Ionizing radiation causes the production of free hydrogenions and hydroxyl ( OH) radicals. With sufficient oxygen, hydrogen peroxide (H2O2) is formed, which disrupts the structure of DNA and, eventually, the cell’s ability to divide. As with chemotherapy, killing is by first-order kinetics. Because dividing cells are more sensitive to radiation damage and because not all cells in a given tumor are dividing at any one time, fractionated doses of radiation are more likely to be effective than a single dose. Providing multiple lower doses of radiation alsoreduces the deleterious effects on normal tissues.
The basis of fractionated dosage comes from the “four Rs” of radiobiology:
· Repair of sublethal injury. When a dose is divided,the number of normal cells that survive is greater than if the dose were given at one time (higher total amounts of radiation can be tolerated in fractionated as opposed to single doses).
· Repopulation. Reactivation of stem cells occurs whenradiation is stopped; thus regenerative capacity depends on the number of available stem cells.
· Reoxygenation. Cells are more vulnerable to radiationdamage with oxygen present; as tumor cells are killed, surviving tumor cells are brought into contact with capillaries, making them radiosensitive.
· Redistribution in the cell cycle. Because tumor cellsare in various phases of the cell cycle, fractionated doses make it more likely that a given cell is irradiated when it is most vulnerable.
The rad has been used as a measure of the amount of energy absorbed per unit mass of tissue. A standard mea-sure of absorbed dose is the Gray, which is defined as 1 joule per kilogram; 1 Gray is equal to 100 rad. Radiation is deliv-ered in two general ways: external irradiation (teletherapy) and local irradiation (brachytherapy). Teletherapy depends on the use of high-energy (>1 million eV) beams, because this spares the skin and delivers less toxic radiation to the bone. Tolerance for external radiation depends on the vulnerability of surrounding normal tissues. Teletherapy usually is used to shrink tumors before localized radiation. Brachytherapy depends on the inverse square law: thedose of radiation at a given point is inversely proportional to the square of the distance from the radiation source. To put the radioactive material at the closest possible distance, brachytherapy uses encapsulated sources of ionizing radia-tion implanted directly into tissues (interstitial) or placed in natural body cavities (intracavitary). Intracavitarydevices can be placed within the uterus, cervix, or vagina, and then (after) loaded with radioactive sources as either low-dose radiotherapy (cesium-137), high-dose radiother-apy (iridium-192, cobalt-60), or as interstitial implants. This method protects health personnel from radiation expo-sure. A new method of treating early breast cancer involves high–dose-rate brachytherapy inserted by balloon catheter into the cavity created by lumpectomy. Interstitialimplants use isotopes (iridium-192, iodine-125) formulatedas wires or seeds. These implants are usually temporary, but permanent seed implants are being investigated.
New strategies are being developed for radiation therapy. For example, intraoperative therapy is being used for previously irradiated patients with recurrent disease who would require unacceptably high dosages of external radiation.
Complications associated with radiation therapy can be acute or late (chronic). Acute reactionsaffect rapidly dividingtissues, such as epithelia (skin, gastrointestinal mucosa, bone marrow, and reproductive cells). Manifestations are cessation of mitotic activity, cellular swelling, tissue edema, and tissue necrosis. Early problems associated with irradia-tion of gynecologic cancers include enteritis, acute cystitis, vulvitis, proctosigmoiditis, topical skin desquamation, and, occasionally, bone marrow depression. Chronic complica-tions occur months to years after completion of radiationtherapy. These include obliteration of small blood vessels or thickening of the vessel wall, fibrosis, and reductions in epithelial and parenchymal cell populations. Chronic proc-titis, hemorrhagic cystitis, formation of ureterovaginal or vesicovaginal fistula, rectal or sigmoid stenosis, and bowel obstructions, as well as gastrointestinal fistulae may result.