Chapter 90Radiation Therapy Alain P. Théon Radiation therapy is the use of ionizing radiation to treat people and animals with malignant tumors and, occasionally, selected benign diseases. These diseases can be classified as inflammatory, degenerative, and hyperproliferative. The analgesic action of ionizing radiation for chronic orthopedic conditions has long been recognized and was first reported soon after the discovery of x-rays.1 The effectiveness of radiotherapy has been demonstrated in people with painful, degenerative joint diseases that were refractory to first-line conservative treatment—for example, nonsteroidal antiinflammatory drugs (NSAIDs) and physiotherapy.2 In horses radiation therapy was found to be effective for painful degenerative and inflammatory musculoskeletal conditions early in the development of veterinary radiation therapy.3 However, limited access to treatment facilities for horses, fear of the long-term hazards of ionizing radiation, and the availability of potent antiinflammatory drugs have decreased the impact of radiation therapy in the overall management of equine lameness. Although most clinical studies on using radiation therapy for equine chronic orthopedic conditions were reported in the 1960s and the 1970s, interest is currently renewed because of a better understanding of the mechanisms of action of radiation and identification of specific indications for treatment. The emergence of the specialty of veterinary radiation oncology will provide the expertise and personnel for expanding the applications of radiation therapy for treatment of noncancerous conditions at veterinary schools and private referral practices. Controlled studies are required to validate the experience-based indications, compare radiation therapy with other treatment options, and improve radiation parameters (single and total dose and fractionation). Several clinical trials have been undertaken at our institution, but adequate long-term observations and reliable assessment of clinical data according to objective orthopedic criteria are difficult to document. Radiobiological Aspects Radiotherapy of nonmalignant conditions requires low doses of radiation, usually one fifth to one tenth the dose used in cancer treatment. The radiobiological mechanisms involved in the therapeutic effects of low-dose radiation used for benign conditions are different from those mediated by high radiation doses used to treat cancer. The therapeutic effects of radiotherapy for cancer result from cell death and inhibition of tumor cell proliferation. The therapeutic effects of low-dose irradiation in treating painful musculoskeletal disorders result from several distinct mechanisms that are not fully understood. Radiotherapy does not work via one single or particular mechanism but rather through a complex interaction of different effects on many cell types. Early data indicating an increase in dermal blood flow and cutaneous temperature after treatment4 led to the misconception that radiation therapy produces a deep counterirritation that promotes increased blood flow and cell recruitment to the treated area to expedite healing.5 This theory, however, is not supported by any current data. The previously observed effects merely reflect inaccurate dosimetry that resulted in high radiation doses to the skin. In addition, evidence shows that counterirritation during the chronic stage of inflammation prolongs healing time and results in further damage.6 Modern theories on mechanisms of low- to medium-dose radiation for treatment of noncancerous conditions are based on new experimental data. The mechanisms are grouped into antiinflammatory effects, analgesic effects, and antiproliferative effects. Antiinflammatory Effects Whereas good evidence exists that high radiation doses induce strong inflammation in normal tissues, equally good evidence exists that low radiation doses have the opposite effect in inflamed tissues. Low-dose radiation therapy has a pronounced antiinflammatory effect on acute and chronic inflammatory processes in joints and periarticular tissues. In experimental animal models of osteoarthritis (OA), low-dose irradiation reduced bone loss, synovial proliferation, cartilage degradation, joint swelling and pain.7 The antiinflammatory effects of irradiation are not caused by cytotoxic effects, because the low doses used are not lethal to cells, and activated inflammatory cells, including lymphocytes,8 monocytes, and macrophages,9 have lost the clonogenic potential and are therefore radioresistant. Clinically observed antiinflammatory effects of low-dose radiation do not result from elimination of inflammatory cells but appear to be caused by functional alteration and regulation of cells involved in the inflammatory response including endothelium, macrophages, and granulocytes.10 Adhesion of white blood cells to activated endothelial cells and induction of nitric oxide synthetase in activated macrophages are reduced. Radiation decreases leukocyte adhesion, thereby reducing recruitment of granulocytes to inflamed tissue, which results in decreased proteolytic enzyme release and reduced tissue necrosis. Radiation-induced inhibition of nitric oxide production results in reduced inflammatory reaction.9,11 Good evidence also exists that radiation-induced reduction of monocyte and macrophage cytokines prevents excessive fibrosis.12 This may explain subjective reduction in joint capsule fibrosis and the functional improvement after treatment of OA.13 Analgesic Effects The analgesic effects of ionizing radiation on degenerative and inflammatory disorders are manifested by early effects of short duration, followed by long-term, delayed effects. The delayed effects, characterized by long-lasting pain relief that develops several weeks after treatment, result from the antiinflammatory effects of radiation. Early effects, characterized by fast pain mitigation, result from radiation-induced modulation of the afferent nociceptive pathways. Analgesia involves non–opioid- and opioid-mediated mechanisms. Although the opioid-mediated analgesia is poorly understood,14 the nonopioid mechanisms (which include modification of pain transmission and perception) appear to be mediated in part by nitric oxide.15-17 Radiation-induced decrease in local nitric oxide production results in desensitization of the nociceptors18 and prevention of neuropathic pain development.19 Antiproliferative Effects Ionizing radiation inhibits cell proliferation and temporarily reduces the production of new cells. This mechanism is assumed for prevention of new bone growth and treatment of chronic synovitis. Low-dose radiation does not interfere with normal bone healing, because native osteoblasts are not irreversibly inactivated by radiation. However, irradiation can inhibit excessive new bone formation from existing bone and within muscle after trauma or surgery. Radiation target cells are pluripotent mesenchymal stem cells that are stimulated to proliferate and differentiate into osteoblasts after trauma (e.g., injury or surgery) as a result of the healing process.20 Surgical trauma initiates a sequence of events during which cell proliferation takes place within a specific time. Radiation administered during this period induces a delay in cell production that results in a full and permanent therapeutic effect. In people the ability of irradiation treatment to interfere with the formation of heterotopic bone is limited to 4 hours before surgery to 48 hours after surgery.21 In horses the timing of radiotherapy to prevent new bone growth is also important, and irradiation usually is performed immediately after surgery. In ponies with experimental osteochondral defects in the antebrachiocarpal and middle carpal joints, radiation therapy was not effective in preventing periostitis and periarticular osteophytes when given 6 weeks after surgical trauma.21 For mature ossification, irradiation alone has no value beyond pain control. In treating chronic synovitis the antiproliferative effects of irradiation only delay progression of the disease process, because no critical period exists during which cell proliferation is required for the expression of damage. The goal of radiation-induced synovectomy is to ablate inflamed, proliferative synovium, with the expectation that after treatment the regenerated synovium will be free of disease. Treatment Side Effects Much of the concern surrounding using irradiation to manage benign conditions is the presumed risk of radiation-induced malignancy. The low doses used, however, are below the threshold associated with an identifiable risk of malignant transformation. In horses, development of in-field sarcoma secondary to radiation therapy to manage benign conditions has not been reported. Reported skin and bone damage likely reflect inadequate treatment techniques according to modern standards. Skin Damage Skin damage including epilation, dry desquamation, and regrowth of depigmented hair was often seen when low-energy orthovoltage radiation or insufficiently filtered radioisotope sources were used. The use of modern irradiation techniques and high-energy megavoltage radiation has eliminated the risk of skin overdose, and skin reactions are no longer observed. Osteopenia Similar to findings in people, experimental22,23 and clinical24 Only gold members can continue reading. Log In or Register to continue Share this:Click to share on Twitter (Opens in new window)Click to share on Facebook (Opens in new window) Related Related posts: Lameness in Horses: Basic Facts Before Starting Thermography: Use in Equine Lameness Counterirritation The Carpal Canal and Carpal Synovial Sheath Stay updated, free articles. Join our Telegram channel Join Tags: Diagnosis and Management of Lameness in the Horse Jun 4, 2016 | Posted by admin in EQUINE MEDICINE | Comments Off on Radiation Therapy Full access? Get Clinical Tree
Chapter 90Radiation Therapy Alain P. Théon Radiation therapy is the use of ionizing radiation to treat people and animals with malignant tumors and, occasionally, selected benign diseases. These diseases can be classified as inflammatory, degenerative, and hyperproliferative. The analgesic action of ionizing radiation for chronic orthopedic conditions has long been recognized and was first reported soon after the discovery of x-rays.1 The effectiveness of radiotherapy has been demonstrated in people with painful, degenerative joint diseases that were refractory to first-line conservative treatment—for example, nonsteroidal antiinflammatory drugs (NSAIDs) and physiotherapy.2 In horses radiation therapy was found to be effective for painful degenerative and inflammatory musculoskeletal conditions early in the development of veterinary radiation therapy.3 However, limited access to treatment facilities for horses, fear of the long-term hazards of ionizing radiation, and the availability of potent antiinflammatory drugs have decreased the impact of radiation therapy in the overall management of equine lameness. Although most clinical studies on using radiation therapy for equine chronic orthopedic conditions were reported in the 1960s and the 1970s, interest is currently renewed because of a better understanding of the mechanisms of action of radiation and identification of specific indications for treatment. The emergence of the specialty of veterinary radiation oncology will provide the expertise and personnel for expanding the applications of radiation therapy for treatment of noncancerous conditions at veterinary schools and private referral practices. Controlled studies are required to validate the experience-based indications, compare radiation therapy with other treatment options, and improve radiation parameters (single and total dose and fractionation). Several clinical trials have been undertaken at our institution, but adequate long-term observations and reliable assessment of clinical data according to objective orthopedic criteria are difficult to document. Radiobiological Aspects Radiotherapy of nonmalignant conditions requires low doses of radiation, usually one fifth to one tenth the dose used in cancer treatment. The radiobiological mechanisms involved in the therapeutic effects of low-dose radiation used for benign conditions are different from those mediated by high radiation doses used to treat cancer. The therapeutic effects of radiotherapy for cancer result from cell death and inhibition of tumor cell proliferation. The therapeutic effects of low-dose irradiation in treating painful musculoskeletal disorders result from several distinct mechanisms that are not fully understood. Radiotherapy does not work via one single or particular mechanism but rather through a complex interaction of different effects on many cell types. Early data indicating an increase in dermal blood flow and cutaneous temperature after treatment4 led to the misconception that radiation therapy produces a deep counterirritation that promotes increased blood flow and cell recruitment to the treated area to expedite healing.5 This theory, however, is not supported by any current data. The previously observed effects merely reflect inaccurate dosimetry that resulted in high radiation doses to the skin. In addition, evidence shows that counterirritation during the chronic stage of inflammation prolongs healing time and results in further damage.6 Modern theories on mechanisms of low- to medium-dose radiation for treatment of noncancerous conditions are based on new experimental data. The mechanisms are grouped into antiinflammatory effects, analgesic effects, and antiproliferative effects. Antiinflammatory Effects Whereas good evidence exists that high radiation doses induce strong inflammation in normal tissues, equally good evidence exists that low radiation doses have the opposite effect in inflamed tissues. Low-dose radiation therapy has a pronounced antiinflammatory effect on acute and chronic inflammatory processes in joints and periarticular tissues. In experimental animal models of osteoarthritis (OA), low-dose irradiation reduced bone loss, synovial proliferation, cartilage degradation, joint swelling and pain.7 The antiinflammatory effects of irradiation are not caused by cytotoxic effects, because the low doses used are not lethal to cells, and activated inflammatory cells, including lymphocytes,8 monocytes, and macrophages,9 have lost the clonogenic potential and are therefore radioresistant. Clinically observed antiinflammatory effects of low-dose radiation do not result from elimination of inflammatory cells but appear to be caused by functional alteration and regulation of cells involved in the inflammatory response including endothelium, macrophages, and granulocytes.10 Adhesion of white blood cells to activated endothelial cells and induction of nitric oxide synthetase in activated macrophages are reduced. Radiation decreases leukocyte adhesion, thereby reducing recruitment of granulocytes to inflamed tissue, which results in decreased proteolytic enzyme release and reduced tissue necrosis. Radiation-induced inhibition of nitric oxide production results in reduced inflammatory reaction.9,11 Good evidence also exists that radiation-induced reduction of monocyte and macrophage cytokines prevents excessive fibrosis.12 This may explain subjective reduction in joint capsule fibrosis and the functional improvement after treatment of OA.13 Analgesic Effects The analgesic effects of ionizing radiation on degenerative and inflammatory disorders are manifested by early effects of short duration, followed by long-term, delayed effects. The delayed effects, characterized by long-lasting pain relief that develops several weeks after treatment, result from the antiinflammatory effects of radiation. Early effects, characterized by fast pain mitigation, result from radiation-induced modulation of the afferent nociceptive pathways. Analgesia involves non–opioid- and opioid-mediated mechanisms. Although the opioid-mediated analgesia is poorly understood,14 the nonopioid mechanisms (which include modification of pain transmission and perception) appear to be mediated in part by nitric oxide.15-17 Radiation-induced decrease in local nitric oxide production results in desensitization of the nociceptors18 and prevention of neuropathic pain development.19 Antiproliferative Effects Ionizing radiation inhibits cell proliferation and temporarily reduces the production of new cells. This mechanism is assumed for prevention of new bone growth and treatment of chronic synovitis. Low-dose radiation does not interfere with normal bone healing, because native osteoblasts are not irreversibly inactivated by radiation. However, irradiation can inhibit excessive new bone formation from existing bone and within muscle after trauma or surgery. Radiation target cells are pluripotent mesenchymal stem cells that are stimulated to proliferate and differentiate into osteoblasts after trauma (e.g., injury or surgery) as a result of the healing process.20 Surgical trauma initiates a sequence of events during which cell proliferation takes place within a specific time. Radiation administered during this period induces a delay in cell production that results in a full and permanent therapeutic effect. In people the ability of irradiation treatment to interfere with the formation of heterotopic bone is limited to 4 hours before surgery to 48 hours after surgery.21 In horses the timing of radiotherapy to prevent new bone growth is also important, and irradiation usually is performed immediately after surgery. In ponies with experimental osteochondral defects in the antebrachiocarpal and middle carpal joints, radiation therapy was not effective in preventing periostitis and periarticular osteophytes when given 6 weeks after surgical trauma.21 For mature ossification, irradiation alone has no value beyond pain control. In treating chronic synovitis the antiproliferative effects of irradiation only delay progression of the disease process, because no critical period exists during which cell proliferation is required for the expression of damage. The goal of radiation-induced synovectomy is to ablate inflamed, proliferative synovium, with the expectation that after treatment the regenerated synovium will be free of disease. Treatment Side Effects Much of the concern surrounding using irradiation to manage benign conditions is the presumed risk of radiation-induced malignancy. The low doses used, however, are below the threshold associated with an identifiable risk of malignant transformation. In horses, development of in-field sarcoma secondary to radiation therapy to manage benign conditions has not been reported. Reported skin and bone damage likely reflect inadequate treatment techniques according to modern standards. Skin Damage Skin damage including epilation, dry desquamation, and regrowth of depigmented hair was often seen when low-energy orthovoltage radiation or insufficiently filtered radioisotope sources were used. The use of modern irradiation techniques and high-energy megavoltage radiation has eliminated the risk of skin overdose, and skin reactions are no longer observed. Osteopenia Similar to findings in people, experimental22,23 and clinical24 Only gold members can continue reading. Log In or Register to continue Share this:Click to share on Twitter (Opens in new window)Click to share on Facebook (Opens in new window) Related Related posts: Lameness in Horses: Basic Facts Before Starting Thermography: Use in Equine Lameness Counterirritation The Carpal Canal and Carpal Synovial Sheath Stay updated, free articles. Join our Telegram channel Join Tags: Diagnosis and Management of Lameness in the Horse Jun 4, 2016 | Posted by admin in EQUINE MEDICINE | Comments Off on Radiation Therapy Full access? Get Clinical Tree
