Introduction

Radiation therapy (RT) is one of the primary modalities for treating malignant diseases and is used in both curative and palliative settings for almost all solid tumors. Commonly combined with surgery, cytotoxic chemotherapy, and immunotherapy, RT is part of first-line cancer treatment in >30% of patients in the United States,1 and approximately one-half of all patients with cancer will receive RT during their care.2 An understanding of RT toxicities is pertinent to oncologists, primary care physicians, and other clinicians engaged in cancer treatment, supportive management, and survivorship care. Here, we review the side effects (expected and unexpected) of therapeutic radiation. Of note, there is a separate, broad class of radiation injury secondary to whole-body irradiation from nuclear accidents/weapons termed “acute radiation syndrome.” A detailed discussion is beyond the scope of this article, but these include central nervous system (CNS) syndrome (within days at high doses from >20 to 30 Grays [Gy] [1 Gy = 100 rads], gastrointestinal syndrome (within weeks at moderate doses from >5 to 8 Gy), and hematopoietic syndrome (within months at low doses from >1 to 2 Gy).

The mechanism of cell killing from radiation is not selective for tumor cells, and optimal delivery of RT is a balance between maximization of tumor dose and minimization of normal tissue dose. Thus the study of radiation toxicity is a core component of radiation oncology training, and practices are guided by an extensive and evolving literature on factors associated with toxicity probability.3, 4 The study of radiation toxicity is also pertinent to nuclear medicine and the evolving field of “theranostics,” in which radionuclides linked to targeting agents have both diagnostic and therapeutic utility, although dosimetric studies on efficacy and toxicity have been limited.5, 6

Modern advances in external-beam RT delivery, including intensity-modulated RT (IMRT), stereotactic RT (stereotactic radiosurgery [SRS] and stereotactic body RT [SBRT]), image-guided (eg, magnetic resonance imaging [MRI]-guided or computed tomography [CT]-guided) brachytherapy, and particle therapy (eg, protons), allow clinicians to spare organs better while selectively targeting tumor-containing regions. Optimal patient positioning and organ/tumor motion management are also critical to maximize the therapeutic ratio of high-precision RT. Toxicity, nonetheless, is common and results from higher RT doses, along with combined effects of other cancer treatments and baseline organ dysfunction. General approaches to some of the more common RT effects are briefly reviewed in Table 1.

TABLE 1. Common Management Considerations Toxicity Timing Management Skin, connective tissues, and breast Dermatitis Acute Dry and avoid irritation; steroid creams (for high risk: mometasone 0.1% bid from RT start), aloe, corn starch, nystatin powder; adhesive silicone, silver sulfadiazine, opiates for severe moist desquamation Fibrosis Late Pentoxifylline (400 mg bid-tid) and vitamin E (400 IU qd) for 6 mo starting 2-4 wk after RT (eg, for RT after postmastectomy reconstruction) Lymphedema Late Physical therapy (manual lymphatic drainage), compression devices/garments, complete decongestive therapy Bone pain flare Acute Dexamethasone 2-8 mg qd for 3-5 d at/before RT or prn for painful bone metastases, depending on expected/observed severity CNS CNS edema/radiation necrosis Both Dexamethasone 2-16 mg qd for ≥1-4 wk based on severity, with GI prophylaxis and steroid taper for longer courses; bevacizumab/surgery for refractory necrosis Cognitive Late Before RT: Memantine 5-10 mg qd, increasing to 20 mg by 4 wk, total 24 wk; after RT: donepezil 5 mg qd for 6 wk, 10 mg qd for 18 wk Head and neck Mucositis Acute Salt and baking soda/hydrogen peroxide rinse or other mouthwash containing lidocaine, diphenhydramine, antacid, and/or nystatin; opiates if severe and affecting nutrition, with long-acting (transdermal preferred) and breakthrough Xerostomia Both Xylitol-containing candies/gums, saliva substitutes, and mouthwashes Dentition/osteoradionecrosis Late Fluoride trays for routine care; pentoxifylline and vitamin E +/− clodronate, antibiotics, and prednisone for conservative management of osteoradionecrosis Fibrosis (dysphagia, jaw, neck) Late Speech/language pathologist for dysphagia, jaw physical therapy for trismus, massage therapy for neck stiffness/lymphedema, acupuncture for pain Lung Pneumonitis Late Prednisone 40-60 mg qd for 2-4 wk, tapering over 4-8 wk total, depending on severity and comorbidities, with GI prophylaxis Heart Pericarditis Acute NSAIDs, eg, ibuprofen 200-800 mg tid prn for 1-2 wk Gastrointestinal Esophagitis Acute Soft/liquid diet; antacids, viscous lidocaine (before swallowing), and/or opiates (before meals); fluconazole for empiric treatment of candida esophagitis Nausea Acute Antacids, prn ondansetron or prochlorperazine (both tid and alternating if severe) Gastritis/ulceration Both Avoid gastric irritants; antacids and prolonged course of proton pump inhibitors; formalin for refractory bleeding, coagulation if severe Enteritis Both Low fiber/residue/fat diet; loperamide (qd/bid prn) and/or diphenoxylate/atropine; subcutaneous octreotide (100 µg tid for 3-5 d) if refractory with dehydration Proctitis Both Steroid creams; for late hematochezia, sucralfate enema, formalin, and coagulation Genitourinary Obstructive urinary symptoms Both Avoid fluids before sleep, minimize caffeine and alcohol; α-blockers (eg initiate/increase tamsulosin dose for 3-6 mo after RT); steroids if severe Cystitis Both Rule out urinary tract infection; phenazopyridine for dysuria; antimuscarinics (eg, oxybutynin, solifenacin) for severe frequency, urge incontinence, and/or bladder spasms Sexual Female Late Topical estrogens, regular vaginal dilator usage, pelvic floor physical therapy Male Late Phosphodiesterase inhibitors (eg, sildenafil), vacuum devices, urologic interventions Abbreviations: +/−, with or without; bid, twice daily; GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; prn, as needed; qd, once daily; RT, radiation therapy; tid, 3 times daily. a Note: This table describes general approaches to select commonly-encountered RT effects; treatment of actual patients should always be individualized. Pathophysiology of Radiation Injury

Mechanisms of radiation injury are summarized in Figure 1. In brief, ionizing radiation directly or indirectly (via reactive oxygen species) damages DNA, prompting a cascade of events that may lead to cell death. The degree of cell killing and resistance varies based on properties such as degree of differentiation and mitotic rate, and also cumulative and fractional radiation dose.7

Pathophysiology of Radiation Effects on Normal Tissue. Ionizing radiation initiates its effects by damaging DNA, prompting a cascade of events potentially leading to toxicity (clinical manifestations of toxicity are indicated with red text). Acute effects are usually inflammatory or reflect epithelial depopulation/repopulation. Late effects often reflect fibrosis, vascular injury, or gradual parenchymal injury, which may decrease global organ function.

RT side effects are categorized as acute, subacute, or late. Acute effects begin within 1 or 2 weeks after starting RT and often are inflammatory or reflect the depopulation of rapidly growing epithelial cells. Timing of symptoms relates to turnover and transit time for normal tissue stem cells to repopulate damaged tissue; patients finishing RT are counseled that acute side effects may continue to worsen before recovery. Late effects often reflect fibrosis, vascular injury, or other gradual changes in slowly dividing tissues, with end-organ damage possibly manifesting years after treatment. Residual DNA damage may rarely cause delayed carcinogenesis.

Because RT is a locoregional treatment, anatomic properties of affected organs and tissues influence the pathogenesis and clinical presentation of toxicity. Organs can be considered to consist of functional units arranged either in parallel (eg, liver and lung) or in series (eg, esophagus and nerve), each with characteristic pathways to toxicity (Fig. 2).3

Parallel Versus Serial Organ Architecture, the Liver as a Model. Parallel organs are sensitive to the percentage volume receiving radiation (and thus the amount of functioning parenchyma remaining) but can tolerate high doses to small areas. The reverse is generally true for serial organs in which damage to one segment can affect total organ function.

Skin, Connective Tissues, and Breast Radiation Dermatitis

Skin, bone, and soft tissue receive significant radiation exposure in most treatment settings. Major late cutaneous toxicity is infrequent because of the physical properties of high-energy x-rays that preferentially spare superficial tissues. Radiation dermatitis (akin to a temporary sunburn), however, is common and expected in the treatment of head and neck, vulvar, anal, skin, extremity (eg, sarcoma), and breast cancers. Effects are caused by cutaneous epithelial depopulation, with symptoms ranging from self-limited erythema to painful moist desquamation. Much of the literature is derived from breast cancer (in which RT is used with lumpectomy for breast conservation or for high-risk features after mastectomy).8 Risk is highest in the postmastectomy setting (approximately 20%-40% grade 2-3 moist desquamation), in which skin is intended to receive a higher dose, and in large-breasted women. Skin folds (eg, inframammary fold, groins, perineum) are particularly susceptible. Management is similar in all clinical situations, with general skin care including cleansing and avoidance of irritation. Steroid creams (eg, mometasone) were found in a randomized trial to decrease moist desquamation by approximately one-third.9 Adhesive silicone dressings and silver sulfadiazine are also effective in decreasing and managing moist desquamation, with a low threshold to supplement with topical antifungals because concurrent yeast infection is common.10, 11 Opiate pain medications should be prescribed in moderate-to-severe cases, as symptoms may worsen for 1 or 2 weeks after RT before quickly improving.

Soft Tissue Fibrosis and Breast Cosmesis

In clinical situations similar to radiation dermatitis, subcutaneous soft tissue can develop late fibrosis from high-dose RT, akin to wound healing after surgery and exacerbated by treatment with any combination of surgery, RT, and/or chemotherapy.12 Although usually subclinical, tissue hardening may produce pain and limitation of motion. Effects are caused by inflammation and acute injury, leading to fibroblast proliferation and increased extracellular matrix deposition, along with vascular insufficiency.

Fibrosis may adversely affect breast cosmesis, although >80% to 85% of women receiving breast conservation (lumpectomy and RT) report good or excellent cosmetic results.13 Patients who require RT after mastectomy with reconstruction are at higher risk of suboptimal cosmesis. Outcomes vary based on reconstruction type and timing (immediate at surgery or delayed after RT), although evidence is conflicting.14, 15 With implant-based reconstruction, fibrosis may lead to capsular contracture and implant failure in 15% to 30% of patients.16 With autologous graft reconstruction, both fibrosis and vascular insufficiency may lead to impaired wound healing, infection, fat necrosis, and graft failure.17 A 6-month course of pentoxifylline and vitamin E (a combination that decreases blood viscosity and inflammation) may be prescribed after RT to lower the risk of fibrosis and improve tissue healing/compliance after RT.18, 19

Lymphedema

Lymphedema can be a management problem for any peripheral tumor site requiring nodal management (eg, axilla for breast cancer, groin for vulvar cancer, and both axilla and groin for extremity melanoma) and occurs because of impaired lymphatic drainage from fibrosis and/or direct nodal removal. Symptoms include swelling, pain, and limited range of motion, which may develop immediately or in months to years.

Lymphedema has been best studied in breast cancer, in which evaluation of the axilla is necessary for most patients planned for curative treatment. Severity and risk relate to the degree of surgery (sentinel lymph node biopsy vs axillary lymph node dissection) and radiation (breast-only RT vs nodal RT). Risk ranges from 5% after sentinel lymph node sampling with or without RT to approximately 20% to 30% after full axillary lymph node dissection followed by comprehensive regional nodal RT.20, 21 Because lymphedema may be irreversible, early detection is important to prevent or delay symptoms. Physical therapy (including manual lymphatic drainage) and compression are the initial management. Complete decongestive therapy is most effective but is a rigorous regimen incorporating manual drainage, compression, skin care, and exercises. Novel surgical techniques involving lymphatic bypass and lymph node transfer have been investigated with promising results.22

Bone

Acute effects on bone include hematologic suppression (discussed separately) and inflammation. Palliative RT for bone metastases may cause an acute “pain flare,” which reflects the release of inflammatory cytokines and tumor response rather than direct RT effects. Steroids are effective for both prophylaxis of RT-associated pain flare and treatment of baseline tumor-associated bone pain. A phase 3 trial showed that pain flare occurred in 26% versus 35% of patients receiving dexamethasone versus placebo, but steroids occasionally caused hyperglycemia.23

Late skeletal effects of RT are most pertinent in children, who may develop deformities because of impaired/asymmetric bone growth.24 Demineralization and osteoporosis may increase the risk of symptomatic fracture, especially of the ribs, femur, and pelvis, although most heal with conservative management. Pelvic insufficiency fractures are more common in females, the elderly, and others with low body mass index or bone density. A population analysis found a 2% to 8% absolute increase in 5-year pelvic fracture risk in patients with pelvic malignancies who received versus did not receive pelvic RT.25, 26 Vertebral body fractures may occur weeks to months after RT for spine metastases (with a slightly higher, 10%-15% risk at 3-12 months with SBRT, which however has the advantage of better tumor control). These tend to be subacute rather than late, with a major contribution from destabilization from tumor cell death, although the risk from tumor progression outweighs that attributed to RT.27

Central Nervous System Acute Effects

RT is frequently used in the treatment of neoplasms in or near the brain and spinal cord, including benign brain tumors, malignant gliomas, ocular/CNS lymphoma, and metastases. SRS is preferred for brain metastases (except when extensive), but whole-brain RT (WBRT) is routinely used for certain settings and histologies (eg, hematologic malignancies and small cell lung cancer) and where SRS capabilities are unavailable. Acute toxicity most often includes fatigue, which is poorly understood but experienced in all RT settings and increases with treatment volume.28 Patients receiving WBRT can also develop mild-to-moderate acute dry mouth and dry eye from dose to the parotid and lacrimal gland, respectively.29, 30 Patients receiving cranial RT occasionally experience headache, nausea/vomiting, and other signs of increased intracranial pressure from generalized edema. Treatment of these and many other acute/subacute inflammatory radiation side effects often involves use of dexamethasone. Surgical decompression is used for extreme situations. Depending on the primary pathology, patients may have mild-to-severe focal neurologic deficits and, rarely, neurologic events like stroke and seizure (data are lacking, but likely <1%).

Neurocognitive

Neurocognitive changes are a well known potential late effect of CNS irradiation and manifests from months to years after treatment, depending on RT dose and volume of irradiated brain. In pediatric patients, cranial RT to developing brain tissue is associated with worse IQ and psychological health.31 In adults, neurocognitive RT effects have been best studied after WBRT, although assessment may be confounded by age, treatment, and disease-related factors. Effects are at least partly because of direct suppression of neuronal stem cells in the hippocampus, an organ implicated in memory formation and whose dysfunction is associated with Alzheimer disease.32 Delayed microvascular changes from vascular endothelial damage may also lead to symptoms mimicking vascular dementia.33 Treatments for those neurologic diagnoses, including memantine and donepezil, may mitigate the neurocognitive effects of cranial RT.34, 35 Recently, hippocampal-sparing WBRT was found to improve both objectively scored and patient-reported neurocognitive outcomes in a large randomized controlled trial, establishing the hippocampus as an “avoidance structure” for cranial RT.36 Patients who require CNS RT and intrathecal chemotherapy/high-dose methotrexate (eg, for CNS lymphoma) may experience severe, progressive leukoencelopathy,37, 38 although risks appear to be minimal with the lower WBRT doses used in most current practice (there was no significant neurotoxicity in one phase 2 trial with 6 years of follow-up).39

Radiation Necrosis

The increasing use of SRS to deliver high-dose, focal RT (while sparing sensitive cranial functional areas and preserving quality of life) has led to increasing recognition of radiation necrosis, which may present months to years after treatment. For patients receiving SRS for metastases, rates of radiation necrosis range from 5% to 20%, depending on factors that include dose and tumor size.40 The etiology is complex, with contributions from CNS edema/inflammation leading to increased intracranial pressure, glial cell injury with neuronal demyelination, and vascular endothelial damage with resultant hypoxia leading to overexpression of vascular-endothelial growth factor (VEGF) and abnormal angiogenesis of small, leaky vessels.40, 41

Patients who develop radiation necrosis may be asymptomatic, with mild radiographic edema, or they may have severe neurologic symptoms with enlarging, ring-like contrast enhancement mimicking tumor progression. Steroids are the treatment of choice for symptomatic patients, with bevacizumab (a VEGF inhibitor) showing some efficacy in patients who are refractory to steroids.42, 43 Patients may require surgery, which may be preferred if underlying tumor progression is suspected. Recent evidence suggests that immunotherapy may increase the risk of radiation necrosis.44, 45 Fractionated SRS (3-5 treatments as opposed to a single treatment) may reduce the risk in this and other high-risk scenarios, as higher radiation dose per fraction tends to produce more late effects.46, 47

Endocrine

Radiation for pituitary adenomas and other skull base tumors, including craniopharyngioma, chondrosarcoma, chordoma, and nasopharyngeal carcinoma, may result in endocrinopathies via effects on the hypothalamic-pituitary axis and may be cumulative with toxicities from surgery or tumor. Effects on the pituitary gland are dose-dependent and age-dependent; growth hormone, prolactin, and thyroid deficiencies appear at doses <30 Gy, with gonadal hormone effects also prominent in children that may affect fertility and onset of puberty.48, 49 At higher doses (eg, >50 Gy), ACTH may be affected, along with more pronounced deficits in the remaining hormones. Up to 50% of patients receiving pituitary-directed radiation may develop endocrinopathies of varying clinical significance, and thus endocrinology consultation is recommended for management.50

Other

Hair loss from follicle stem cell depletion occurs to various degrees in most settings involving cranial RT (especially with WBRT), and the risk of permanent or severe hair loss increases with doses >40 Gy.51 The risk of cataracts is 20% with lens doses of 7 Gy and is >70% with doses >20 Gy.52 There is an age-dependent risk of cerebrovascular disease through late vascular injury, particularly to vessels within the circle of Willis.53

The most severe late toxicities of CNS RT are rare and include complications from high dose to the brainstem,54 radiation myelopathy from high dose to the spinal cord,55 and vision loss from damage to the optic nerve or chiasm.56 Effects are caused predominantly by white-matter damage from glial and vascular injury.57 A rich RT literature exists that has established dose limits for these critical organs; doses below these limits have a very low probability of producing these injuries. For instance, based on several seminal monkey experiments, the spinal cord was shown to be more sensitive to total dose (myelopathy increased at doses >60 Gy) than volume (length) of exposed cord. Tolerance for further irradiation increases over time; the spinal cord can tolerate around 50% more dose a year or more after initial RT.58, 59 Clinical experiences in humans have been consistent with these estimates. To minimize the risk of a particularly severe toxicity to negligible (eg, almost 0%) levels, the universal dose limit for the spinal cord (and, similarly, for the brainstem and optic tracts) has been established at approximately 50 Gy given with conventional dose-fractionation schedules.55

Head and Neck Acute Effects

RT is often used as a primary treatment or with surgery and chemotherapy for head and neck cancers (HNCs) (oral cavity, paranasal sinuses, nasopharynx, oropharynx, and larynx). IMRT is standard of care for HNC, with its ability to spare sensitive anatomy. Patients receiving RT for HNC often experience moderate-to-severe acute mucosal toxicity (correlating with treatment volume and dose) requiring aggressive supportive management. Mucosal epithelial damage leads to progressive, painful mucositis, which is more severe with concurrent platinum-based chemotherapy (which increases the relative risk of grade 3 mucositis by ≥50% in randomized trials).60 Pain management with liquid or transdermal narcotic medications is usually required. A gargle of salt and baking soda or hydrogen peroxide can be useful. Commonly used oral formulations (eg, magic mouthwash, BMX mouthwash, etc) incorporate a combination of lidocaine, diphenhydramine, antacid, and/or nystatin.61 Palifermin (keratinocyte growth factor)62, 63 and doxepin (a tricyclic antidepressant)61, 64 also reduce mucositis severity but are not routinely used. Nutritional status is critical and feeding tubes are sometimes needed; these should be planned in advance of fulminant symptoms to minimize treatment breaks. Other common acute toxicities include nausea and dry mouth with bothersome, thick saliva. Patients may develop loss of taste (dysgeusia) early in treatment because of decreased saliva, blockage of taste receptor pores, and direct damage to taste receptor cells. Small studies suggest that zinc supplementation has a mild protective effect.65

Xerostomia

Xerostomia (dry mouth) is a significant toxicity of head and neck RT that begins during therapy and may improve for up to 1 or 2 years. Xerostomia occurs because of RT-induced apoptosis of acinar cells in the parotid and submandibular glands, with some contribution from minor salivary gland damage. Salivary recovery ranges from complete to minimal and depends on the volume of these organs receiving threshold doses (20-30 Gy for parotid, 30-40 Gy for submandibular glands).66 Patients who require bilateral neck RT are at highest risk. Amifostine (a selective radioprotector) may reduce xerostomia when given during radiation, but its use is challenging because of the requirement for daily intravenous infusion and toxicities, including nausea, vomiting, and hypotension.67 Treatments for xerostomia have limited efficacy. Patients are counseled to use saliva-stimulating candies/gum (containing xylitol), saliva substitutes, and mouthwashes (eg, Biotene) and to carry beverages. Muscarinic cholinergic agonists improve salivary flow but may cause toxicity.68, 69 With modern techniques, it is usually possible to lessen the dose to the salivary glands so that long-term symptoms are mild or moderate.70

Dysphagia

In combination with surgery, chemotherapy, and local tumor destruction, RT may lead to dysphagia and aspiration from damage to the larynx and muscles involved in swallowing (including tongue, pharyngeal constrictors, and epiglottis). Effects are worsened by xerostomia, neck fibrosis, and, rarely, cranial neuropathies (eg, hypoglossal nerve palsy). Some patients need a permanent feeding tube, either from persistent acute dysphagia that fails to recover or from late toxicity. Studies suggest improved outcomes with the use of swallowing exercises; speech language pathologists are critical in management and determining dietary and feeding tube needs.71 Fortunately, severe late dysphagia is less common in patients treated with modern conformal techniques with minimization of radiation dose to the pharyngeal constrictors and larynx.72 Furthermore, treatment de-intensification efforts are changing standard of care for human papillomavirus-associated oropharynx cancer (now the most common variant, and very sensitive to both radiation and chemotherapy) using reduced radiation and chemotherapy intensities to minimize mucositis, xerostomia, and dysphagia while retaining >90% locoregional control rates in prospective trials.73, 74

Dentition

Patients receiving RT for HNC are at risk for dental caries from decreased saliva production and direct demineralization of the enamel and dentine-enamel junction. Pre-RT and post-RT dental evaluations, along with interventions including topical fluoride, are recommended. Uncommonly, hypoxia from decreased blood flow can lead to osteoradionecrosis (approximately 5% risk in the modern era) with exposed and necrotic bone, usually the mandible. Risk factors for osteoradionecrosis include poor baseline oral hygiene, areas of bone receiving high (>60 Gy) dose, and either pre-RT or post-RT dental extractions; it is therefore generally advised to extract only nonrestorable teeth.75 Hyperbaric oxygen has been investigated in both the prophylactic and treatment settings with mixed results76-78 and is recommended only in refractory cases of osteoradionecrosis. One phase 2 trial showed promising efficacy using prolonged pentoxifylline, vitamin E, clodronate, antibiotics, and prednisone with devitalized tissue removal. Of 54 patients with refractory osteoradionecrosis, 62% and 92% had healing by 4 and 12 months, respectively.79 Most patients improve with conservative management.80

Ototoxicity

Cisplatin (with known ototoxicity) is commonly used in the treatment of HNC and, in combination with radiation effects on the middle and inner ear, may lead to hearing loss and tinnitus.81 RT-associated sensorineural hearing loss may worsen over months to years after treatment. The risk increases with RT dose to the cochlea (>30% risk of some degree of hearing loss at doses >45 Gy) because of a combination of vascular insufficiency, neuronal demyelination, and loss of hair cells. Conductive hearing loss may result from damage to middle ear structures (such as the tympanic membrane) or effusion resulting from eustachian tube dysfunction, which is more likely to be reversible. Vestibular deficits, including vertigo and imbalance, may also occur.82

Other

Hypothyroidism is common in patients receiving RT for HNC because of exposure of the thyroid gland, and screening is recommended starting 6 months after RT. Neck RT can lead to increased atherosclerosis of the carotid arteries and slightly increases the risk of stroke in the decades after treatment. Screening ultrasound has been recommended by some starting 3 to 5 years post-RT, as carotid intima thickness may increase by 20% to 40% when receiving high doses.83 Patients receiving RT for sinonasal and nasopharynx cancer are at risk for CNS toxicities, as discussed above. Radiation in combination with neck dissection may lead to neck fibrosis, producing shoulder and neck stiffness, lymphedema, and trismus.84 In severe cases, fibrosis and direct damage to nerves (often in areas with gross disease that receive more intensive treatment) may produce brachial plexopathy,85 which may also occur with apical lung tumors and, rarely, with breast cancer treatment (<2% absent tumor-related factors).86 Physical therapy incorporating jaw exercises and massage/manual drainage are important and are incorporated early in post-RT follow-up. Acupuncture may reduce pain in these settings.87

Lung

RT-induced lung injury is important to consider with treatment for lung and esophageal cancer and other thoracic malignancies, including (to a lesser degree) breast cancer. Lung injury usually manifests as subacute radiation pneumonitis or progressive, late fibrosis, and clinical severity correlates with volume of the irradiated lung. Effects are caused by endothelial damage and congestion o