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Radiation Damage Discussion
edited and compiled by doctordee
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Some Important Points
Areas that have been irradiated should be regularly observed not only for recurrence of the initial tumor or its metastasis, and for late radiation effect, but also for the possibility of development of a New Cancer. Additional or returning symptoms may indicate recurrence OR metastasis of original tumor, OR radiation damage, OR a New Primary Cancer developing at that site. Differentiation of radiation pathology from recurrent or metastatic tumor or new malignancy can be difficult.
Because the target organ for the development of late effects is most probably the endothelial cells lining the blood vessels, much of the permanent damage is caused by impairment of circulation, as these blood vessels undergo premature and progressive aging, scarring, and arteriosclerosis. Hyperbaric oxygen should be considered when managing late-onset sequelae in previously irradiated patients. The use of hyperbaric oxygen for radiation-induced bone and soft tissue complications is safe and results in few significant adverse effects.
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Subsequent surgery--Irradiation for malignancy in an area makes subsequent surgery more difficult. Injection of intravenous contrast medium [and subsequent Xrays] might help identify the vascular structures within the area, especially when disease process and post-irradiation fibrosis have destroyed the tissue planes. Because of the damage to blood vessels, there may be poor healing in previously irradiated areas. Hyperbaric oxygen therapy can help irradiated tissues heal faster.
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One study followed 221 consecutively treated patients for 8 to 42 years after post mastectomy irradiation. Complications requiring in-hospital treatment were observed in 24 of 221 patients (11%). There were four sarcomas of the treated chest wall, three squamous carcinomas (two in the esophagus), two angiosarcomas of the swollen homolateral arm, nine chronic ulcers, five respiratory insufficiencies, six pathologic fractures of the radiated shoulder or ribs, two fatal cardiomyopathies, one persisting leukopenia with fatal brain abscess, and one severe neurovascular impairment of the arm. In a comparable group of 394 consecutive post mastectomy patients who were not irradiated, one similar event, a myxosarcoma of an unswollen arm, was observed. Only long-term follow-up can determine the ultimate risks of radiotherapy.
Fetch PMID: 6498728

Spiral CT scans of abdomen, pelvis and chest, with or without contrast, every three months, has its own radiation risk as well. Admittedly, it is smaller than irradiation for eradication of malignancy. The radiation burden from diagnostic CT scans may ultimately contribute to carcinogenesis, mutagenesis and other radiation damage.
Fetch PMID: 9693333

Radionecrosis is the death of tissue in small patches, in the areas of irradiation. If it occurs in bone, the structural strength of the bone is much decreased. If it occurs in the brain, it can lead to dementia and death.

References: Radiation Damage & Radiosensitivity
References: Arterial Damage as the Cause of Late Effects
Early and Late Side Effects
Acute side effects are sometimes referred to as "early side effects." The symptoms may occur soon after the treatment begins and usually are gone within a few weeks of finishing therapy. "Late effects of radiation" is permanent damage and may take months or years to develop and can be progressive.

Acute radiation damage from abdominal or pelvic irradiation will usually present with skin reaction, digestive tract reaction and/or bone marrow depression. White blood cells and platelets decrease rapidly. Red blood cells also can decrease. These symptoms go away in a matter of weeks. The damage to the bone marrow is cumulative, however, and repeated irradiation or chemotherapies can result in myelodysplasia [See Myelodysplasia]. Acute severe digestive tract reaction increases the risk for late effect radiation damage.

The incidence of late effect abdominal radiation effects depend upon the type of radiation, the amount of exposure, and the fields chosen, as well as other, patient-related, factors. It is best to ask the oncologist who is prescribing the radiation, for the acute AND late effect risk profile involved in the particular regimen he has chosen. Discuss alternatives with him/her, as well as ways to shield other organs or remove them from the field of irradiation.

Late Effects of Radiation: Permanent Radiation Damage

Essentially, the late effects of radiation are probably due to one of two processes occurring in exposed tissues:
  • damage to the endothelial wall of the blood vessel
  • damage directly to the chromosomes of the affected cells
Chromosomal damage is likely the cause of the New Cancers that develop years later, and at least part of the problem with the Myelodysplasia Syndromes. Some tissues are very sensitive to radiation, and the cells do not recover from treatment: bone cells die and bone becomes osteoporotic, salivary tissue also dies. Most of the other symptoms of late effects probably come from damage to the irradiated blood vessels that service the tissues, resulting in those blood vessels undergoing premature aging, scarring, and arteriosclerosis. The organs that rely upon these damaged vessels for their blood supply are compromised, and often undergo ischemic damage, or cannot function reliably.

References: Radiation Damage & Radiosensitivity
References: Arterial Damage as the Cause of Late Effects
Damage & Risks to Structures Usually Within the Beam
Arteries

Late radiation symptoms at most sites are caused by widespread, premature blood vessel aging, radiation-induced arteriosclerosis, and radiation-induced blood vessel obliteration, leading to tissue death and scarring. Compromise of tissue circulation can occur wherever the blood vessels were exposed to radiation. It is established that small and medium sized arteries undergo extensive radiation damage. Larger artery stenosis [e.g. carotid, axillary, subclavian] may also present in patients who have undergone radiotherapy.

The arterial changes resemble chronic, progressive arteriosclerosis. This may be due to a combination of scarring around the artery, direct damage to the arterial wall, severe damage to and obliteration of the tiny arteries that nourish the larger arteries' walls, and acceleration of naturally occurring arteriosclerosis. Factors that may predispose to arterial occlusion that relate to radiotherapy include maximum tissue dose, beam energy and field size. The time interval between radiotherapy because of malignancy and onset of symptoms due to radiation-induced arteriosclerosis ranged from 1 month to 29 years in one study.

A typical finding at angiography was the well-localized vascular lesion in the previous radiation area, its localisation clearly distinguishable from typical arteriosclerosis. Due to absence of multifocal arteriosclerotic lesions, long-term results of vascular reconstruction are good and will certainly contribute to further improvement of life quality after curative therapy for malignant disease. Aneurysms of arteries also can occur in association with radiation treatment. An aneurysm occurs when an artery wall is very weak in an area, and the wall bulges out.

Irradiation of large blood vessels in the course of tumor therapy represents a long-term local risk factor for development of arteriosclerosis. Inclusion of major arteries into the radiation field is often inevitable: in a series of clinical studies, a consistent 3- to 4-fold increase in carotid stenoses is observed following radiation therapy of head and neck tumors. The majority of clinically symptomatic stenoses, however, is not observed earlier than 8 years post irradiation. Although observations in other peripheral arteries do not allow estimating incidences, they do confirm, however, the finding of a very long latent time. Following mediastinal or thoracic wall irradiation, the risk of coronary artery disease is significantly increased after 10 years or more. Radiation related arterial injury is sharply limited to arterial segments included in the treatment field and is often observed in unusual locations. The histological appearance and development however, is not fundamentally different from lesions observed in cases of generalized arteriosclerosis. Experimental observations indicate that patients with general arteriosclerosis risk factors might have a particularly increased risk of developing arterial injury following therapeutic irradiation.

The studies of late radiation effects upon Skin, Brain, Bone, Heart, Lung, Eye, Spinal Cord and Muscle, all seem to reinforce the concept of the blood vessel wall being the prime site of radiation damage. Most, even all, of the subsequent damage is due to the loss of blood supply to these tissues, and consequent cell death. The tissues then show widespread fibrosis [a kind of scarring.] The effect of radiation can be an on-going process; the percentage of small arteries with cell wall damage increasing with the time after radiotherapy.

References: Damage to ARTERIES
Bone

Where bone is directly in the radiation beam or field, radiation damage to bone is probably twofold. There is damage to the blood vessels supplying the bone, and probable damage to the bone cells. Early on, new bone is no longer made, without subsequent resumption. Fractures may no longer heal, and osteoporosis might occur. This has been noted in jaws, spine, and ribs, among other locations. The presence of a connective tissue disorder in a patient with other risk factors such as steroid use, old age and osteopenia should alert the clinician to the risk of radionecrosis following radical irradiation. In addition, bone marrow would be affected. [See Myelodysplasia]

References: Bone Damage
Skin

For open lesions in the irradiated area, local antibiotic treatment is difficult, as most of the substances used are known to inhibit wound healing. Discuss choice of antiseptic ointment with your doctor.
Radiation burns to the hand consist of ulcerative necrotic changes of the skin and subcutaneous tissues.
Longterm effects of radiation exposure on the skin include possible skin aging [atrophy] and increased risk for New Cancer formation in the skin. There is also an unusual effect of possibly having allergic drug reactions appear at the site of the previous radiation exposure.

References: Radiation Damage to Skin
New Cancers

Ionizing radiations have been shown to be carcinogenic to man, even in low dosage. High radiation dosage and severe radiation damage are not essential for radiation-associated New Cancers. After irradiation for malignancy, the latent period for New Cancer induction varied from 5 years to 31 years in one study, peak frequency was between 5 and 10 years in another. All these cases showed no evidence of recurrence or metastases of the original primary lesion. Another group of people receiving irradiation for a noncancerous condition also had an increase of cancer deaths. Cancer mortality remained high for up to 50 years for this group. The risk of a second cancer from radiation damage may persist to the end of life.

Areas that have been irradiated should be regularly observed not only for recurrence of the initial tumor, and other late effects of irradiation, but also the possibility of later development of a New Cancer. And for New Cancers, the necessity of systematically searching for previous irradiations in the affected zone is emphasized.

Death from cancer, in relation to radiation dose, was evaluated among 4153 women treated with intrauterine radium (226Ra) capsules for benign gynecologic bleeding disorders between 1925 and 1965. Deaths due to cancer in this group were increased, especially cancers of organs close to the radiation source.

For organs receiving greater than 5 Gy: excess mortality of 100 to 110% was noted for cancers of the uterus and bladder 10 or more years following irradiation.

Among cancers of organs receiving average or local doses of 1 to 4 Gy: excesses of 30 to 100% were found for leukemia and cancers of the colon and genital organs other than uterus.

Among organs typically receiving 0.1 to 0.3 Gy: a 30% excess was noted for kidney cancer (based on eight deaths), and there was a 60% excess of pancreatic cancer among 10-year survivors, but little evidence of dose-response.

Estimates of the excess relative risk per Gray were 0.006 for uterus, 0.4 for other genital organs, 0.5 for colon, 0.2 for bladder, and 1.9 for leukemia [see myelodysplasia].

For organs receiving greater than 1 Gy: cancer mortality remained elevated for more than 30 years, supporting the notion that radiation damage persists for many years after exposure.
Fetch PMID: 2217730

Post irradiation sarcoma of soft tissue and bone is a well-known occurrence. It occurs in the irradiated area. The five-year survival for this is about 30%, and follows the usual sarcoma pattern, with size and grade of tumor and successful surgical excision being important determinants.

References: New Cancer as a Late Effect of Irradiation
Bone Marrow: Myelodysplasia

Myelodysplasia, also known as Myelodysplastic [pronounced MY-eh-low dis-PLAH-stic] Syndromes, are conditions that affect the bone marrow.

The bone marrow makes blood cells. Red blood cells that carry oxygen. White blood cells that fight infection. Platelets that make clots and prevent bleeding.

The stem cells in the bone marrow are the "parent cells" of the cells [red, white & platelet] which are eventually released into the blood. The myelodysplastic syndromes are caused by damage to the stem cells of the cell line[s] affected. The damage is to the DNA [genes] of the stem cells.

Patients treated for cancers with high dose radiation have a higher incidence of therapy-related myelodysplasia. Alkylating agents used in chemotherapy are known to induce myelodysplasia, as well. There are other causes, too, but these are two causes that are important to LMS patients.

If the red blood cell line is affected, the patient becomes anemic, and requires transfusions. Eventually there is an iron buildup in the body, called hemosiderosis, which can cause further problems.

If the white blood cell line is affected, the patient is more prone to get seriously ill with infections. Sometimes some of the white cell line transforms to leukemia.

If the platelet cell line is affected, the patient is prone to hemorrhage, and internal bleeding.

The progress of the condition depends upon which cell lines are affected and how badly, and whether leukemia develops.

Development of myelodysplasia puts a limit on how much radiation and chemotherapy a person can have. A patient might be cured of his or her cancer, but then succumb to myelodysplasia or leukemia as a result of the treatment for the cancer.

[Reference for this section: Harrison's Principles of Internal Medicine, 14th Edition, pp. 676-8]

Other References for this Section: Bone Marrow Damage
Possible Late Effects in Individual Irradiation Areas

CHEST
General

Radiation therapy is used to treat many intrathoracic and chest wall malignancies. A variety of changes may occur after radiation therapy to the thorax. In the chest, irradiation indicates potential for injury to arteries, ribs, nerves, and esophagus, as well as to the heart and lungs.

Radiation therapy produces dramatic effects in the lung. Radiation pneumonitis [lung inflammation] can be a major complication for patients receiving chest irradiation. Pulmonary necrosis is an uncommon, severe, late complication of adjuvant postoperative irradiation. Bronchiolitis obliterans with organizing pneumonia is a distinct separate entity characterized by patchy, migratory, peripheral air-space infiltrates. Radiation therapy can also cause spontaneous pneumothorax, mesothelioma, and lung cancer. In the mediastinum, radiation therapy may cause thymic cysts, calcified lymph nodes, and esophageal injuries.

Cardiovascular complications of radiation therapy are often delayed and insidious. Premature coronary artery stenosis occurs after radiation therapy to the mediastinum. Radiation therapy may also give rise to calcifications of the ascending aorta, pericardial disease, valvular injuries, and conduction abnormalities. Women who undergo chest irradiation before the age of 30 years have a high risk of developing a second breast cancer. Radiation-induced sarcomas are an infrequent but well-recognized complication of radiation therapy. Other chest wall injuries due to radiation therapy are osteochondroma and rib or clavicle [collar-bone] fractures.

When irradiating the mediastinum for malignancy, the radiotherapeutic technique (site and number of fields, division of dose), and especially the dose absorbed, seem to be relatively closely related to the frequency and severity of the post-irradiation lesions of the heart and lung.

Knowledge of the imaging features of injuries caused by radiation therapy can prevent misinterpretation as recurrent tumor and may facilitate further treatment. Additional or returning symptoms may indicate recurrence OR metastasis of original tumor, OR radiation damage, OR a New Cancer developing at that site. Differentiation of radiation pathology from recurrent or metastatic tumor or new malignancy can be difficult.

Rib

Standard fractionated dosage of radiation to the chest gave about 6% incidence of late bone damage to the ribs, causing spontaneous, radiation-induced osteoporosis and rib fracture within the treated area.

Heart

Irradiation of the left side of the chest puts the heart at risk for early and late effects of radiation. Irradiation of the mediastinum [the central portion of the chest cavity, housing the esophagus, heart, & major blood vessels,] may create a subclinical [unnoticed] cardiomyopathy [damage to the muscle of the heart] in more than one-half of the patients. In addition, irradiation of the mediastinum can make further surgery difficult due to post-irradiation sequelae, and pacemakers can be susceptible to irradiation; consequently, modest radiation doses could induce life-threatening arrhythmias.

The greatest risk for most cancer patients is inadequate treatment of their disease. Although mediastinal radiotherapy is a safer procedure than it was 20 years ago, it still may damage the thoracic viscera, including the heart. Cardiovascular problems tend to present subtly years later, when the patient may not recall the prior radiation or may not deem it significant. Awareness of this long latency period and of the wide spectrum of heart disease that may result from radiotherapy is essential for management of these patients. Radiation-induced pericardial constriction is frequently associated with coronary artery disease, mostly silent, with valvular insufficiency, and with pericardial and myocardial disease. Thorough cardiac evaluation in such patients is mandatory. Surgical treatment frequently uncovers an underlying restrictive myopathy [muscle abnormality] that presents a serious challenge to treat.

Cardiac late effect damage from therapeutic irradiation, can and does cause ischemic heart disease and angina, heart block requiring a pacemaker, heart arrhythmias, pericardial disease including pericardial constriction, heart valve damage [e.g. aortic stenosis, mitral insufficiency] with heart failure, and damage to the heart muscle itself with scarring [e.g. dilated, flabby left ventricle]. Patients often require surgical treatment and postoperative complications are common.
All of the cardiac damage has a common anatomical denominator: fibrosis [death of tissue, with subsequent scarring], which develops progressively following the radiotherapy. It has now been demonstrated that the incidence of cardiac radiation lesions can be reduced by homogeneous distribution of the dose of radiation administered to the mediastinum, by treating each side alternately, by fractionating the radiation and staggering the sessions and by reducing the cardiac mass which is irradiated.

Radiation induced heart disease, with its clinical manifestations, is becoming a growing problem. Its prevalence is increasing, keeping pace with the increased survival of many malignancies. The majority of patients with radiation induced heart disease is constituted by Hodgkin's disease survivors, followed by non Hodgkin's disease, esophageal carcinoma, thymoma, lung cancer, breast cancer and metastatic seminoma.

Cardiovascular mortality associated with radiation therapy correlates with the dose of radiation to the heart and the amount of the heart that was irradiated. All of the following factors are thus important: laterality of the tumor [left sided irradiation causes more cardiac damage], portal arrangements [shielding, overlap], radiation energy, fractionation, and total dose. The study illustrates that an increased cardiovascular mortality can be avoided by the use of appropriate techniques and avoidance of excessive treatment.

All patients undergoing chest irradiation require serial cardiac evaluation. Important risk factors of radiation-induced heart disease are previous chemotherapy, total radiation exposure, administration next to the heart and/or on the left side of the chest. The cardiac damage limitation basically is founded on prevention. Significant results have been obtained with fractional exposition, high-energy utilization and "split" zone covering. A comprehensive individual patient risk evaluation will provide a substantial benefit for the future. The consultant cardiologist should cooperate with the oncologist and the radiotherapist, providing specific competence and continuing care.

Lung

Radiation therapy produces dramatic effects in the lung. Radiation pneumonitis [lung inflammation] can be a major complication for patients receiving chest irradiation. Pulmonary necrosis is an uncommon, severe, late complication of adjuvant postoperative irradiation. Bronchiolitis obliterans with organizing pneumonia is a distinct separate entity characterized by patchy, migratory, peripheral air-space infiltrates. Radiation therapy can also cause spontaneous pneumothorax, mesothelioma, and lung cancer.

Acute radiation-induced pulmonary effects on Xray and CT scan must be differentiated from malignancies and other abnormalities. The CT scan results from acute radiation to the chest were lung opacities in an irregular pattern within the radiation beam boundaries. There was increased lung density, loss of lung volume, and pleural thickening. Sharply defined nodular opacities are atypical of radiation damage. Confinement of the findings within the irradiated volume was the only specific characteristic of post-irradiation changes.

For the lung, the blood flow was the function most affected by radiation. In some cases in which the Xray changes were mild, the functional measurements indicated severe vascular damage. The radiation appears to reduce the number and efficiency of functioning lung units within the irradiated region.

Nerve

Radiation-induced neuropathy has affected the phrenic nerve [diaphragm dysfunction] and vagus nerve [vocal cord paralysis] as well as the brachial nerve plexus [pain and changes in movement and feeling of the arm]. Other more subtle damage to the nerves may occur without being recognized as late radiation injury. Symptoms appeared 7 months to 25 years after irradiation. Tumor recurrence or metastasis has to be eliminated as a cause for these symptoms.

Esophagus

Acute radiation injury to the esophagus is observed in approximately half the patients receiving radiation therapy. It can result in substantial morbidity.

Skin

Severe skin reactions are commonly observed after breast irradiation. Chronic ulcerations, soft tissue damage and osteonecrosis are well-known though relatively rare long-term radiation-induced injuries. The ever-present possibility of recurrence or persistence of the primary malignant neoplasm must be always suspected.

References: Chest Irradiation Damage
HEAD and NECK
General

Radiation treatment plays an important role in the management of head and neck cancer.

Cranial irradiation for nasopharyngeal cancers carries a risk of other structures becoming injured by the radiation. Incidental damage to the hypothalamus of the brain can cause hypopituitarism [See Brain.]

Unfortunately several radiation-induced side effects may occur including mucositis, hyposalivation, radiation caries, trismus ['locked' jaw] and radiation bone injury possibly progressing to tooth loss or osteoradionecrosis. It is generally accepted that most side effects can be prevented or reduced in severity. There should be a general protocol for prevention and treatment of oral side effects, and timely referral to a dental team before irradiation starts.

Eustachian tube patency showed deterioration if maximum irradiation dosage for nasopharyngeal cancers was more than 70 Gy. Mucosal reactions were observed in 30-35% of the patients with tumors of the oral mucosa. The most frequent radiation damage in a long-term period was fibrotic changes of the skin and subcutaneous connective tissue.

A study was done on patients with nasopharyngeal carcinoma, to compare accelerated-hyperfractionated radiotherapy with conventional dosing. In this study, the survival criteria were not significantly different. However there was significantly increased radiation-induced damage to the CNS.There was more damage to the temporal lobe, cranial nerves, optic nerve, neck soft tissue, and the pituitary gland. And the complications occurred sooner.

Eyes

The eye's sensory retina, as well as other central nervous system tissues, is highly resistant to radiation damage. But the retinal blood vessels are extremely sensitive to radiation damage, producing damage to the retina that is like the damage from other diseases that obliterate the blood supply. In one study, radiation retinopathy [damage to the retina] occurred in 63% of patients who had orbital irradiation, and 36.3% who had periorbital irradiation. The first group had damage appearing earlier, with greater involvement, and also had three cases of glaucoma developing. Care must be taken when irradiating periorbital structures as well.

Jaw

Radiation damage in the oral soft tissues and jawbones makes the atmosphere favorable for anaerobic microorganisms. The present results indicate that the role of A. israelii in the pathogenesis of osteoradionecrosis of the jaws has not been fully appreciated. See BONE.

Thyroid

The thyroid gland may be inadvertently irradiated while cancer in another structure is being treated. The thyroid is an organ that is usually susceptible to exposure to ionizing radiation, both by virtue of its ability to concentrate radioiodine (internal radiation) and by routine medical usage: Chest Xray, Dental Xray, X-irradiation of cervical lymph nodes etc. (external radiation). Iodine-131 is widely used for the therapy of Graves' disease and thyroid cancers, of which the disadvantage is radiation-induced hypothyroidism but not complications of thyroid tumor. The thyroid gland is comparatively radioresistant, however, the data obtained from Hiroshima, Nagasaki and Marshall islands indicates a high incidence of external radiation-induced thyroid tumors as well as hypothyroidism. The different biological effects of internal and external radiation remains to be further clarified. Interestingly, recent reports demonstrate the increased number of thyroid cancer in children around Chernobyl in Belarus. There was an increased incidence of thyroid dysfunction and thyroid neoplasia when compared to the general population, in children who received neck irradiation for cancer.

Salivary Glands & Mouth

The salivary glands have a greater sensitivity to radiation damage than the gustatory tissues. The decrease in salivary secretion was correlated with the amount of salivary glands irradiated. When the rest of the major salivary glands are irradiated, most of the parotids have to be outside of the treated volume to prevent severe dryness phenomena.

Radiotherapy to the parotid bed is not without morbidity. Complications may arise as a result of radiation damage to neighboring structures [brain, spinal cord] and there is also potential to induce malignant disease.

References: Damage from Head and Neck Irradiation
BRAIN

References: Radiation-Induced Brain Damage

Radiation therapy plays an integral part in managing intracranial tumors. While the risk: benefit ratio is considered acceptable for treating malignant tumors, risks of long-term complications of radiotherapy need thorough assessment in adults treated for benign tumors. In one study of post-irradiation effects for benign brain tumors, 38% had delayed side effects of radiotherapy [visual deterioration, pituitary dysfunction, brain tissue changes, new cancers].

Areas that have been irradiated should be regularly observed not only for recurrence of the initial tumor or its metastasis, and for late radiation effect, but also for the possibility of development of a New Cancer. Additional or returning symptoms may indicate recurrence OR metastasis of original tumor, OR radiation damage, OR a New Cancer developing at that site. Differentiation of radiation pathology from recurrent or metastatic tumor or new malignancy can be difficult.

Fraction size, total dose, and treatment time are all important factors when considering the biological effects of radiation. A total dose of >40 Gy was frequently a major predictor of radiation damage. The combination of chemotherapy and radiation therapy seems to aggravate the course of radiation damage.

Intracranial Radiation Damage

Essentially, the late effects of radiation are probably due to one of two processes: damage to the wall of the blood vessels, or damage directly to the chromosomes of the exposed cells. Chromosomal damage is likely the cause of the New Cancers that develop years later. Most of the other symptoms of late effects probably come from damage to the irradiated blood vessels that service the tissues, and subsequent tissue death and atrophy. Radiation necrosis is the death of normal tissue in small, localized areas, as a result of radiation exposure.

The steroid responsive neurological deterioration assumed to represent late radiation damage is radiation dose dependent. It might be useful for prevention of radiation damage to use split-course-method or shrinking-technique at doses of 40 Gy or more. Radiation damage may present in a CT scan as a multifocal, disseminated lesion, and misdiagnosed as tumor spread. There is a need for prevention, appropriate diagnosis, and subsequent life-saving management.

The long-term changes during late delayed radiation-induced brain damage: The radiation damage appeared as an enhanced lesion. The volume and number of enhanced lesions continued to increase for 3 to 23 months (mean 10.3 months). The lesions then stabilized, and in four long-term survivors, the lesions then decreased in size. The intervals from onset to regression were 12, 13, 17, and 35 months (mean 19.3 months). But two patients showed a relapse of the enhanced lesion. Finally, the radiation-damaged brain became atrophic. Late delayed radiation-induced brain damage continues to progress for over a year and then regresses, but thereafter a relapse may occur.

Whole-Brain Irradiation.

Late effects of Whole Brain Irradiation can include abnormalities of cognition [thinking ability] as well as abnormalities of hormone production. The hypothalamus is the part of the brain that controls pituitary function. The pituitary makes hormones that control production of sex hormones, thyroid hormone, and cortisol. Both the pituitary and the hypothalamus will be irradiated if whole-brain irradiation occurs. Damage to these structures can cause disturbances of personality, libido, thirst, appetite, or sleep, and other symptoms, as well. The CT scans show cortical atrophy and/or third ventricle dilation in approximately 1/2 of the patients so affected. Psychiatric symptoms can be a prominent part of the clinical picture presented when radiation necrosis occurs. Psychiatric consultation should be obtained in the diagnosis and management of such patients.

Focal Irradiation.

Late effects of Focal [specific site, rather than general] Irradiation, whether external beam or implant, could be seen in those tissues which were exposed to the radiation. Blindness or other focal symptoms can occur as a late effect.

Late radiation necroses and late delayed radiation damage occurred in 50% of patients after permanent implantation of Iodine-125 seeds. The occurrence of radiation necrosis was correlated with total radiation dose, amount of implanted radioactivity, and with velocity of tumour shrinkage. A rapid shrinkage of tumour after interstitial Iodine-125 implantation may cause a significant irradiation of surrounding brain tissue, which was initially lying outside the target volume. The risk of radiation damage could probably be minimized either by reduction of irradiation dose, or by using temporary implants of Iodine-125.

There is a need for precision, high dose radiotherapy.

Stereotactic radiation therapy of intracranial lesions. Fractionated Stereotactic RadioTherapy is a noninvasive form of localized radiation that may be a suitable alternative to interstitial therapy. It uses a linear accelerator (6 MV photons). Treatment relies on a fixation system permits a precise use of the coordinates estimated at stereotactic computed tomography. The field of treatment can be exactly outlined in the CT images during repeat examinations, thus facilitating the recognition of changes induced by radiation. A dose of 40 Gy or more was a major predictor of steroid responsive neurological deterioration assumed to represent late radiation damage. Hypofractionated SRT is a noninvasive, well-tolerated, outpatient-based method of delivering palliative, high-dose, focal irradiation.

Boron neutron capture therapy. It can be suggested that BNCT is a radiotherapy that can produce "cure" of both malignant and benign brain tumors while preserving a good quality of life if conducted without previous conventional radiotherapy. Out of 87 patients operated on before May 1987, 18 lived or have lived longer than 5 years. Nine of these 18 lived or have lived longer than 10 years out of 53 patients operated on before May 1982. Among more-than-10-year survivors, only two died at 17 and 12 years. All of the others are still alive. The two died of delayed radiation damage because BNCT was applied to glioblastomas that recurred after their conventional radiotherapy. They lacked evidence of tumors when they died. Out of these nine more-than-10-year survivors, three had been previously treated by conventional external radiotherapy and they developed radiation damage that brought all patients ultimately to an incapacitated condition. Two of the three died. All the other 6 who were free from previous radiation history are active in their jobs and have no evidence of tumors.

References: Radiation-Induced Brain Damage
ABDOMEN & PELVIS

References: Abdominal and Pelvic Radiation Damage

In several series of patients treated by radiation, the early gastrointestinal complication rate varied from approximately 10 to 20%. The late gastrointestinal complication arising varied from approximately 2 to 11%. In one study, there was an 8.2% incidence of late complications developing in those patients who had experienced early complications, compared with a 3.0% incidence of late complications developing in patients without early complications. Thus, the risk of developing a late complication was greater by a factor of 2.7 in those patients developing an early one. However, of the patients developing late complications (75%) did not experience a severe acute one.

The median time for severe radiation late effects [adhesion, fistula, structure, perforation, colitis, or vascular occlusion] after radiotherapy was 18 months, as against 9 to 10 months for milder symptoms. Rectal bleeding is a factor with a significantly poorer prognosis.

The most consistently observed changes in Radiation Bowel Disease were in the arteries, arterioles and to a lesser extent the veins. The damaged blood vessels showed small clots, death of cells making up the blood vessel wall, and swelling and edema around the vessel wall. The blood vessels are a main site of injury in RBD and that the wall of the blood vessels is an initial target for radiation damage. The effect of radiation was an on-going process; the percentage of small arteries with cell wall scarring increased with the time after radiotherapy. [See Arteries]

Vitamin B12 malabsorption after irradiation for gynecological tumours is common, and routine follow-up of patients should include a blood test for B12 levels.

The effects of pelvic radiotherapy on 202 prostate cancer patients [men] were reported as a major alteration in bowel function in 11%, significant bladder symptoms in 4%, and loss of potency in 35%.

Cause of Radiation Damage:

Dosage, timing, inflammation , poor nutrition, previous operations, and the presence of infection have all been implicated in causing or exacerbating late effects.

One study found that the only factors significantly related to late intestinal complications were the beam arrangement and, consequently, the treated volume. Detailed analysis showed that radiation sequelae developed in 12/106 (11.3%) patients treated with the two sagittal fields technique, while small bowel toxicity was observed in only 2/85 (2.3%) patients treated with the three--or four--fields technique. The difference is statistically significant (p < 0.05).

Pelvic radiation tissue toxicity increased significantly when the dose exceeds 45 Gy, with the incidence of marked bladder and rectal changes rising from 8% to 51% and from 24% to 48%, respectively [MR scans]. Similar dose-related changes are seen in other pelvic organs. In asymptomatic patients, minimal MR changes were seen in the bladder (47%) and in the rectum (33%).

The incidence of bladder, rectal, & vaginal radiation damage differs for different irradiation methods and different fractionalization of dosages. Some factors that contribute to risk of complications due to late radiation damage of the small bowel are: hypoalbuminemia, more than one laparotomy prior to irradiation and a short interval (< 12 months) between irradiation and surgical intervention.

Description of Damages and Treatment:

Small bowel obstructions due to extensive matted small bowel adherent to the pelvic operative sites are frequent sequelae of radical hysterectomy, being more common if concomitant radiotherapy is given.

Radiation therapy of cancers in the pelvic region may lead to radiation proctitis [inflammation of the rectum]. Radiation injury to the rectal wall results in damage and obliteration of the blood vessels, causing death of local tissue and subsequent scarring. Patients with radiation proctitis may be minimally ill and heal spontaneously. However, symptoms of proctitis may persist, and the disease progress to chronic bleeding and/or stricture and fistula formation. Medical therapy is often unsuccessful, and surgery is eventually required. Because of numerous postoperative complications and no guarantee of success, surgery is often recommended as a last resort.

Ureteral stricture is a rare late complication of curative radiotherapy. During the first 5 years after treatment, tumor recurrence is the most common cause of ureteral stricture in patients treated with radiotherapy. However, radiation injury to the ureter, although rare [continuous actuarial risk increase of approximately 0.15% per year], may not become apparent for many years, necessitating continued vigilance. Radiation injury can also occur to the kidneys as well as the ureters.

Arterial occlusions[blockages] are a rare yet dramatic complication of radiotherapy for gynecologic cancer. Three patients underwent amputation of a lower extremity when they developed chronic arterial insufficiency after pelvic radiotherapy. The patients were irradiated at the ages of 28, 30, and 35 years. Two received neutron beam therapy and one received conventional photon beam therapy. All three had extensive late radiation morbidity to the bladder and rectum and had multiple prior surgeries. The amputations occurred at the ages of 48, 48, and 55 due to accelerated arteriosclerosis. Two patients died as a result of this complication.

The differentiation of the variations in appearance which can be produced by radiotherapy damage from recurrent malignancy can be difficult.

Surgical treatment of intestinal radiation injury.

Many cases require operative intervention. This usually consists of resection, the establishment of a bypass anastomosis [joining bowel in such a manner as to bypass the problem area] or enterostomy [creation of a stoma for bowel]. There is a high complication rate, and often a significant mortality, partly due to the poor general condition of the patient, and partly due to the radiation induced impairment in wound healing, which may lead to insufficiency of the anastomosis [join] and the development of fistulae [draining channels from one area to another].

The endoscopic spectrum of late radiation damage to the rectosigmoid colon included abnormalities of the mucosa with characteristic telangiectasis, luminal narrowing, superficial or deep solitary ulcers or more extensive diffuse ulceration and fistulae. Late radiation damage presented as stenoses , fistulas , perforations, rectal ulcers and hemorrhagic proctitis. Resection with end-to-end-anastomosis and bypass were the operations most frequently performed on the small bowel, whereas most colonic and rectal lesions were treated by colostomy alone. The postoperative course complications include fistulas, peritonitis, pulmonary embolism, and ulcer perforations. This series had a 10.7% death rate.

Another series of twenty-eight patients with late radiation damage presented with rectovaginal fistulas, hemorrhage from ulcerative proctitis, low rectal strictures, rectal ulcer and rectal carcinoma. Associated pathology in these patients included urinary fistulas, small bowel fistulas or stenoses and a variable degree of fibrosis of the pelvic cellular tissue. Treatment involved subtotal rectal resection with restoration of continuity by means of a perianal sleeve anastomosis between healthy colon and the rectal stump denuded of its mucosa. Technical success was achieved in 35 of the 37 patients, with no mortality. Where anastomosis was possible at a higher level, all 19 patients cured of fistula, ulcer, stenosis or hemorrhagic proctitis were fully continent at 1 year.

A review of 43 consecutive patients requiring operation for serious intestinal radiation injury was undertaken to elucidate the efficacy of surgical treatment. The overall operative mortality was 14%; morbidity, 47%; and the postoperative symptom-free period, 18 +/- 30 months. Colostomy (N = 20) carried the lowest risk of mortality, 0%, as compared with resection (N = 17) and bypass procedure (N = 6), which were accompanied by the mortalities of 24% and 33%, respectively. During the follow-up (3-13 years) 12 patients (28%) died of recurrent cancer and 9 patients (21%) of persistent radiation injury, which yielded an overall mortality of 65% after resection and 50% and 65% after bypass and colostomy procedures, respectively. Continuing radiation damage led to 15 late reoperations. Ten of these were performed after colostomy, four after resection, and one after bypass. We conclude that colostomy cannot be regarded as a preferred operative method, because it does not prevent the progression of radiation injury and because it is, for this reason, associated with a higher late-complication rate. A more radical surgery is recommended but with the limitation that the operative method must be adapted to the operative finding.

References: Abdominal and Pelvic Radiation Damage
SPINAL CORD

References: Radiation Damage and the Spine

Inflammation of the spinal cord nervous tissue is called myelitis. Damage to the spinal cord [myelopathy] can result in paralysis. The spinal cord may be inadvertently damaged while irradiating another organ or structure. However, spinal cord symptoms do not always mean late effect radiation damage, they sometimes are due to recurrent or metastatic tumor.

The incidence of permanent damage to the spinal cord as a complication of radiation therapy generally correlates positively with total radiation dose. However, several reports have indicated that fraction size is also an important factor in the development of late damage in normal tissue. Low fraction sizes appear to decrease the incidence of such damage, but increasing the number of doses per day increases the incidence of damage. If re-irradiation of the cord is necessary, latent time to myelopathy decreases following retreatment. The risk of myelitis that accompanies higher spinal cord irradiation doses must be weighed against the therapeutic gains.

The Post-irradiation Lower Motor Neuron Syndrome. Six men who had presented with testicular neoplasms and received irradiation were studied. A predominantly motor disorder affecting the legs ensued after variable and often prolonged latencies (3-25 years). However, all patients also developed mild sensory features either initially or on prolonged follow-up. Mild sphincter symptoms occurred in three of five surviving cases after a mean of 7.9 years. The first reported neuropathological study, uncomplicated by metastatic disease, of this area of the spinal cord showed a radiation-induced vasculopathy. Radiation exposure exceeded 40 Gy both in our series and in previous reports. The natural history of this disorder is one of relentless deterioration occasionally punctuated by 1-2-year periods of stability. Post-irradiation lumbosacral radiculopathy is a more accurate name for this condition.

References: Radiation Damage and the Spine
LIMB

Late radiation edema of the extremities may develop after therapy of malignancies. It is associated with radiation damage of lymph and veins, and with scarring of tissues in the radiation zone, which can result in muscle atrophy. Serious late radiation damage, such as grave functional deficiency, and/or painful scarring or contractures, might require amputation later. Bone damage can also occur. The generalized late effect risks of New Cancer and Bone Marrow damage, also apply.

There is a relatively wide variation in the duration and degree of post-irradiation edema in soft tissues. This edema seems to persist longer between muscle compartments than in fat or muscle itself. One study suggested that the edema resolved more slowly and that muscle atrophy was more severe in a neutron treated group as compared to a proton treated group.

Re-irradiation is sometimes an option for local control, if the tumor recurs. Combined conservative surgery and re-irradiation provided superior local control to local re-excision alone and a functional outcome superior to amputation. Combined treatment with re-irradiation should be considered the primary salvage therapy for patients who fail combined therapy and who are suitable for conservative re-excision.

References: Radiation Damage to Limbs


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