Gilleece, Terri

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Chapter 13 Radiotherapy-Related Treatment ReactionsBrachytherapy ReactionsBrachytherapy is the treatment of disease using discrete sealed radioactive sources. It originated in 1901(1) with the use of Radium-226 and is therefore one of the oldest forms of radiotherapy. Over the years more suitable radiation sources have been employed because Radium-226 has a complicated decay scheme with some high energy photon emissions and gaseous Radon-222 making radiation protection an issue.There are advantages and disadvantages to this type of ‘close’ (brachy) therapy. A high dose can be delivered to the tumour while the surrounding and overlying tissues can be spared some or all of the effects of radiobiological interactions because of the steep dose gradient of the alpha and beta emissions of these sources. This dose distribution therefore reduces the side effects to the patient. Brachytherapy treatment regimes can vary from a few minutes to 10 days, so compared to external beam radiotherapy treatments the schedules are usually preferable for the patient.(2) On the negative side, the sources require insertion within body cavities, implantation into tissues, or application to surface tissues (this latter technique has been largely replaced by electron beam treatments). Such techniques, whether permanent or temporary, can be problematic and uncomfortable for the patient. Brachytherapy is a successful treatment method for a range of conditions (3-6)Intracavitary implant for  Pelvic tumours (cervix, body of uterus, vagina), oral cavity, naso- , oro- ,  and hypopharynx Intraluminal implants for oesophagus, bronchus, bile ducts, vascular (non-malignant)Interstitial implants for prostate, lung, pancreas, brainSurface application of eye plaques for intraocular tumours, pinna, skinAs with all forms of radiation treatments, side effects are possible and vary according to the type of source, dose, treatment site and time since treatment. The best way to reduce side effects from brachytherapy is with careful treatment planning techniques and to ensure that applicators and sources are correctly positioned. Bowel and urinary preparation can ensure that adjacent organs are removed from the proximity of high dose targets during pelvic brachytherapy. Metal ‘buttons’ or plates can be placed in positions to reduce the dose to surrounding tissues.(7) Acute side effects:The most obvious side effects from brachytherapy are pain, swelling and bruising around the site of implant. There will undoubtedly be inflammation, even with intracavitary implants, but this will be increased with intraluminal and interstitial work. The reactions will be obvious if surfaces are visible e.g. Irridium-192 wire implants in the mouth or breast, but we must remember that the same intensity of  reactions occur at all sites. Analgesia is prescribed to overcome this discomfort. If the area is accessible, ice packs can be applied. Pain and swelling should ease rapidly, and implants are usually removed without the aid of anaesthetics.Late side effects:Telangiectasia and permanent pigmentation of the skin are amongst the most common late side effects. Again attention should be paid to internal sites as telangiectasia can result in bleeding around the site. If bleeding does occur it is usually mild and intermittent, but it can cause considerable distress for the patient who has already had a diagnosis of cancer.As radioactive sources are being implanted it is possible that these may induce cancerous growths. This is of particular significance if brachytherapy is being employed for cardiac restenosis as this is a non-malignant disease.(6,7) The long-term implications of the use of intravascular brachytherapy are still unclear as it is a relatively new technique. The specific side effects from the most common brachytherapy treatment regimes are discussed below.Prostate:Brachytherapy for prostate tumours can result in a higher dose to the tumour than that administered during EBRT, typically 145Gy to a PTV of prostate plus 2-3 mm margin compared to 64 – 74 Gy with EBRT. The organs at risk are the bladder, rectum and neurovascular bundle. The toxicity to these structures during brachytherapy is decreased in comparison to EBRT or surgery, therefore the risk of urinary incontinence and impotence is reduced. The most common side effect of prostatic brachytherapy is grade 2 urinary symptoms.(8) Table 1 lists the possible side effects and methods of treatment. Insert table 1 The side effects of prostatic brachytherapyGynaecological Malignancies:Cervical, vaginal and endometrial cancers can be treated with combinations of surgery, brachytherapy and/or EBRT, depending on the stage of disease.  Gynaecological Brachytherapy reactions are described, but because brachytherapy is frequently given in combination readers are advised to familiarise themselves with common reactions to pelvic EBRT in addition to those listed below.Bowel and RectumUsing metal filters or packing the rectum, can reduce the brachytherapy dose to this structure. Some tenesmus, mild rectal bleeding and diarrhoea may occur at the time of treatment but should settle quickly with the help of medication such as loperamide and dietary advice. Less than 3% will develop obstruction, bleeding, necrosis, or fistula as late reactions. If a fistula does develop, it is usually at the site of the anterior rectal wall behind the posterior vaginal fornix.(9) The treatment for proctocolitis is conservative administration of Predsol enemas, progressing to colostomy if other treatments fail.Careful planning and the use of a rectal probe to give ‘real’ time dose rate can reduce the possibility of developing rectal complications.(10)(6)(Witt, Haas et al. 2003)BladderBladder irritation is less likely than bowel side effects. If it does occur during or immediately after treatment it is usually mild and increasing fluid intake can relieve the symptoms. Cranberry juice is often suggested as it can alter the acidity of the urine, making it more comfortable for the patient to micturate. Late bladder side effects are usually mild and include frequency and telangiectasia. The latter can cause haematuria, which can be treated by diathermy. It is estimated that the late effects to the bladder will affect around 1 in 5 patients. Again careful planning and accurate imaging prior to treatment should eliminate the possibility of severe symptoms. Infection Cervical tumours are often infected. Dilatation of the uterine canal for the insertion of brachytherapy sources can spread the infection. Drainage of pus and administration of antibiotics are required.Vaginal dryness/ StenosisThe possibility of permanent dryness along with shortening and narrowing of the vagina should be discussed with the patient prior to consent for treatment. Oestrogen creams can address the issue of dryness and regular use of dilators can help maintain the patency of the vagina.Hormone TherapyBeatson, who noted that inoperable breast cancers sometimes regressed after oopherectomy, described the significance of hormone action on cancers of the reproductive system in 1896.  In modern medicine, in addition to surgical interventions such as oopherectomy and orchidectomy, we now have a range of hormonal drugs to alter the hormone profile of the patient. We can either lower the plasma protein of hormones that are known to stimulate the tumour or give additive hormones that compete with the tumour dependent hormones during the synthesis process. However, just as natural hormone variations and imbalances (such as puberty and menopause) can cause unwanted side effects, so too can hormonal drug treatments.Insert Table 2: Hormone therapy and reactionsImmunotherapyImmunotherapy is a form of treatment that utilises the body’s own response mechanisms. These therapies can be used to either enhance the immune systems response or suppress it. It is useful for many conditions, malignant and non-malignant. The form of immunotherapy we are probably all familiar with is vaccination, where antibodies are stimulated to provide protection against a disease e.g. MMR vaccine. Immunotherapy is also commonly used to treat allergies.Immunotherapy can be divided into two categories: ‘Active’ where the body’s own immune system is stimulated to fight a disease and ‘Passive’, which rely on antibodies  produced in a laboratory to initiate a response to the disease. The majority of immunotherapy agents employed for treatments are specific immunotherapies, where only one type of cell or antigen is targeted while non-specific immunotherapies have a more general effect on the immune system.The most common form of immunotherapy used for cancer treatment is monoclonal antibody (MAb) therapy. MAb’s were originally derived from murine (mouse) cells and were likely to cause allergic reactions in the patient. Since their initial development, the mouse antibody proteins have been replaced by human cells to give chimeric or humanised antibodies depending on the degree of humanisation that has been achieved.  Insert Table 3. Cancer immunotherapySide Effects of MAbs and precautionsCompared to the effects of cancer chemotherapy, the side effects of MAb treatment are low, particularly since the development of chimeric and humanised forms. If side effects do occur are usually mild and associated with allergic reactions that occur during or shortly after the first administration of the agent producing a Type I hypersensitivity reaction. Patients develop symptoms such as fever, chills, itching and skin rashes. In more severe cases they can develop angio-oedema, bronchospasm and hypotension.(11)Patients should be injected while lying on a bed and drugs to relieve anaphylaxis should be at hand. As with all procedures, a full explanation should be provided before administration of the agent and the importance of the patient reporting any unusual sensations or discomfort should be emphasised. Ensure the patient is being observed carefully for any signs of allergic reaction during the administration of the agent.  Manufacturers advice and information is available for all drugs, the staff should familiarise themselves with these and ensure that the patient remains in the department for some time after the drug has been administered. If a reaction does occur, the administration of epinephrine, antihistamines and corticosteroids may be required.(12)Long Term side effectsWhilst the greatest possibility of side effects from MAbs occurs at the time of injection, MAbs can also have side effects that are related to the antigens they target. Avastin targets new blood vessel growth, but this can have long-term repercussions causing bleeding or poor wound healing. MAbs that target epidermal growth factor receptors may cause acne-like skin rashes. With the range of agents increasing staff should familiarise themselves with the possible long term side effects of each agent used in their department. Side Effects of Prostatic BrachytherapySite/Symptom	Time post-implant	Side Effect	TreatmentSkin/perineum	Immediately	Bruising	Pain/Tenderness	Haematoma (rare)	Cleanse gently	Apply ice packUrinary	48-72 hours				7-10 days	(may take 6-10 months to resolve)	Haematuria 			Dysuria	Increase in nocturia	Urinary retention	Urinary Incontinence		Encourage oral fluids/I.V. hydration		Rule out UTI	Urinary catheter for 48hrs	Analgesics	Reduce caffeinated/alcoholic beverages	Decrease liquid intake after 8pmBowel/proctitis	3 – 4 weeks	Soft stools > 3/day	Diarrhoea	‘Gassy’ bowel movements	Painless rectal bleeding	Low residue diet	Loperamide Hydrochloride	Cortisone suppositories		Late proctitis	12 months	Mild intermittent rectal blood on bowel movement	Colonoscopy to rule out colorectal cancer or fistula (rare)Painful Ejaculation		Burning sensation during ejaculation/blood streaked semen	Patient information at time of implant	Reassure patientPassing seed with semen(Rare)	Up to 2 months		Wear condom if patient is worried about this rare possibility.Table 1. Side effects of prostatic brachytherapy (5,7,8)Brachytherapy for treating penile cancerHormone type	Action	Drugs	Side effectsOestrogens	Prostate cancers: Action in males is to inhibit release of luteinising hormone (LH) reducing testicular androgens. Possible direct effect on prostate.	Diethylstilbestrol	Loss of libido, shrinkage of genitalia, gynaecomastia. Anti- oestrogens	Action not fully understood, but binds competitively to oestrogen receptors (ER-positive), possibly reduces amount of free oestrogen	Tamoxifen	Hot flushes, nausea and vomiting have been the most commonly reported symptoms (25% of patients) for both pre and post-menopausal women. Pre-menopausal women also reported amenorrhoea, altered menses. There is a minor increased risk of endometrial cancer.Progesterone	Utilised in breast and endometrial cancers, but exact mechanism unclear although there is thought to be an antioestrogenic effect.	Megastrol	Medroxyprogester-one		Weight gain, fluid retention, vaginal bleeding, amenorrheoa, nausea and thrombophlebitis (1) increased risk of blood clotting (2).Antiandrogens	Prostate cancers. Androgen agonist suppresses testicular and adrenal androgens. (used in combination with LHRH analogues)	Flutamide	Casodex	(1) Hepatotoxicity (monitor during 1st 3 months), gynaecomastia, insomnia, tiredness.	(2) Hot flushes, pruritis, abnormal LFT’s, somnolence, dry mouth, dyspepsia   Luteinising Hormone releasing hormone (LHRH) analogues [Males]	Prostate cancers. LH & Follicle-stimulating hormone (FSH) levels fall (after an initial surge) and the corresponding peripheral androgens & oestrogens decrease.	Zoladex	Initial hormone surge can cause symptoms to increase (tumour flare); this should last no longer than 2 wks.	Hot flushes, gynaecomastia, loss of libido, nausea.	LHRH analogues [Females]	Advanced breast cancers. Has similar action as oopherectomy.	Zoladex	Hot flushes, tumour flare, nausea.Aromatase inhibitors		Endocrine sensitive breast cancers (advanced or recurrent). It exhibits oestrogen depleting effects as it prevents oestrogen synthesis. 	1.  Anastrazole (non-steroidal)	2.  Letrozole	3.  Exemestane (steroidal) 	Hot flushes, osteopenia (higher fracture rate than with tamoxifen), arthralgia (can be severe at first, but improving with time), muscle stiffness, hair thinning.	(3) Sweating & dizziness.Glucocorticoids	(adrenal hormones)	Control carbohydrate & protein metabolism. Cytotoxic properties for acute leukaemias, lymphomas, breast cancers. Reduce cerebral oedema, vomiting, and spinal cord compression 	Naturally occurring: cortisone & hydrocortisone	Synthetic: 1. prednisone 2. prednisolone 	3. dexamethasone	Adrenal insufficiency, fluid retention possibly leading to cardiac failure, round (moon) face, GI upset, increase risk of infections & tissue reactions with associated healing problems, thinning and/or bruising of skin, muscle weakness, psychosis. Table 2.  Hormone therapy and reactions (11,13)Antibody	Name	Type	Target	UsesAlemtuzumab	Campath	humanised	CD52	Chronic lymphocytic leukaemiaBevacizumab	Avastin	humanised	vascular endothelial growth factor	colorectal cancerCetuximab	Erbitux	chimeric	epidermal growth factor receptor	colorectal cancerGemtuzumab ozogamicin	Mylotarg	humanised	CD33	acute myelogenous leukaemia Ibritumomab tiuxetan	Zevalin	murine	CD20	non-Hodgkin lymphoma Panitumumab	Vectibix	human	epidermal growth factor receptor	colorectal cancerRituximab	Rituxan, Mabthera	chimeric	CD20	non-Hodgkin lymphomaTrastuzumab	Herceptin	humanised	ErbB2	breast cancerTable 3. Cancer Immunotherapy (14)(1) Tobias J, Thomas PRM. Current Radiation Oncology. London: Arnold; 1996. (2) Tobias J, Thomas GL editors. Current Radiation Oncology. London: Arnold; 1994. (3) Bensaleh S, Bezak E, Borg M. Review of Mammo-Site brachytherapy: Advantages, disadvantages and clinical outcomes. Acta Oncol 2009 2009;48(4):487-494. (4) Blank LECM, Koedooder K, Van Der Grient HNB, Wolffs NAW, Van De Kar M, Merks JHM, et al. Brachytherapy as part of the multidisciplinary treatment of childhood rhabdomyosarcomas of the orbit. International Journal of Radiation Oncology Biology Physics 2010 01 Aug 2010;77(5):1463-1469. (5) Buron C, Le Vu B, Cosset JM, Pommier P, Peiffert D, Delannes M, et al. Brachytherapy versus prostatectomy in localized prostate cancer: results of a French multicenter prospective medico-economic study. Int J Radiat Oncol Biol Phys 2007;67(3):812-822. (6) Witt MEAOCN, Haas MCNS, A.N.P.C., Marrinan, Marie A. MSN,A.P.N., A.O.C.N., Brown CNCS, A.O.C.N. Understanding Stereotactic Radiosurgery for Intracranial Tumors, Seed Implants for Prostate Cancer, and Intravascular Brachytherapy for Cardiac Restenosis. Cancer Nurs 2003 December;26(6):494-502. (7) Schlegel W, Bortfeld T, Grosu A- editors. New Technologies in Radiation Oncology. Heidelberg: Springer; 2006. (8) McLaren D. Kidney, bladder, prostate, testis, urethra, penis. In: Bomford CK, Kunkler IH, editors. Walter and Miller's Textbook of Radiotherapy. 6th ed. London: Churchill Livingstone; 2003. p. 487. (9) Viani GA, Pellizzon AC, Guimaraes FS, Jacinto AA, Dos Santos Novaes PER, Salvajoli JV. High dose rate and external beam radiotherapy in locally advanced prostate cancer. American Journal of Clinical Oncology: Cancer Clinical Trials 2009 April 2009;32(2):187-190. (10) Stewart AJ, Viswanathan AN. Current Controversies in High-Dose-Rate versus Low-Dose-Rate Brachytherapy for Cervical Cancer. Cancer 2006;107(5). (11) Tobias J, Hochhauser D. Cancer and its Management. 6th ed. Oxford: Wiley-Blackwell; 2010. (12) Carney PH, Ollom CL. Infusion reactions triggered by monoclonal antibodies treating solid tumours. J Infus Nurs 2008;31(2):74-83. (13) Drugs.com. 2011; Available at: www.drugs.com. Accessed 08/27, 2011. (14) Waldmann TA. Immunotherapy: past, present and future. Nature Medicine 2003;9(3):269-277. 

Radiotherapy-related Treatment Reactions: Brachytherapy Reactions

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