Continuing Education Activity

Radiotherapy causes DNA break and subsequent cell death. This affects the cancer cells more severely than the normal cells. However, with the growing number of patients receiving chemotherapy, providers come across patients who develop side effects of radiotherapy. Early recognition and prompt management of the acute side effects can prevent the persistence of these effects in the long term. This activity reviews the evaluation and treatment of radiation toxicity in different cancers and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Review the pathophysiology and common side effects of radiation therapy.
• Outline strategies for the treatment of radiotherapy side effects.
• Describe the importance of careful patient selection and tailored radiotherapy regimen to minimize complications.
• Explain the importance of monitoring the development of late side effects in long term radiotherapy survivors.

Introduction

Overall, cancer rates are projected to increase from approximately 9 million in 2017 to approximately 26 million new cancer cases by 2030.[1][2] About 30% to 50% of all cancer patients receive irradiation either alone or with chemotherapy and surgery.[3] Therefore, around 7 million patients receive radiotherapy worldwide every year. Improved cure rates of all malignancies have resulted in more providers being confronted with a large number of patients with a wide range of chronic morbidities in long term survivors. Hence all providers must be aware of the common adverse effects of radiation therapy.

Side effects of radiotherapy are classified as acute (early), consequential, or late effects on normal tissues over time. Acute radiation toxicity is seen within a few weeks after treatment and usually involves intermitotic cells (skin and mucosa). Consequential effects are seen when acute complications are not treated and cause persistent damage.[4] Late complications emerge months to years after exposure and usually involve postmitotic cells (liver, kidney, heart, muscle, and bone). This chapter briefly outlines a review of common complications of radiotherapy.

Function

Ionizing radiations generate free radicles, which subsequently damage vital cellular components and lead to double-stranded DNA breaks (DSBs), resulting in chromosomal aberrations and rearrangements. These lethally damaged cells may continue to divide a limited number of times before undergoing mitotic or apoptotic cell death, explaining the latency of acute side effects. Normal cells can repair DNA breaks better than tumor cells.[5] Some cells undergo apoptosis due to the resulting damage, and some cells die during mitosis due to improperly repaired chromosomal damage.[6] Certain cell types, especially spermatogonia, serous cells in the salivary gland, and lymphocytes, undergo apoptosis during interphase after irradiation.[7][8] Some stem cells differentiate in response to irradiation and leave the reproductive pool, as seen in fibroblasts, which results in excessive fibrosis and scarring.[9] Moreover, irradiation activates various cellular signaling pathways, which lead to expression and activation of proinflammatory, profibrotic cytokines, coagulation cascade, and vascular injury.[10][11][12][13][14] These changes contribute to edema, inflammatory responses, erythema in the skin, increased intracranial pressure in the central nervous system, and lung fibrosis. Moreover, some DSBs affecting cell cycle signaling and tumor suppressor genes can promote malignant transformation and subsequent malignancies 10-20 years after radiotherapy. Since radiotherapy requires oxygen-free radicles, it's essential to ensure adequate oxygen delivery to the tumor before radiotherapy e.g., treatment of anemia before radiotherapy.

Issues of Concern

Acute radiation damage predominantly involves rapidly proliferating cells, e.g., epithelial surfaces of the skin or digestive tract. Radiation damages the stem cells, which manifests when tissues are lost as part of normal cell turnover, but there is inadequate replacement by stem cells due to radiation damage.[6] This results in a break in the protective barrier - commonly in the skin, oral mucosa, and gastrointestinal tract, especially 1-5 years within the completion of radiotherapy. Subsequently, compensatory hyperplasia within stem cells results in recovery. Therefore, symptoms resolve over a few weeks. When acute damage fails to heal completely and persists into the late period, such lesions are consequential late effects. Such effects are more commonly seen in regimens that involve chemotherapy in combination with radiotherapy, where tissues fail to repair due to concomitant cytotoxic effects from chemotherapy.

Late complications occur in tissues with slow turnover, e.g., brain, kidney, liver, the wall of the intestine, subcutaneous tissue, fatty tissue, and muscle. Consequences of radiation in such tissues include fibrosis, atrophy, necrosis, and vascular damage - telangiectasia and carcinogenesis. Late effects are a result of a complex interplay of various cytokines and adaptive cellular processes. Damage to vasculature results in increased permeability and subsequent release of vasoactive cytokines, TGF-beta, and fibrin, promoting collagen deposition. Most of these tissues or organs have a threshold dose above which late effects increase.[15][16] 

Leucocyte adhesion to damaged endothelial cells results in the formation of thrombi and subsequent distal ischemia, which results in distal atrophy and necrosis. Further cell loss may perpetuate the cytokine storm and dysregulated cellular interactions. The type of cytokines released depends on the tissue type and is responsible for the differential response of tissues to irradiation. e.g., the predominant response in the lungs is fibrosis, while in the brain, the predominant response is necrosis.[15][17]

Radiation injury results from an interplay of radiobiologic factors, intrinsic radiosensitivity, the volume of tissue or organ irradiated, total dose, dose per fraction, the severity of acute effects, and combination with surgery and chemotherapy.[18][19][20][4] The terms minimal tolerance dose (TD 5/5) and maximum tolerated dose (TD 50/5) refer to the dose at which severe life-threatening complications occur in 5% and 50% of the recipients within five years of radiotherapy.[21] Experimental evidence suggests that fraction size is the dominant factor in determining late effects.[20][22] Host related factors that influence the risk of late sequelae are old age, BMI, anemia, associated infection, comorbid conditions, concomitant chemotherapy regimens, and intrinsic radiosensitivity of organs at risk.

Clinical Significance

All tissues have variable sensitivity and response to radiation injury. Common sites of irritation and their associated complications are described here:

Head and Neck

Skin and Mucosa - Acute response involves erythema, inflammation, and desquamation of dry and moist surfaces, which manifest as mucositis, pruritis, hypersensitivity, pain, ulcers in the mucosa.[23] If mucositis is severe, it can result in feeding difficulty and necessitate a feeding tube. These acute reactions usually start healing towards the end of treatment or may progress to consequential effects. Other reactions seen as later complications include alopecia, telangiectasia, fibrosis of the masticator muscles resulting in trismus, alterations in taste sensations, and dysphagia. Skin and muscle fibrosis leads to trismus in 5-10% of patients. Severe mucositis with head and neck cancers is associated with feeding difficulties compounded by cancer cachexia, impairs healing, and response to stress. Management of severe mucositis is scrupulous oral hygiene, topical analgesics, dietary modification, opioid analgesics, doxepin rinses, antacid+diphenhydramine mouthwash (aka miracle mouthwash), mucoadhesive hydrogel, and enteral tube feeding in severe cases. 

Salivary Glands - Salivary gland irradiation may result in cell death by apoptosis, manifesting as swelling and tenderness after the first dose of treatment, progressing to xerostomia and subsequent severe dental caries and osteonecrosis, difficulty wearing dentures, eating and speech difficulties. Recovery of salivary gland function, if occurs, takes months or years.[24] Management of xerostomia complications includes appropriate oral hygiene and dental care with fluoride treatment, chlorhexidine rinses, and regular follow up with a dentist. 

Nervous System - Acute effects or cranial irradiation include fatigue, loss of appetite, nausea, vomiting, headaches, hearing loss, acute encephalopathy (rare), and worsening neurologic symptoms (due to edema of the irradiated tumor and surrounding tissues). Long-term neurologic sequelae can be persistent fatigue, neurocognitive effects, cerebrovascular disease, neuroendocrine dysfunction, and secondary malignancies.[25][26][27] Spinal cord irradiation can result in acute transient myelopathy due to demyelination manifesting as Lhermitte syndrome. Late effects include lower motor neuron syndrome, telangiectasias, and subsequent hemorrhage.[28] progressive myelopathy, which results in variable irreversible neurologic deficit ranging from minor sensory symptoms to complete paraplegia. Experimental studies and anecdotal evidence supports the use of glucocorticoids, hyperbaric oxygen, or bevacizumab to treat radiation myelopathy, which may result in partial recovery.[29][30][31][29]

Thorax - Breast, lung, esophageal, and lymphatic system cancers are frequently treated with irradiation as part of the treatment regimen.

Lung - Early phase clinical effects of lung irradiation include congestion, cough, dyspnea, fever, and chest pain caused by radiation pneumonitis. Radiographic studies reveal infiltrates within the irradiated field. Severe cases result in hypoxia and subsequent right-sided heart failure. Partial irradiation on the lung may occasionally induce bilateral immune-mediated pneumonitis that generally resolves without treatment.[32] The natural course of pneumonitis is either a gradual resolution of the acute phase followed by a chronic phase causing inflammation and fibrosis, which develops over months to years. The degree of fibrosis is proportional to the area irradiated; hence if a large area is irradiated, the patient may develop restrictive lung disease presenting with cough, shortness of breath, chest discomfort, and a significant reduction of diffusion capacity and respiratory volume.[33] As presentation is similar to tumor recurrence, a  PET scan differentiates a tumor from radiation injury. Management of early radiation pneumonitis includes an appropriate assessment to rule out other causes of acute respiratory distress and the use of systemic steroids with gradual taper.

Heart - Radiation injury to the heart can manifest as acute pericarditis, pericardial effusion, constrictive pericarditis, valvular dysfunction, conductive system dysfunction, and myocardial fibrosis.[34] Radiation therapy increases the risk of ischemic heart disease by causing myocardial microvascular disease or macrovascular coronary artery stenosis.[35][36] The vast majority of the acute morbidity is related to concomitant use of chemotherapy and hormonal therapy; therefore, individualized treatment plans help minimize the risk of acute cardiac effects. Myocardial nuclear imaging studies before radiation therapy(RT) can aid in risk stratification and guide radiotherapy dosing and technique. Long term effects of radiation cardiotoxicity manifest approximately ten years after RT and contribute to high mortality in younger women diagnosed with breast cancers.[37]

Abdomen and Pelvis

Gastrointestinal System - Acute radiation toxicity presents as anorexia, nausea, vomiting, abdominal cramps, and diarrhea about 2-3 weeks after radiation therapy. Radiation injury to the large bowel presents with large volume watery diarrhea. Chronic effects include chronic diarrhea, malabsorption, recurrent bouts of ileus or obstruction, proliferative mucosal telangiectasias, or ulceration. The rectum is the most commonly affected normal tissue in radiotherapy for prostate and cervical cancer. Symptoms of acute radiation injury are diarrhea, increased mucus secretion, and tenesmus due to loss of mucosal epithelium. Long term complications are increased stool frequency, urgency, rectal bleeding, pain, variable degrees of incontinence and strictures, and fistula formation.[38] Treatment strategies include oral anti-inflammatory agents, analgesics, stool softeners, steroid enema, blood transfusions (for bleeding), and mechanical dilatation of strictures. For severe or refractory complications, hyperbaric oxygen, endoscopic or surgical intervention involving colostomy may be necessary.[39]

Urinary Tract - RT can cause varying degrees of irritation and functional impairment of bladder transitional epithelium and mucosa. Acute presentation varies from mild dysuria, increased frequency, urgency, microscopic hematuria to urinary incontinence, gross hematuria, and bladder necrosis.[40] Chronic effects include detrusor dysfunction, urge incontinence, hydronephrosis, mucosal ulceration, and fistula formation.[40] Treatment is symptomatic with pain management, anticholinergics or antispasmodics, cranberry juice, hyperbaric oxygen, or surgical interventions for late complications.

Gonads - Irradiation to ovaries leads to infertility or premature ovarian failure even at low doses with increased sensitivity with advancing age. Women under 40 with a strong desire to preserve fertility, ovarian transposition procedure can reduce the risk of irradiation. The long term management is a hormone replacement therapy for menopausal symptoms. Radiotherapy may result in impotence and testicular dysfunction in males. Patients undergoing radiotherapy should be offered sperm or egg cryopreservation options before undergoing RT.

Cervicitis and Vaginitis - Acute symptoms of mucositis include erythema, ulceration, exudative changes, serous discharge, and increased predisposition to infection. Full-thickness ulceration may be seen with brachytherapy for cervical cancers. Late side effects include fistulas (rectovaginal or rectovesical), vaginal stenosis, and vaginismus. Treatment is conservative for mild symptoms; persistent non-healing mucositis, ulcers, or fistulas can be treated with hyperbaric oxygen or pentoxifylline [41][42], and mechanical dilatation for vaginal stenosis.[41]

Miscellaneous - Radiation-induced lymphedema causes local swelling and obstructive symptoms. Treatment is usually patient-directed, including physiotherapy, limb elevation, compression therapy, manual lymphatic drainage, or complete decongestive therapy and intermittent pneumatic compression in severe cases.[43][44]

Other Issues

Radiation induces secondary malignancies - absolute risk ranges between 0.2% to 1% per year in cancer survivors after radiotherapy. There is a bimodal distribution of RISMs in relation to occurrence after radiotherapy. The first peak is within three years of radiation exposure, predominantly driven by hematological malignancies like acute leukemias. The second peak, seen over ten years after therapy, is driven primarily by solid malignancies.[45]

Primary Cancers and Their Associated Secondary Malignancies

• Hodgkin's disease - Breast, lung, thyroid, stomach
• Breast - Lung, leukemia, opposite breast
• Testis- Leukemia, lymphoma, pelvic malignancy, bone, and soft tissue sarcoma
• Cervix - Bladder, rectum, leukemia, sarcoma
• Childhood cancers - Thyroid, breast, leukemia, sarcoma

Enhancing Healthcare Team Outcomes

Radiotherapy is the single most effective non-surgical treatment of cancer.[46] In terms of overall cost, RT consumes only 5% of total spending for cancer care while forming a significant part of the treatment plan for ~40% of patients and is responsible for a cure in ~16%.[46] There has been huge progress in the field to improve effectiveness and minimize side effects. Some techniques that can be used to reduce side effects are 

1. Stereotactic Surgery (SRS) and Stereotactic Body Radiation Therapy (SBRT): Single fraction treatment (SRS) or multifunctional (SBRT) administration of high dose radiation to particular target areas from multiple directions to maximize dose delivery at highly specific points helps reduce exposure to surrounding normal tissues. Commonly utilized in intracranial, spinal, or extracranial sites in sensitive tissues(e.g., lungs, pancreas, head and neck cancers)
2. Brachytherapy: Radiation source is placed inside the tissue or next to the target area and slowly emits radiation, which is active only for a short distance. Commonly utilized for prostate cancer and gynecological malignancies.
3. Fractionation: Delivers radiation in multiple fractions allows time for normal tissues to repair before the next dose of radiation. Experimental evidence suggests that fraction size is the dominant factor in determining late effects.[20][22] Therefore, hyperfractionated radiotherapy - where the number of fractions is increased, and the dose per session is reduced can reduce late complications without affecting local tumor control. 
4. Image-Guided Radiotherapy and Intensity-Modulated Radiation Therapy: Utilizes real-time imaging for precise sculpting of dose distribution to guide external beam therapy to avoid irradiation of sensitive tissues deliberately.
5. Targeted Radionuclide Therapy: Employs radionuclides that decay within the body at target tissues without accumulating in the normal tissues. Examples include radioisotopes of Iodine 131 for thyroid cancer treatment, Radium-223 for bone metastases, radionuclide linked anti-CD20 monoclonal antibodies for leukemia, lymphomas, and radionuclides embedded in resin microspheres for direct intraarterial embolization of tumors in use of liver cancers.
6. Intra-Operative Radiation Therapy: Intraoperative delivery of high dose targeted radiation therapy based on clinical and frozen-section pathology results to identify areas at increased risk of local recurrence with appropriate shielding maximizes the dose of radiation to target tissue and limits exposure to surrounding normal tissues.

Modification of techniques of therapeutic irradiation can play an essential role in reducing complications and enhancing local tumor control. Careful planning for radiotherapy considers likely patterns of locoregional tumor spread, uncertainties in positioning the patient for each treatment, tumor and organ movement during therapy and between treatment, tumor, and local tissue sensitivity helps to determine the appropriate irradiation dose, treatment intervals, and technique. Combined chemoradiation leads to prolonged mucosal, gastrointestinal, and urinary toxicities.[19] Acute toxicity can be mitigated by fractionation, reduction in a dose per fraction, the increasing gap between fractions and use of radioprotectors, and growth factors in the acute phase[47], while chronic side effects can be minimized by decreasing exposure to radiosensitive tissues.

The use of appropriate tools to classify and measure toxicities can help guide treatment strategies and guidelines for radiotherapy in individual cancer treatments.

• Identify patients at a higher risk of radiation toxicity- e.g., patients with active collagen vascular disease, inflammatory bowel disease, and atherosclerotic vascular diseases.
• Use of predictive factors of clinical radiosensitivity - e.g., age, BMI.[48]
• Cancer-specific predictive biomarkers may help identify individual curves or subsets to determine the appropriate dosing regimen.[49][50]

Coordination of care by a surgical and medical oncologist, pathologist, radiotherapist, and interdisciplinary care team consisting of oncology and radiotherapy trained nurses and PCAs, psychiatrists, neurologists, pharmacists, nutritionist, and pain management services to make an individualized patient-centered care plan can significantly reduce toxicity and improve long term quality of life for cancer survivors.

Nursing, Allied Health, and Interprofessional Team Interventions

Nursing interventions and patient education play an essential role in reducing the side effects of radiotherapy. Specific strategies that can be useful include

1. Identification of patients at risk of complications and initiation of appropriate therapy (low BMI increases the risk of diarrhea while high BMI patients are at greater risk of skin and mucosal complications).[51][52]
2. Oral hygiene instruction for all patients receiving head and neck irradiation. Consultation with a dentist and treatment of periodontal disease before radiotherapy can minimize the risk of jaw osteoradionecrosis. Use of bland rinses, cryotherapy, mucosal protective agents, antiseptic mouthwashes, topical analgesics, and anti-inflammatory agents or growth factors as necessary. Regular assessment and monitoring of high-risk patients can reduce long term sequala in these patients and improve the overall quality of life. Dietary modifications that alleviate symptoms include avoiding spicy or acidic foods, caffeine, alcoholic beverages, alcohol-containing mouthwashes, and sharp foods (e.g., chips, popcorn).
3. Nutritional assessment and dietary consult can improve the healing of damaged tissues. It is especially important in patients with cancer cachexia compounded by radiotherapy associated fatigue, loss of appetite, alterations in taste sensations, and mucositis.
4. Wound care interventions for skin ulcers with hydrocolloid dressings and regular cleaning and hyperbaric oxygen therapy for refractory cases.
5. The use of probiotics reduces radiation enteritis symptoms, and dietary modifications such as a low-residue diet with no grease, spices, and adequate fiber intake can reduce symptoms of proctitis. 
6. Vaginitis douches with dilute hydrogen peroxide use for cleaning and prevention of infection following pelvic irradiation.
7. Smoking cessation is a critical intervention to reduce the risk of secondary lung cancer in patients who receive mediastinal radiotherapy for Hodgkin disease. Some studies suggest up to a 20-fold increase in risk compared to non-smokers.[53]