Principles of Radiation Therapy
Theodore Hong
Thomas DeLaney
Modern radiation therapy represents an important means of achieving local and regional control of malignancy in addition to providing palliation. When given with the intent of controlling disease and attempting cure, it is termed radical or curative; when given for symptomatic relief, it is designated palliative. Although the design and implementation of such therapy is the responsibility of the radiation oncologist, the primary physician shares in the decision to use the modality, monitors and supports the patient while it is being administered, and watches for and treats late complications. The primary care physician needs to be familiar with basic aspects of radiation therapy, its applications, and its side effects.
PRINCIPLES OF MANAGEMENT
Determinants of Radiosensitivity
Exponential killing of both tumor and normal cells occurs after an initial, sublethal accumulation of radiation damage. The ability of cells to accumulate some radiation damage before the manifestation of cell death is believed to be linked to repair capacity. The general shapes of the radiation response curves of cells in culture are remarkably similar, with most of the difference in radiosensitivity a consequence of subtle differences in the ability of cells to accumulate and repair radiation damage. Cells in the S phase of the cell cycle (when DNA synthesis is taking
place, but no mitosis) are the least sensitive to radiation, probably because of the enhanced capacity for repair in this phase. In response to radiation injury, normal cells initially stop proliferating because of “checkpoints” in the cell cycle designed to allow the cell to repair DNA damage before cell division is attempted. Malignant cells often have mutations in these critical cell cycle regulatory genes (such as p53) that perturb the checkpoint function, so progress through the cell cycle is uninterrupted despite the presence of radiation-damaged DNA; as a consequence, cell death occurs during mitosis.
place, but no mitosis) are the least sensitive to radiation, probably because of the enhanced capacity for repair in this phase. In response to radiation injury, normal cells initially stop proliferating because of “checkpoints” in the cell cycle designed to allow the cell to repair DNA damage before cell division is attempted. Malignant cells often have mutations in these critical cell cycle regulatory genes (such as p53) that perturb the checkpoint function, so progress through the cell cycle is uninterrupted despite the presence of radiation-damaged DNA; as a consequence, cell death occurs during mitosis.
The response to irradiation is also affected by the volume of the tumor. Except for uniquely radiosensitive tumors (lymphomas and seminomas), larger tumors are more difficult to eradicate with any given dose of irradiation. This is in part related to the larger number of tumor cells that must be killed. Another part of the reason for this resistance, however, is tissue hypoxia. Oxygen facilitates the cytotoxic effect of x-rays, which is mediated in part by oxygen free radicals. Hypoxic cells are about three times more refractory to irradiation than are cells treated in the presence of oxygen. Interior areas of large tumors can become hypoxic and relatively refractory to radiation. However, as the tumor shrinks, the access of its hypoxic cells to oxygen increases, and they become more susceptible to radiation if doses are given in sequential fractionated fashion (see later discussion in Minimizing Adverse Effects section). Nevertheless, the presence of anemia (hemoglobin levels <10 to 12.5 g/dL) has been shown to have a negative effect on radiotherapy treatment outcome in multiple anatomic sites, which has led to the clinical practice of administering red blood cell transfusions to maintain hemoglobin levels during a course of radiotherapy.
Strategies for Improving Response
Effective approaches include the use of particle beams, concurrent chemotherapy, and compounds that sensitize hypoxic tumor cells. Particle beams such as neutrons are less dependent on oxygen for their cytotoxic action than are x-rays and have been investigated as another means of treating large, poorly vascularized tumors. The relatively unfavorable physical dose distribution of neutrons in patients treated in clinical trials, however, prompted significant clinical interest and trials of other particles, such as protons, which have significantly better dose distribution properties than do conventional x-rays or neutrons, so the dose to the tumor can be increased substantially while adjacent normal tissue is spared. Many chemotherapy compounds, such as cis-platinum, 5-fluorouracil, and paclitaxel, enhance radiation cytotoxicity, which results in simultaneous improvement in local and distant control of tumor. Compounds that sensitize hypoxic tumor cells and improve their response to radiation therapy are under investigation.
The dose of irradiation that can be safely directed at a malignancy is limited by the tolerance of the organs surrounding it. Although the energy (i.e., voltage) of the radiation determines its ability to penetrate tissue, it is the amount of radiation actually absorbed that determines the biologic effects. High-energy megavoltage beams spare the skin, with better cosmetic results. Focusing beams on a tumor from multiple directions concentrates the dose in the tumor and avoids excessive irradiation of critical adjacent normal structures. Damage can be particularly injurious when radiation is absorbed by cells of the heart, liver, brain, intestines, bone marrow, kidneys, or lung (see Table 89-2). These structures have defined radiation tolerances that are related to the volume irradiated and the dose received. Usually, trade-offs must be made between therapeutic benefits and adverse effects.
Minimizing Adverse Effects
The probability of radiation-induced complications depends on how narrow the difference is between the dose needed for control of the tumor and the dose that causes injury to normal tissue. (The ratio of the two doses is termed the therapeutic ratio.) The greater the difference in doses, the better is the result. Dose fractionation, shielding of normal tissue, and use of imaging techniques to define tumor volume and location precisely have helped to limit the adverse effects of radiation therapy.
Fractionating the dose helps to widen the margin of safety and improve the selective killing of tumor cells. Normal cells repair sublethal radiation damage more effectively than do tumor cells. Traditional fractionation programs provide about 200 centigray (cGy) or rads per treatment, applied five times per week. Newer fractionation schemes hyperfractionate radiation with two to three treatments per day to exploit differences in radiation repair capacity between tumor and normal tissue maximally and accelerate the treatment to overcome the repopulation of tumor cells that occurs during the conventional treatment of some tumors.
Shielding helps to protect vital organs adjacent to the portal from radiation exposure. Often, custom-fabricated lead shields or analogous, automated blocking devices in the head of the newer treatment machines (multileaf collimators) are used to prevent the irradiation of normal tissue abutting the tumor.
Computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scans have improved the delineation of tumor volume and the surrounding anatomic structures so that the target can be more precisely defined. Simulation reproduces the geometry of the actual radiation portal and helps to ensure that only the desired tissue is irradiated. CT-based simulation is increasingly used for this purpose; patients are scanned in the treatment position with markers on the skin or other structures to allow the tumor to be referenced to a reproducible spatial coordinate system. The CT data set is transferred electronically to a three-dimensional treatment system that allows the tumor, normal tissues, and doses to be displayed in three dimensions. This technology permits the radiation dose to the tumor to be escalated, so the tumor control rate is increased while normal tissue is simultaneously protected; as a result, fewer side effects to normal tissue are produced.
Specific applications of this technology include stereotactic radiosurgery, stereotactic body radiotherapy, and intensity-modulated radiation therapy (IMRT). For stereotactic radiosurgery/body radiotherapy, the patient is rigidly immobilized in a head or body frame for CT stimulation and radiation treatment. IMRT employs sophisticated, computer-controlled radiation planning and treatment delivery to target the tumor with heterogeneous beams from multiple angles, resulting in better conformation of the high-dose radiation region to the tumor and lower radiation doses to selected normal tissues. In addition, amifostine is the first compound to be shown to be a clinically useful and preferential protector of normal tissue from radiation damage.
Three basic delivery modes are used. External sources (teletherapy or external beam) are the most frequently applied. Brachytherapy, in which encapsulated sources are placed directly into the body at tumor sites, has selective advantages in the treatment of very localized disease. Improvements in imaging and radiation treatment planning have resulted in a resurgence of interest in brachytherapy at such sites as the prostate, where the therapeutic ratio for this technique is high. Systemic delivery via radionuclides is the third mode. Recently, intravenous administration of radionuclide-labeled monoclonal antibodies has found utility for effective and selective treatment of some lymphomas. The theoretical attractiveness of the latter two methods is closer proximity of the radiation source to the tumor and the limited exposure of normal tissue to radiotherapy.
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