
   Radiation Therapy and Radiation Damage
   written and compiled by doctordee May 2001


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Radiation Therapy and Radiation Damage
* NCI publications
* Why Choose Radiation?
* Types of Radiation
* How it works
* Treatment Choices 
* Prevention of Unwanted Radiation Damage 
* Radiosensitizers 
* Adding Chemotherapy, Hyperthermia, or Antiangiogenesis
* Discussion of Radiation Damage 
         Some Important Points 
              Damage & Risks to Structures Usually Within the Beam
                  Arteries
                  Bone
                  Skin
                  New Cancers
                  Bone Marrow
          Chest ** Head and Neck ** Brain ** Abdomen and Pelvis ** Spinal Cord ** Limb
* Medical Journal References  
* Glossary* 
*You can download the CancerNet Dictionary, and use it as a split-screen glossary, for definitions of medical terms in the journal abstracts. 



National Cancer Institute Publications

These give important information in simple, clear language.
Your Tax Dollars at Work.
 http://www.cancer.gov/cancer_information/


1. Radiation and You:  A Guide to Self-Help During Cancer Treatment.
Go to the link to the www.cancer.gov/ site right now, and download and read Radiation and You, FIRST.  
http://www.cancer.gov/cancer_information/doc_img.aspx?viewid=32136103-0800-407b-83c8-28fd87267753
http://www.cancer.gov/cancer_information/doc_img.aspx?viewid=32136103-0800-407b-83c8-28fd87267753
http://www.cancer.gov/cancer_information/doc_img.aspx?viewid=32136103-0800-407b-83c8-28fd87267753
This online booklet is for patients who are receiving radiation therapy for cancer. It describes what to expect during therapy and offers suggestions for self-care during and after treatment.  It should be read and re-read by you and your caretaker.  It is very well written, and therefore this website will not address the issues it covers.


2. Radiation Enteritis (PDQ(r))  
http://www.cancer.gov/cancer_information/doc_pdq.aspx?version=provider&viewid=2f4ac28e-80a9-4892-a380-8b713247281d
If you have radiation treatment of the abdomen or pelvis, one of the side effects of this is enteritis-inflammation of the bowels.  This inflammation can be acute [coming on suddenly during treatment, but getting better] or chronic [late effects of radiation do not appear immediately] and stay around.  Sometimes a patient gets both acute and chronic side effects.  The chronic side effects, called "late effects" are permanent damage.  Not everyone is badly affected by late effects.  The following is a link to a PDQ article on Radiation Enteritis, Acute and Chronic, written at both the patient and the health professional levels, with a tab arrangement so that you can go back and forth between the two levels.  If you read the patient's version first, the doctor's version will be easier to understand. 




3. Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ(r))

http://www.cancer.gov/cancer_information/doc_pdq.aspx?version=provider&viewid=6419bde1-8247-46a9-b2a5-165810c72ff4

If you are having radiation treatment to your head or neck, there are certain complications that develop.  You MUST see your dentist before starting therapy.  The link below is to a PDQ article about Head and Neck Radiation, and it is written at both the patient and the health professional levels, with a tab arrangement so that you can go back and forth between the two levels.  If you read the patient's version first, the doctor's version will be easier to understand.  



4. There are many other publications available from NCI relating to this topic.
Cancer patients, their families and friends, and others may find the following National Cancer Institute books useful. They are available free of charge by calling 1-800-4-CANCER, or download them from the website.
* "Chemotherapy and You: A Guide to Self-Help During Treatment" 
* "Eating Hints for Cancer Patients Before, During, and After Treatment" 
* "Get Relief From Cancer Pain" 
* "Helping Yourself During Chemotherapy" 
* "Questions and Answers About Pain Control: A Guide for People with Cancer and Their Families" 
* "Taking Time: Support for People With Cancer and the People Who Care About Them" 
* "Taking Part in Clinical Trials: What Cancer Patients Need to Know"  
* Video "Taking Part in Cancer Clinical Trials: Patient to Patient"
* Publications Available in Spanish 
* "Datos sobre el tratamiento de quimioterapia contra el cancer" 
* "El tratamiento de radioterapia; guia para el paciente durante el tratamiento" 
* "En que consisten los estudios clinicos? Un folleto para los pacientes de cancer" 



About Choosing Radiation 


Radiation causes damage, short and long term, and has risks of other complications. So why choose it? Mainly because Cancer kills people. Radiation can kill cancer cells. Given a choice, most people would probably prefer to be alive, with damage that they could live with, or face years later. 
And radiation does not only save lives from cancer, it can lengthen survival time, decrease pain, and prevent amputations. 
For Leiomyosarcomas, surgery is almost always the best therapeutic choice, as well as the chance for cure. But in situations where the tumor is inoperable, radiation can be used to shrink it, so the tumor can be surgically removed. 
For brain tumors, focused radiation as in the 'gamma knife' offers a chance of tumor control, or even of killing the tumor completely. 
In certain selected instances, radiation might be used against other metastases as well. 
In some situations, when a primary or recurrent tumor is removed, use of radiation might increase the time to next recurrence. 
When surgical resection does not leave clear margins, radiation therapy might kill the cancer cells left behind. 
But radiation has its longterm consequences, as well as the short term ones. The tissues that are exposed to radiation are usually not just the cancer. All of the organs around the tumor and in the path of the radiation can be damaged by radiation aimed at the tumor. Some of the longterm consequences can be very serious. It is one of the purposes of this web page to help people understand some of the problems that could develop. This treatment modality can be effective, but is not without risk. And awareness of possible long term complications of radiation may make it easier for cancer survivors to notice the complications sooner, with possibly better outcomes and less suffering.  Furthermore, the use of protectants [like amifostine], or radiation sensitizers could, perhaps, ameliorate some of the effects on normal tissue and intensity the effects on the cancerous tissue. 


Why This Web Page Was Constructed: 


Because I received the following letter: 
"When my wife received radiation, pelvic and a vaginal implant, we asked about side effects. We were told possible fatigue and diarrhea. That was it. No one mentioned the long term effects or the impact it would have on future surgeries for a disease that relies on surgery for control." "For my wife these side effects were radiation proctitis, an atrophied vagina, a bladder fistula after surgery. After her last surgery a colostomy was required because of a radiation-damaged colon. I have found that many list members were in the same boat. They enter treatment with little understanding of the long term impact of radiation." 

AND this letter:
"She is still in hospital as recovery is very slow due to the fact that the tumor was in the area of radiation. The radiation therapy was to prevent or significantly reduce the likelihood of a met in that area: I think that there is a real question about the efficacy of radiation. Looking back we wish that my wife did not agree to have it done. Not only was the surgery very difficult [to remove a recurrence in the irradiated area] but the recovery will be slow and difficult, especially in respect of the invasion of the bladder."


AND I also received this letter: 
"There has been very little on the list about IORT*. Not that many hospitals have it. Duke has been doing it for only about 1 year. Most of the papers refer to retroperitoneal sarcomas and conclude that it provides benefit for local control. My wife received it at my request during her last pelvic surgery a couple months when we knew clear margins would not be possible and the recurrence was exactly in the same place. The obvious benefit was that all organs could be moved aside. Still with that and the other radiation, 7 years of CT scans, bone scans, etc., I will be surprised if she does not develop leukemia if she makes it another 5 years. Bottom line, however, is that this should be investigated as a possible better alternative to external beam." *IORT is Intra Operative Radio Therapy. 



Ultimate Risks of Radiotherapy? Only long-term follow-up can determine the ultimate risks of radiotherapy.  One study followed 221 consecutively treated patients for 8 to 42 years after post mastectomy radiation. 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 arm, nine chronic ulcers, five respiratory insufficiencies, six pathologic fractures of the radiated shoulder or ribs, two fatal cardiomyopathies, one persisting leucopoenia 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.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6498728&dopt=Abstract


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Types of Radiation & How It Works



The absorption of energy from radiation in tissue often leads to ionization. Ionization involves actual ejection of one or more electrons from the atom.  Ionizing radiation is electromagnetic (photon, includes gamma rays and Xrays) or particulate radiation (like electrons or protons). X-rays are produced artificially and mechanically while gamma rays are produced by nuclear disintegration [decay of radioactive isotopes.]  [Harrison's Principles of Internal Medicine, 14th Edition, page 2559.]


Xrays and gamma rays can be thought of as beams of photons [packets of energy] traveling in straight lines. The photons have no weight or charge, and the amount of energy in each determines whether the radiation is ionizing or non-ionizing. Both Xray and gamma ray beams lose their strength [attenuate] continuously and steadily as they pass through tissue [from reacting with the tissue.]  Attenuation of the rays indicates use of the energy to create free radicals and other damage in the tissue.  


Radiation particles include electrons [beta particles], protons, neutrons, and helium nuclei [alpha particles]. 
Electrons are small, negatively charged, and can be accelerated. They penetrate tissue to a limited depth, and can be used to treat problems near to the surface. 
Protons are positively charged, and are about 2000 times heavier than electrons, and can be accelerated to increase their energy. Protons tend to stop abruptly when traversing tissue. In their sudden stops, most of their energy is abruptly given up, so there is a compact, enhanced region of ionization. This is called a Bragg Peak. 
Neutrons are the same weight as protons, but are not charged. 
Helium nuclei consist of two protons and two neutrons. Their mass and charge are so heavy that unless accelerated to very high energies, they do not penetrate very far into tissue.


Other RadioIsotopes are also used to deliver ionizing radiation. Radioisotopes are unstable atoms, whose nuclei decompose, releasing gamma rays and/or electrons, protons, neutrons, or helium nuclei. What is released depends upon the particular radioisotope.  Radioisotopes can be placed in suitable containers and left in place either temporarily or permanently, or administered by mouth or intravenously to reach tissues that will preferentially take them up or injected straight into tumors, or placed in beads or resins and injected into liver arteries that feed tumors.


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& How it Works


"Radiation must generally produce double-stranded breaks in DNA to kill a cell, owing partly to the high capacity of mammalian cells for repairing single-strand damage. Radiation can also produce effects indirectly by interacting with water (which makes up approximately 80 percent of a cell's volume) to generate free radicals, which can damage the cell. Free radicals are highly reactive chemical entities that lack a stable number of outer-shell electrons. A free radical is not stable and has a life span of a fraction of a second. It is estimated that most x-ray--induced cell damage is due to the formation of hydroxyl radicals..." [Harrison's Principles of Internal Medicine, 14th Edition, page 2560.]



What makes a tumor radiosensitive? "It is known that radiation therapy can be successfully used to cure or control some types of human tumors, while consistently failing in others. This has been ascribed to several factors including differences in the intrinsic sensitivity of the tumor cells and in their ability to recover from radiation damage. In this study, human tumor cells from an osteogenic sarcoma, a glioblastoma, and two medulloblastomas, as well as cells from human skin, were established in tissue culture, and ...survival ... determined. No significant differences in ... survival ... could be detected among these human tumors or skin cells, despite the wide variability in their radiocurability. In addition, skin cell strains derived from patients exhibiting markedly sensitive or resistant skin reactions during fractionated radiotherapy showed no differences in survival characteristics from normal controls. It is therefore suggested that the wide range of radiocurabilities seen among various human tumors cannot be explained on the basis of inherent cellular factors responsible for the survival of tumor cells after x-irradiation." 
J Nucl Med 1998 Sep;39(9):1551-4 PMID: 1069484 PubMed 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1069484&dopt=Abstract


Tumor damage depends upon amount of hypoxic cells [which are radioresistant], radiation dose, doses of chemotherapy and/or other radiosensitizer given, ambient temperature, timing of drug dose and radiation exposures. The effectiveness of oxygenating the hypoxic cells to make them radiosensitive depends upon how densely the tissue is vascularized, hemoglobin concentrations and affinities for oxygen, and levels of carbon dioxide breathed in [causes blood vessels to dilate and deliver more blood to tissues], as well as use of hyperbaric [high pressure] oxygen treatment.



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Treatment Choices


Radiation Treatment is either given externally or internally, and it involves use of either beams or radioisotopes to deliver gamma rays [high energy Xrays], or protons, or neutrons, or electrons, or alpha particles to the tumor. The idea is to get a high dose of radiation to the tumor while the surrounding normal tissue is protected from radiation damage.


External Radiation involves beams of either high-energy rays, or neutrons, or electrons or protons.  External radiation therapy does not cause your body to become radioactive.

* Electron beams and proton beams and alpha particles [helium nuclei], because of the nature of their particles, weighted and charged, do not penetrate as deeply or as widely as neutrons or gamma rays.  They are capable of delivering tumor directed radiation that is very focused.  Proton beams, because of the nature of the proton interaction-it gives up a major part of its energy just at or before the boundary of its excursion-is especially suited for getting at LMS tendril extensions.  For isolated tumors growing where it would be difficult to get clear margins, and where ablation [RFA or cryo] would not be possible, this might be the treatment of choice. 

* Proton beam treatment is available at several centers in the US.  However, currently, only Loma Linda and possibly the Boston site will deal with metastatic tumor, and then if it is not part of extensive disease.  

* Neutron Beam treatment with high-energy neutrons has had some effect on large, difficult-to-treat LMS tumors of patients on the LMS list.  The Fermi Laboratory does this treatment.

* External Beam gamma ray - Fractionated Radiation Therapy treatment involves exposure of normal tissue to the radiation.  It is given in a fraction of the total dose [usually 1/30th] at a time, so it is called fractionated [made into fractions].  In hyperfractionated radiation therapy, the daily dose is divided into smaller doses that are given more than once a day. The treatments usually are separated by 4 to 6 hours.  Besides the inconvenience, sometimes the toxicity is increased.  Ask to see references if this is offered to you.

* External Beam gamma ray - Three-dimensional conformal radiation therapy is a radiation technique that is being used in some cancer centers. Computer simulation produces an accurate image of the tumor and surrounding organs so that multiple radiation beams can be shaped exactly to the contour of the treatment area. Because the radiation beams are precisely focused, nearby normal tissue is relatively spared. This technique is being used to treat prostate cancer, lung cancer, and certain brain tumors. 


* External Beam gamma ray - Stereotactic radiosurgery, which uses gamma rays or a linear accelerator, is useful for treating certain kinds of brain tumors and some malformations in the brain's blood vessels. One technique, called the 'gamma knife,' uses many powerful, precisely focused radiation beams. The patient wears a special helmet to focus the gamma rays and aim them at the target tissue from many directions. The treatment is painless and bloodless and, unlike conventional brain surgery, there is no danger of infection. Other systems use a linear accelerator to deliver the radiation in arcing paths around the patient's head.  Normal tissue is relatively spared.


* External Beam gamma ray - The cyberknife is a new, but less common, treatment that is being used to treat brain tumors. This system uses a miniature radiation machine and a robotic arm that moves around the patient's head while delivering small doses of radiation from hundreds of directions. During treatment a computer analyzes hundreds of brain images and adjusts for slight movements by the patient. This makes it possible to deliver the treatment without using a frame to hold the patient's head still. Only the tumor receives the high doses of radiation and healthy tissue is relatively spared. 


* Intensity-modulated beam radiotherapy (IMRT) delivers a highly conformal, three-dimensional (3-D) distribution of radiation doses that is not possible with conventional methods. IMRT allows for the treatment of multiple targets with different doses, while simultaneously minimizing radiation to uninvolved critical structures. With 3-D computerized dose optimization, IMRT is a vast improvement over the customary trial-and-error method of treatment planning.  It allows high doses of radiation to be delivered to tumor tissue while reducing radiation damage to healthy tissue.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10631687&dopt=Abstract



Internal radiation therapy allows a higher total dose of radiation in a shorter time than is possible with external treatment and places the radiation source as close as possible to the cancer cells. The radioactive material, sealed in a thin wire, catheter, or tube (implant), is placed directly into the affected tissue. This method of treatment concentrates the radiation on the cancer cells and lessens radiation damage to some of the normal tissue near the cancer.  Implants may be removed after a short time, or left in place permanently.  
The type of implant and the method of placing it depend upon the size and location of the tumor.




* Brachytherapy is implant radiation therapy.  For most types of implants, you will need to be in the hospital.
* Interstitial Radiation --implants are put directly into the tumor.
* Intracavitary Radiation  --implants are placed in special applicators inside a body cavity.
* Intraluminal Radiation -implants are placed in special applicators inside a body passage. 
* Remote brachytherapy --a computer sends the radioactive source through a tube to a catheter that has been placed near the tumor. The radioactivity remains at the tumor for only a few minutes. In some cases, several remote treatments may be required and the catheter may stay in place between treatments. High dose-rate (HDR) remote brachytherapy allows a person to have internal radiation therapy in an outpatient setting. High dose-rate treatments take only a few minutes. Because no radioactive material is left in the body, the patient can return home after the treatment. 



* Unsealed internal radiation --given by injecting a solution of radioisotope into the blood, or into a body cavity, or giving an oral dose of a target-seeking radioisotope.  

* Intraoperative Radiation combines surgery and radiation therapy. The surgeon first removes as much of the tumor as possible. Before the surgery is completed, a large dose of radiation is given directly to the tumor bed (the area from which the tumor has been removed) and nearby areas where cancer cells might have spread. This can be done by external beam or by exposure to other radiation source. Sometimes intraoperative radiation is used in addition to external radiation therapy. This gives the cancer cells a larger amount of radiation than would be possible using external radiation alone. 



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Prevention of Unwanted Radiation Damage



In some post-irradiation studies, radiation damage is present in 90% or more of 10 year survivors. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2209839&dopt=Abstract
Since late radiation effects themselves can be lethal, but undertreating cancer also has its risks, prevention of unwanted radiation damage is important.

UV radiation damage to membranes, proteins, DNA and other cellular targets is predominantly related to oxidative processes. Vitamin E and possibly other antioxidants partly protect cells from radiation damage.


Infection existing in tissues that are irradiated create worse long term effects, including bone necrosis, central nervous system necrosis, and persistent infection. "All patients who developed chronic persistent infection during or shortly after the radiation therapy, increased local tissue sensitivity to late radiation damage. As a result, severe bone, cerebellar and brainstem necrosis was observed at doses that are normally considered safe. We therefore strongly recommend that any infection in a proposed irradiated area should be treated aggressively, with surgical debridement if necessary, before radiotherapy is administered, or that infection developing during or after irradiation is treated promptly." 



Close observation over function of large nerve trunks and plexuses while the patients are receiving radiation to the area is necessary. Early diagnosis and treatment of radiation plexitis and neuritis is essential for adequate recovery of limb function. Diagnosis of radiation damage to the peripheral nervous system should rest on clinical electrophysiological findings defining the degree of the nerve fiber injury.  Hyperbaric oxygen therapy has been useful in restoring nerve function.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10465478&dopt=Abstract
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8635114&dopt=Abstract


Saline breast implants might be used to displace organs away from the radiation field when treating malignant tumors of the trunk, thereby minimizing the radiation dose to uninvolved organs. In patients with pelvic tumors the bowel can be fixed to the upper abdomen by use of Polyglycolic acid mesh (Devon) to minimize radiation associated small bowel injury. There is no severe disturbance of bowel motility, and after 3 to 4 months the small bowel will again descend into the pelvis.



Techniques that concentrate radiation in small areas, like IORT, and implantation radiation, can prevent large areas of healthy tissue from becoming inadvertently damaged. Intraoperative radiotherapy (IORT), with radiation applied directly to the tumor or tumor bed with the abdomen open is a useful process. Stomach and intestines can be easily excluded from the radiation field to avoid late radiation damage.


The use of a radiation protectant such as amifostine prior to irradiation might prevent normal tissue damage, while not preventing tumor lysis.  For further details, see the section on amifostine in the Chemotherapy web page on this site.
Pubmed search for radiation treatment protectants:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=radiation%20treatment%20cancer%20protectant



References: Radiation Damage Prevention
 
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Radiosensitizers


Radiation modifiers, including hyperbaric oxygen, chemical radiosensitizers, normal tissue protective agents, and local and systemic hyperthermia are continually being investigated. A radiosensitizer is a compound that would make tumor cells more sensitive to the effects of radiation, and have no effect upon normal cells. This would allow a given dose of radiation to have a greater effect upon the malignant tissue. Some radiosensitizers lead to an increase in sensitivity of the hypoxic and therefore radioresistant parts of tumours against X- and gamma-radiation. With sufficient concentration within the tumour, they can act where the radiation can reach, even in the deeper parts of the body. 



A number of chemical compounds that modify radiation effects have been discovered and tested both in the laboratory and clinically over the past 25 years. There are classes of compounds: aminothiol radio-protectors which act on well vascularized oxygenated cells and concentrate in tissues such as skin, gut and marrow; nitromidazole radiosensitizers [metoclopramide derivatives, which cause DNA strand breaks and inhibit DNA repair, and thereby sensitizes radiation and chemotherapeutic drugs in human tumor cell cultures]; pyrimidine analogues which are incorporated into the DNA of cycling cells and cause radiosensitization; and cancer themotherapy agents which, in addition to their ability to kill tumor cells directly, also may sensitize tumor and normal cells to radiation. In addition, 2-deoxy-D-glucose prevents efficient utilization of glucose in cells, and has a greater effect on tumor cells. Not being able to generate energy from glucose inhibits the repair of radiation damage preferentially in tumor cells.


Tumor damage depends upon amount of hypoxic cells [which are radioresistant], radiation dose, doses of chemotherapy and/or other radiosensitizer given, ambient temperature, timing of drug dose and radiation exposures. The effectiveness of oxygenating the hypoxic cells to make them radiosensitive depends upon how densely the tissue is vascularized, hemoglobin concentrations and affinities for oxygen, and levels of carbon dioxide breathed in [causes blood vessels to dilate and deliver more blood to tissues], as well as use of hyperbaric [high pressure] oxygen treatment.


Radiotherapy combined with razoxane [a radiosensitizer] seems to improve the local control in inoperable, residual, or recurrent Soft Tissue Sarcoma compared to radiotherapy alone. The combined treatment is a fairly well tolerated procedure at low costs. It can be recommended for inoperable primary Soft Tissue Sarcoma or gross disease after incomplete resection, conditions that are associated with limited local control and a grave prognosis


COX-2 9 (Cyclooxygenase-2) is overexpressed in many types of malignant tumors. It mediates production of prostaglandins, which in turn may stimulate tumor growth and protect against damage by cytotoxic agents. Treatment with a selective inhibitor of COX-2 [like Vioxx or Celebrex] may greatly enhance tumor radioresponse without markedly affecting normal tissue radioresponse. COX-2 inhibitors might have marked value for increasing the therapy/damage ratio of irradiation.



 
References on Radiosensitivity and Radiation Damage
References on Radiosensitivity and Radiochemotherapy
  

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Adding Chemotherapy, Hyperthermia, or Antiangiogenesis


Chemoradiotherapy protocols are a recent development in the management of tumours where preservation of organ function is important. It is now recognized that such combined treatment may produce adverse effects above the accepted dose thresholds for either modality, including increased cardiotoxicity with adriamycin.
However, there was a study done for inoperable lung cancer that showed local control and survival was improved by combining radiotherapy with daily low-dose cisplatin. As usual, the risk benefit profile requires consideration. 

The dosages and timing of the chemotherapy agent(s) and the radiation determine the effectiveness of the regimen. Timing between Xray irradiation and chemotherapy dose may be critical.

Hyperthermia in combination with chemotherapy has a strong biological rationale based on thermal enhancement of cytotoxicity and partial circumvention of resistance. Weekly locoregional hyperthermia or whole-body hyperthermia using the Aquatherm apparatus, in combination with chemotherapy is feasible. Some results in patients with metastatic sarcomas were promising.

The formation of a blood supply (angiogenesis) is critical to the growth of solid tumors. Addition of antiangiogenic agents to treatment with cytotoxic therapies might make standard anticancer therapies more powerful.

Interleukin-1 might have a protective effect on normal tissues' response to radiation and chemotherapy damage, while not affecting tumor response to treatment. For some drugs, the protection might be dependent on sequence of administration.

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References: Radiochemotherapy



Radiation Damage Discussion 
* Some Important Points 
* Early and Late Side Effects 
* Damage & Risks to Structures Usually Within the Beam
               Arteries
               Bone
               Skin
               New Cancers
               Bone Marrow
* Chest
* Head and Neck
* Brain
* Abdomen and Pelvis
* Spinal Cord
* Limb


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. 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10465478&dopt=Abstract

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.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8635114&dopt=Abstract

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.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6498728&dopt=Abstract

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. 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9693333&dopt=Abstract

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
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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
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Damage & Risks to Structures Usually Within the Beam: 



               Arteries
               Bone
               Skin
                   New Cancers              
                   Bone Marrow




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
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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
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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
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New Cancers 


References: New Cancer as a Late Effect of Irradiation
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. 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
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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
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Specific Discussion: Possible Late Effects in Individual Area Irradiation


Chest
Head and Neck
Brain
Abdomen and Pelvis
Spinal Cord
Limb



CHEST 

General
Rib
Heart
Lung
Nerve
Esophagus
Skin
References: Chest Irradiation Damage


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
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HEAD and NECK 



     Eyes
     Jaw
     Thyroid
     Salivary glands & mouth
     References for this Section


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
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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 th