Medical Radiology - Lazar A.P. 2008

Radiation Therapy
Enhancing the Effectiveness of Radiation Therapy

The efficacy of radiotherapy can be enhanced either by increasing the radiosensitivity of the tumor or by mitigating radiation reactions in normal Tissues. This is achieved using a range of Physical and Chemical factors known as radiomodifying agents (or radiomodifiers).

Radiomodifiers comprise radioprotectors and radiosensitizers. Radioprotectors are pharmacochemical and biological agents that selectively mitigate the effects of radiation on normal tissues. Pharmacochemical protectors lower METABOLISM, induce Hypoxia, and protect hemopoiesis; Examples include Cysteine, cystamine, mercamine, and sulfhydryl-bearing compounds. Agents employed to amplify radiation-induced damage to tumors are termed radiosensitizers. These include chemical agents that exacerbate primary radiation damage by increasing tumor oxygen levels (e.g., heparin), enhance primary DNA damage, and potentiate the radiation effect (e.g., 5-fluorouracil, methotrexate).

The most common Methods for manipulating tissue radiosensitivity rely on the oxygen effect. Oxygen therapy is a method of tumor oxygenation during irradiation wherein patients breathe pure oxygen at standard atmospheric pressure. Hyperbaric oxygen therapy involves tumor oxygenation during irradiation by having patients breathe pure oxygen within specialized hyperbaric chambers at 3–4 atm. Regional tourniquet hypoxia is an irradiation technique for patients with extremity malignancies involving the application of a pneumatic tourniquet. This method is based on the principle that upon tourniquet application, the partial pressure of oxygen in normal tissues drops nearly to zero within the first few minutes, whereas it remains significantly elevated in the tumor for some time. Hypoxic radiospraying (or hypoxic radiotherapy) is a technique where the patient breathes a hypoxic gas mixture containing 10% oxygen and 90% nitrogen (HGM-10) before and during the irradiation session. The selective protection of normal tissues afforded by this method allows for a 20% increase in single and total doses, which can reach up to 40% when the oxygen content is reduced to 8% (HGM-8). Electron-affinic compounds (EACs) are chemical substances capable of mimicking the action of oxygen (due to their high electron affinity) and selectively sensitizing hypoxic Cells. The most widely used EACs are metronidazole and misonidazole, particularly when applied topically in a dimethyl sulfoxide (DMSO) solution, which achieves a high local drug concentration within the tumor and significantly improves Radiation therapy outcomes.

Tissue radiosensitivity can also be modulated using non-oxygen-dependent agents, such as DNA Repair inhibitors. Examples include 5-fluorouracil and halogenated analogs of purine and pyrimidine bases. Hydroxyurea, an antitumor DNA Synthesis inhibitor, is similarly employed as a radiosensitizer. Actinomycin D, an antibiotic, attenuates post-radiation tumor recovery. DMSO serves as a protective agent for the Skin and mucous membranes, exhibiting radioprotective, anti-inflammatory, and local anesthetic properties.

Thermoradiotherapy is a radiation Treatment modality that involves heating the tumor to 42–45 °C using microwave or short-wave diathermy devices. At such temperatures, impaired venous outflow from the tumor leads to preferential heating and, consequently, the destruction of neoplastic cells.

The induction of artificial hyperglycemia via administration of large doses of glucose leads to acidification of the tumor tissue, causing some cells to perish while rendering others more susceptible to tumoricidal agents. An optimal approach is considered to be the simultaneous or sequential application of irradiation, hyperthermia, and hyperglycemia. The Use of multiple agents that alter the radiosensitivity of both tumor and normal tissues is known as polyradiomodification.

The therapeutic efficacy of radiotherapy can also be improved by modifying the fractionation schedule. The primary method for this is dose fractionation. The prescribed total dose is divided into smaller portions (fractions), and the tumor is irradiated repeatedly (fractionated). The favorable impact of fractionation on the therapeutic ratio is attributed to the fact that healthy tissues surrounding the tumor recover more completely between treatment sessions than malignant cells do.

In external beam radiotherapy, conventional (or standard) fractionation is the most prevalent approach, involving daily doses of 2.0–2.5 Gy administered 5 days a week. Single doses of 3–4 Gy fall under moderate fractionation. As individual fraction sizes increase, their number decreases, thereby shortening the overall treatment time. For palliative and symptomatic management, hypofractionation is frequently utilized, consisting of one or two large fractions of 5–15 Gy.

Recently, split-course radiotherapy has seen widespread clinical application. This approach utilizes varying fraction sizes delivered across irregular time intervals. The initial phase employs moderate or large focal doses aimed at eradicating radiosensitive tumor cells. This is followed by a 2-3 week break to allow for the recovery of mitotic activity in the cells surviving The first phase. Additionally, tumor reoxygenation occurs during this period due to tumor volume reduction, thereby increasing the radiosensitivity of the remaining tumor cells. In the final phase, small- or moderate-dose fractions are administered to deliver the remaining prescribed total focal dose.

The mitotic cycle lasts no more than a week in tumor cells, compared to 1–3 days in normal cells. Consequently, a treatment break of 2–3 weeks does not lead to tumor progression, whereas normal tissues recover during this time alongside capillary proliferation. This facilitates a reduction in normal tissue toxicity and improves overall treatment outcomes.