviving).
- Late-responding tissues have minimal or slow cell turnover.
- Toxicity presents months to years after radiation and may be permanent.
- g., peripheral nerves, spinal cord, kidneys
- Skin is both an early- and a late-responding tissue, with the epidermis showing early effects and dermis showing late effects from radiation.
Organ structure can be visualized as functional units of cells either in parallel or in series, like an electrical circuit.
Parallel structures can tolerate high doses to small volumes because the untreated organ still functions, whereas relatively low doses to large volumes cause a significant decrease in organ function (e.g., lung, liver, kidney). Serial structures require that all cells act in coordination, so that even small volumes receiving a high dose can cause significant injury (e.g., spinal cord, bowel).
Typical acute effects of radiation involve early-responding tissues and include mucositis, desquamation, and hematopoetic cytopenia. Late effects include fibrosis, ulceration, and organ dysfunction.
Nonlethal DNA mutations caused by ionizing radiation can result in a radiation-induced malignancy. These typically occur after a long latent period of years and are related to the tissues irradiated and age of the patient at the time of treatment.
Strategies to improve radiosensitivity
Many chemotherapy agents also target DNA, and combination treatment can result in increased radiosensitivity, both of the tumor and normal tissues (Table 8.1). The most commonly used agents in combination with radiation are 5-fluorouracil and cisplatin. Anthracyclines and bleomycin are generally not used concurrently with radiation because of overlapping toxicities.
Because DNA damage is dependent on free radicals, hypoxic cells are relatively radioresistant compared with their nonhypoxic counterparts. Hypoxia can be combated by the following:
- Treating anemia to keep hemoglobin level above 10 g/dL
- Concurrent hyperthermia— heat improves blood flow and has direct cytotoxic effects
- Antiangiogenic drugs can normalize tumor vasculature to improve blood flow
Table 8.1 radiosensitivity of different tumors and organs
|Most sensitive||LymphomaSmall cell lung cancer||Germ cellsBone marrow|
|Moderately sensitive||Rectal cancerBreast cancer
|Least sensitive||Melanoma||CNSConnective tissue|