Treatment - Radiotherapy

Like surgery, radiotherapy is a local modality for cancer treatment. The inherent difference in radiosensitivity between the tumor and adjacent normal tissues allow it to destroy the former with minimal disruption to the latter. Success also depends on the ability of normal tissues to sustain and repair damage from radiation, and for a patient to function adequately with diminished normal organ function.

Ionizing radiation of various types and energies - usually x-rays or gamma-rays - are used to destroy localized populations of cancer cells. The location and anatomic extent of the lesion limit the procedure. As with surgery, results are best with relatively small lesions detected before they produce dysfunction of major organs or spread be-yond the limits of feasible treatment fields. The tolerance of adjacent normal tissue limits the amount of radiation that can be given.

X-rays are nonparticulate, high-energy electromagnetic ion-izing radiation (photons of 4 to 25 MeV) produced by a machine like a linear accelerator; gamma rays are high-energy radiation emitted by decay of natural or artificially produced radioisotopes, such as radium-226, cobalt-60, or cesium-137. These radiations have high energy and short wave-lengths with extremely high penetrating power in materials of low atomic number (e.g., water and tissue) but are stopped by materials of high atomic number like lead. There is no difference in the physical characteristics or biological effects of x-rays and gamma-rays. Through ionization of water mol-ecules the radiation produces free radicals and oxi-dants within the target cells. These chemically reac-tive agents break and damage DNA molecules. Although the exact mechanism is undefined, irradia-tion through altering nucleotide sequences seems to produce a change in transcription and defective re-pair, which leads to cell death.

Cobalt irradiation units are cheaper and are still the workhorse of radiation oncology, especially in the developing world. But linear (electron) accelerators are photon generators that are becoming more widely em-ployed in developed countries. Because of reduced skin doses and lesser internal scatter, high doses of radiation can be deliv-ered to tumors at any depth in the body by megavol-tage irradiation. Orthovoltage x-rays have lesser energy, but they deliver higher doses to superficial tissues where they are used to treat skin cancer. Linear accelerators deliver sharper beam margins (a more focussed beam, with a smaller penumbra) than cobalt units and can also provide electrons that are particulate and penetrate in a tighter range with an abrupt fall off in tissues (Bragg effect), sparing deeper normal tissues from irradia-tion. Linear accelerators can also provide electrons. Their low penetrance spares deeper tissues so that they are useful for skin lesions, such as myosis fun-goides, and for intraoperative radiotherapy. External beam therapy (teletherapy) is given from a source outside the body. Brachytherapy delivers radiation from sealed radioactive materials inserted in or near the tumor. Because the source is close to or within the tumor the dose is more localized than with teletherapy. Intracavitary inserts (for cervical or vaginal cancers) or interstitial implants (for prostate cancer) are used. In head and neck cancer implants that give a high-intensity boost to the tumor bed can be used together with teletherapy.

Other forms of particulate irradiation that are more pene-trating than electrons are under experiment in specialized centres. These include fast neutrons and charged particles such as protons, helium ions, and negative pi mesons. These particles produce a more intense deposition of energy per unit path in the tissue (high linear energy transfer, or LET) than ordinary photons and have a more precise localization of energy release. They also have, theoretically, a greater relative biologic effectiveness because hypoxic areas of tumors respond better to them than to conventional photons. The depth of particle penetration is more accurately controlled so that normal tissues are spared. Early and prom-ising studies are in progress with ocular melanomas, head and neck and salivary gland cancers, and gastric and pancreatic cancers with intraoperative radiother-apy. Electron beam therapy delivers energy that is rapidly absorbed with reduced dose to adjacent normal tissues. It is used to treat superficial tumors like skin cancers or mycosis fungoides.

Radiation dosage is expressed in units called grays (Gy), which measure the amount of energy absorbed per unit volume of tissue (1 Gy is the absorption of 1 J (Joule) of energy per kilogram of tissue). One gray equals 100 rads. The effects of radiation depend on the time over which it is delivered and the dose per fraction. Usual dose fractionation is about 10 Gy (1000 rads) per week delivered in 1.5 to 2.5 Gy (150 to 250 rad fractions). Megavoltage equipment now allows exper-imentation with shorter and more intense dose frac-tionation. A given dose of radiation kills a constant percentage of cells rather than a constant number. At high doses cell survival drops proportionate to increasing radiation dose with first order kinetics. But at low radiation doses the curve shows a shoulder from a reduced rate of cell death that may be due to cellular repair mechanisms.

Free radicals and reactive oxygen intermediates are produced by ionizing radiation. They damage local cellular constituents with DNA as the primary targets. DNA double-strand breaks are the critical lesion that kills cells either within a few hours or after cellular division (mitotic cell death). Both lead to apoptosis (programmed cell death), a genetic program that activates cellular nucleases and leads to a fragmentation of genomic DNA. The nucleus condenses and then the cell membrane loses integrity. A tumor suppressor gene, p53, is involved in regulating apoptosis. P53 is mutated or deleted in a high proportion of tumor cells, thus affecting their ability to respond to ionizing radiation with apoptosis. If cells fail to undergo apoptosis, they may die from necrosis in which the cell membrane integrity is lost before the DNA is degraded.

Tissues differ in their radiosensitivity. Normal intestinal mucosa, bone marrow and skin proliferate rapidly and so are particularly susceptible to cytotoxicity. Radiation damage may be delayed or appear only after stress (e.g. prolonged healing after a fracture in an irradiated long bone) in slowly proliferating normal tissues. Radiosensitivity is determined partly by the capacity and extent of cellular repair mechanisms. Repair is complete in normal tissues in 4 - 6h after radiation. Hypoxic tissues are relatively resistant to radiation damage since oxygen is needed to generate and sustain free radicals. A two to three times higher dose of radiation is needed to kill anoxic cells compared to oxygenated ones. Thus the centre of larger tumor masses will be relatively insensitive to radiation because of anoxia from poor vascularization.

Radiotherapy requires a multidisciplinary team approach with radiation oncologists, medical physicists, radiation technologists, dosimetrists and nurses. Computerized treatment planning is done first based on CT and MRI scans using a simulator that produces x-ray images to show the exact location of beams. The treatment plan is calculated by computer, and lasers, skin markings, casts and molds are used to position patients exactly the same way for each treatment. Modern programs are beginning to use conformal radiotherapy with three-dimensional treatment planning for increased accuracy. The objective is to irradiate the whole tumor volume uniformly for maximum tumor kill while sparing adjacent normal tissues to minimize implications. Dose to vital structures is minimized by using multiple fields from external sources which converge to focus on the tumor. Radiation is delivered in fractionated doses (eg 180-300 cGy daily five times per week for a total course of 5 to 8 weeks). Fractionation improves the control and therapeutic index by influencing reoxygenation of hypoxic tumor, cellular repair of normal tissues and repopulation of tissues that were destroyed. Fractionated schedules can be accelerated to reduce treatment time. This may give more acute toxicity from the increased daily does, but tumors with rapid doubling times (as in some head and neck cancers) may respond better. In hyperfractionation smaller doses are given several times a day to increase the total number of treatments for a greater therapeutic index.

About half of cancer patients eventually are treated with radiotherapy in countries where good facilities are readily available. Much of it is for palliative management (bone and brain metastases, alleviation of bleeding, pain and obstruction) using doses lower than those used for curative therapy, and hence with less toxicity for the patient.

Radiotherapy can be curative as the sole treatment modality (eg limited stage Hodgkin's disease or prostate cancer; some head and neck tumors; some non-Hodgkin's lymphomas; limited stage gynecologic and nervous system tumors, and some skin cancers). Radiotherapy is also used in curative, multimodality strategies with surgery (eg squamous cell carcinoma of the anus or breast cancer). Urgent radiotherapy is used to treat complications such as impending spinal cord compression, obstructed airway or superior vena caval obstruction.

Whole body irradiation is used infrequently in clinical practice. Most radiation therapy is directed toward specific anatomic sites or regions, and the patient may experience a systemic reaction as well as effects produced on normal tissues within the treat-ment field. Radiation sickness is characterized by general debility, anorexia, and vomiting that begins soon after the onset of treatment and subsides promptly when therapy is stopped or the dose re-duced. Occurrence relates to dose and to volume and type of tissue treated.

The early regional toxic effects of radiation pro-duced within days result from acute cell injury and death, sometimes with tissue necrosis complicated by infection involving the repopulation of rapidly dividing tissues. These reactions are self-limited. They do not limit the amount of radiotherapy that can be given, but may require it to be halted temporarily until normal tissue repairs itself. Symptoms reflect the sites irradiated: systemic symptoms like fatique; local erythema or moist desquamation of skin; gastrointestinal symptoms from irradiation of the abdomen or pelvis like dysphagia, nausea, vomiting or diarrhea; oropharygeal mucositis and xerostomia from head and neck irradiation; and leukopenia, thrombocytopenia or anemia from irradiation of large amounts of bone marrow. Within weeks tissue regenerates, but with scarring and fibrosis. Severe late radiation effects, occurring after months, arise chiefly from depletion of normal tissue stem cells or vascular damage that produces tissue atrophy and necrosis and ulceration in the skin or delayed development of organ dysfunction as in radiation nephritis or myelitis. Such changes may be progressive and are independent of the occurrence or severity of acute reactions. Neoplastic changes may occur years later. Radiation is carcinogenic, mutagenic and teratogenic. It is associated with an increased rate of secondary leukemia and solid tumors. In long-term survivors after radiotherapy for Hodgkin's disease secondary leukemias occur within the first few years of treatment, but secondary solid tumors take more than ten years.

Radionuclides. 131-Iodine is used systemically for well-differentiated thyroid cancer which selectively metabolizes the isotope. 89-Strontium is used to treat bony metastases. It is used for palliation to relieve pain, as in prostate cancer, and can cause myelosuppression.

Radiosensitizer Drugs. As a tumor mass en-larges, it outgrows its blood supply. The peripheral edge of the tumor remains well vascularized, but the center becomes hypoxic and may infarct or undergo necrosis. Irradiation is less effective to hypoxic tissues than to well-oxygenated ones, since the free radical state of molecular oxygen is needed to interact with the ionization products created by the radiation beam for its effect. In experimental tumor systems, the size of the hypoxic fraction is directly proportional to the failure rate of local treatment. Hyperbaric oxygen, high LET radiation, and hypoxic cell sensitizer drugs have all been used to improve the destruction of hypoxic cells. The nitroimidazoles have the greatest potential as radiosensitizers since they penetrate to hypoxic centers of tumors in spite of poor blood supply. Examples are metronidazole or misonidazole. Their use in clinical trials to date has been limited owing to neurotoxicity. Thiol-depleting agents like N-ethylmaleimide or buthionine sulfoxime render cells radiosensitive, as do certain cytotoxic drugs such as bromodeoxyuridine and idoxuridine in noncytotoxic doses. The toxic effects of doxorubicin, dactinomycin, and bleomycin are enhanced on normal tissues such as skin, heart, and lungs when used with radiother-apy. Some chemicals are also radioprotectors, but ethiofos, for example, protects normal and tumor tissue equally.

Hyperthermia. The means to produce safe and effective deep internal hyperthermia in humans in the range of 43° to 45° C. is only now being developed with radiofrequency, microwave, ultrasound, and other sources, so that most investigation has centered on superficial lesions. Experiments show that for the roughly one third of tumors that can be heated, hyperthermia alone may be beneficial as a single agent. Its greatest potential may be in combination with other therapies. A synergistic or additive effect may exist between heating and both chemotherapy and radiotherapy, leading to the hope of reducing doses of both to provide effective treatment with fewer side effects. Heat kills cells in the S phase, the most radioresistant phase of the cell cycle, and tumor cells are more sensitive than normal cells. Sensitivity to heat is increased in the interior of tumors under low pH, hypoxia, poor perfusion, and nutrient supply where radiation is poorly effective. Current emphasis is on the use of microwave hyperthermia to potentiate photon radiotherapy.

Photodynamic Therapy

Light-absorbing substances like hematopor-phyrin derivatives are selectively retained by tumor cells which are then killed when exposed to laser beams of appropriate wavelengths. Superficial and localized lesions of the skin or intrabronchial tumors now respond to laser beams through an endoscope. The approach is new and still experimental.

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