Chapter 54: Radiation Complications

The ultimate determinant of the efficacy of any anticancer therapy is the therapeutic ratio. The therapeutic ratio for a given dose of radiation therapy (RT) is defined as the ratio of the tumor control rate to the observed normal tissue toxicity. The larger this ratio is, the better tolerated the treatment is at any given dose. Indeed, the “definitive” therapeutic dose for most solid tumors has been determined by the clinically observed radiotolerance of the surrounding normal tissues, not the dose required for tumor sterilization. Therefore, with an understanding of acute and chronic toxicities of radiation, one can potentially improve the therapeutic ratio through effective intervention

Factors Affecting Side-Effect Profile

Clinical:

• The location of the primary tumor and its proximity to critical structures

• The tolerance of the surrounding normal tissue to RT

• The associated use of other modalities of therapy such as surgery or chemotherapy

Physical:

• The arrangement and energy of the radiation beams and the anatomic structures in their path

Biologic:

• The tissue response to RT at the molecular level

• The individual's biological sensitivity to radiation

Radiation Side Effects: Acute and Late Phases

Early or acute side effects

• Largely represent killing of rapidly proliferating cells, such as the epithelial lining of mucosal surfaces, skin, and bone marrow

• Occur during or shortly after RT

• Usually begin 2–3 weeks into RT, increase progressively, and resolve after completion of radiotherapy

• A majority recover without long-term sequelae because of the repopulation of normal stem cells

• The use of concomitant chemotherapy may significantly prolong and worsen acute reactions

Late or chronic side effects

• Probably represents cell loss from microvascular injury (perhaps secondary to endothelial apoptosis) and organ or tissue atrophy. Inflammation is rarely seen unless infection becomes superimposed

• Occur months or years after RT

• Generally progress slowly and are usually irreversible

• Can result in permanent undesirable effects of RT without sacrificing tumor control

Morbidity Scoring

Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0)¹

Tolerance Dose (TD)

• Refers to the normal tissue tolerance of each organ to radiation

• TD 5/5 is the dose that results in a 5% rate of major complications within 5 years after treatment (presumes that RT is given with the conventional fraction size of 1.8–2 Gy/day). TD 50/5 is the dose that results in a 50% rate of major complications within 5 years after treatment

• Attempts have been made to define the TD 5/5 for each organ²

• The defined TD 5/5 should be used only as a guideline and not as an absolute. In the current era of combining chemotherapy and radiation or using altered fractionation schedules, adjustments in the tolerance doses are necessary

Radiation Complications

Skin: Early (Acute) Side Effects

Presentation

1. Seen as early as 7–10 days after starting RT

2. Clinical characteristics include erythema (as early as the second week) → increased dryness → hyperpigmentation → loss of hair (epilation) → dry desquamation at 4–5 weeks

3. Moist (wet) desquamation is seen 5–7 days after dry desquamation with continuation of RT dose

4. Important to rule out infection (cellulitis). Examine the patient carefully for any signs of lymphangitic streaking and a careful examination of regional nodal stations must be performed

5. The patient should be questioned about the presence of any pain or pruritus

Management

1. Erythema, dryness, hyperpigmentation, and epilation

   General

   • Avoid topical products on the skin within the RT portal during radiation delivery

   • When topical products, such as Eucerin Original Moisturizing Lotion or Keri Original Moisture Therapy lotion are used, they must be washed off prior to delivery of radiotherapy

   • Avoid shaving, if possible

   • Specifically avoid any topical products containing metals (silver sulfadiazine) until after completion of radiotherapy as scatter from the metals can exacerbate the skin reaction to radiation

   • Wash skin gently with lukewarm water and pat it dry

   • Keep skin well moisturized⁴ and encourage regular moisturization after RT with nonirritating, fragrance-free topically applied lotions such as Eucerin Original Moisturizing Lotion or Keri Original Moisture Therapy lotion

   • Pruritus: Add hydrocortisone cream 1% or 2.5% to the moisturizer; apply topically to intact skin twice daily

2. Moist desquamation

   General

   • A treatment break from radiotherapy may be required to allow for skin healing

   • Serial examinations must be performed to assess response to therapy and healing (granulation tissue identified at wound site)

   • Apply compresses topically with 0.9% sodium chloride or aluminum acetate solution (Burow or modified Burow solution) 3 or 4 times daily to clean and remove dead skin

   • Use nonionic moisturizers such as Aquaphor Healing Ointment or a vitamin A and E ointment topically to provide a barrier to infection and loss of body fluid

   • Use a nonadhesive dressing when necessary to prevent added irritation

   • Antibiotics: Use a topical antibiotic cream if infection occurs

     • Apply triple antibiotic ointment (polymyxin B sulfate + neomycin sulfate + bacitracin zinc) topically twice daily to affected area, or

     • Apply silver sulfadiazine topically twice daily to affected area. This must be discontinued prior to reinitiation of radiotherapy

   • Analgesia: Use systemic medications for pain control as needed: Oxycodone, hydromorphone, or morphine

Skin: Late (Chronic) Side Effects

Presentation

1. Hyper- or hypopigmentation/increased risk of basal cell carcinoma and melanoma

2. Telangiectasias

3. Permanent alopecia

4. Chronic ulceration, cutaneous atrophy

5. Fibrosis

6. Edema

7. Photosensitivity

8. Increased risk of basal cell carcinoma and melanoma

Management

• Hyper- or hypopigmentation/increased risk of basal cell carcinoma and melanoma

  • Permanent use of skin moisturizers with SPF >15 and protection from the sun are advised

• Chronic ulceration not responding to conservative therapy

  • Usually requires surgical repair

  • Hyperbaric oxygen treatment can lead to reepithelialization and eliminate the need for surgical intervention. Hyperbaric oxygen is considered after the failure of conservative management

  • Pentoxifylline 400 mg orally 2–3 times daily. May increase blood flow and promote healing⁵

• Radiation-induced fibrosis: Pentoxifylline and α-tocopherol (d-α-tocopherol or dl-α-tocopherol acetate; vitamin E) can potentially reduce fibrosis⁴

  • Pentoxifylline 400 mg orally 2–3 times per day

  • α-Tocopherol 1000 units/day orally

Soft Tissues and Bone: Early (Acute) Side Effects

Presentation

1. Soft-tissue edema can develop especially in treatment of the head and neck regions

2. Bony fractures can develop potentially in any site of irradiation (pelvic radiation is of particular concern)

Management

1. Soft-tissue edema

   • A temporary tracheostomy may be required when a patient develops laryngeal edema (when the possibility of laryngeal edema is high, a prophylactic tracheostomy can be performed before starting RT)

   • Short course of steroids:

     • Dexamethasone orally 2–4 times per day. Begin with a dose of 4 mg per day, gradually decreasing doses and administration frequency toward discontinuation over 14 days, with dose and duration of treatment depending on response

2. Bony fractures

   • Consult an orthopedic surgeon. Consider prophylactic intervention

Soft Tissues and Bone: Late (Chronic) Side Effects

Presentation

1. Soft-tissue edema

   • Common late effect; more common with RT + neck dissection

   • Edema can occur in the neck, oral cavity, pharynx, or larynx

2. Soft-tissue necrosis

   • Rare late complication. May present as an unhealed wound, chronic ulceration

3. Soft-tissue fibrosis of the neck

   • Common late effect, especially with RT + neck dissection

   • Woody fibrosis of cervical soft tissues with limited range of motion

4. Trismus

   • Caused by temporomandibular joint (TMJ) fibrosis and/or masticator fibrosis

5. Osteoradionecrosis (ORN) of the mandible

   • Uncommon late effect of RT to head and neck. This is most commonly observed in the molar and premolar regions.⁶ Clinical presentation is typified by erythema of the mucosa overlying the area of necrosis. This can progress to ulceration and ultimately the underlying necrotic bone is exposed. Risk increased by xerostomia and poor dental/oral hygiene

6. Long bone fractures

   • Most typically occurs after high-dose radiotherapy treatment used in the management of extremity sarcoma. The risk is significantly increased after periosteal stripping⁷

7. Pelvic/hip fractures

   • Pelvis: Increased likelihood after pelvic radiation, particularly in women after age 65 years irradiated for pelvic malignancies.⁸ Anal cancer is of particular concern with an approximate 3-fold increased incidence

   • Hip: The most vulnerable location for fracture within the pelvic skeletal architecture is the femoral neck. The best available data suggests that cigarette use may contribute. Although there is no clear predictive dose response correlation with femoral neck fractures, it is rarely seen when the total dose is kept below 42 Gy³

Management

1. Soft-tissue edema

   • Elevation of head and neck while in bed

   • Short course of steroids:

     • Dexamethasone orally 2–4 times per day. Begin with 4 mg per day, gradually decreasing doses and administration frequency toward discontinuation over 14 days, with dose and duration of treatment depending on response

2. Soft-tissue necrosis

   • Conservative management:

     • Good oral hygiene

     • Pentoxifylline 400 mg orally 2–3 times per day

     • α-Tocopherol 1000 units per day orally

     • Antibiotics for possible underlying infection that prevents healing. Choice of agents depends on the sites of infection. Use anaerobic coverage for mucosal lesions; Gram-positive coverage for skin ulcers

   • Hyperbaric oxygen, and, if necessary, surgical intervention with planned hyperbaric oxygen in persistent cases is recommended after failure of conservative management

3. Soft-tissue fibrosis of neck

   • Range-of-motion exercises of the neck and shoulder for prevention

4. Trismus

   • Preventive jaw stretching exercise

5. Osteoradionecrosis (ORN) of the mandible

   • Xerostomia and poor dental and oral hygiene increase the risk of developing ORN. See “Head and Neck: Salivary Gland and Taste Buds” for recommendations

   • Prevention:

     • Full dental evaluation with correction of periodontal disease before starting RT is necessary

     • To maintain healthy teeth: Daily topical fluoride application using a fluoride tray: 1.1% w/w sodium fluoride toothpaste (PreviDent 500 Plus) topically for 10–15 minutes twice daily during and after completion of RT

6. Long bone fracture

   • If suspected, an orthopedic surgeon should be contacted immediately. Additionally, tumor recurrence must be ruled out. Surgical stabilization may be appropriate. In rare cases, for example with tumors located within the anterior thigh compartment, prophylactic placement of a femoral rod may be considered in consultation with the surgeon⁹

7. Pelvic/hip fractures

   • Pelvis: Preventive measures such as ensuring that a patient has had the current standard screening for osteoporosis and appropriate treatment is important. Usual treatment after identification of an insufficiency fracture is physical therapy and pain control. This regimen will usually result in an improvement in symptoms within 1–2 months, often with a complete resolution within 12 months.¹⁰ An orthopedic surgeon should be consulted for recommendations regarding management

   • Hip: The best therapy is obviously prevention. Care must be taken to minimize the femoral neck/head dose as much as possible using blocking or through identification of the femoral head and neck as a separate avoidance structure, if intensity modulated radiation therapy (IMRT) is being used. Upon diagnosis of the fracture, the patient must be referred to an orthopedic surgeon. Special mechanical reinforcement, for example with the use of acetabular reinforcement rings, may be required due to poor bone healing after irradiation¹¹

Ears: Early (Acute) Side Effects

Presentation

1. Otitis externa

2. Serous otitis media, or infectious otitis externa or media

   • Usually occurs after the third or fourth week of RT and can persist after completion of RT

Management

1. Otitis externa

   • Hydrocortisone otic drops; instill into the ear 3 times daily, or

   • Hydrocortisone 1% + neomycin 5 mg + polymyxin B 10,000 units otic drops: Instill solution into the ear 3 times daily, or

   • Anesthetic otic drops: Instill into the ear 3 times daily for pain in the external ear canal

   • In the case of tympanic perforation, or in the treatment of otitis media in a patient with myringotomy tubes, use ciprofloxacin hydrochloride/dexamethasone otic drops

2. Serous otitis media or infectious otitis externa or media

   • Decongestants or antihistamines:

     • Diphenhydramine 12.5–50 mg orally 3 times per day

     • Loratadine 10 mg orally once per day, or another nonsedating antihistamine (eg, cetirizine HCI, levocetirizine dihydrochloride, desloratadine, or fexofenadine HCI)

   • If medical therapy is not effective, consult an otolaryngologist for consideration of myringotomy tube insertion

   • If infection is suspected, oral antibiotics should be used:

     • Amoxicillin 500 mg orally every 8 hours for 10 days

Ears: Late (Chronic) Side Effects

Presentation

1. Permanent sensorineural hearing loss

   • Can occur in patients who receive a high dose to the cochlea (>60 Gy)^12,13

Management

1. Permanent hearing loss

   • Prevention is the best treatment. However, in a situation in which a high dose to the cochlea is unavoidable, such as with posterior fossa radiation, a hearing aid may be needed. Limit the cochlear dose to <60 Gy when possible. The use of chemotherapy concomitantly may increase the risk of sensorineural hearing loss. When the posterior fossa is being treated to high dose, the use of conformal techniques, such as intensity modulated radiation therapy (IMRT) may be of benefit¹⁴

Oral and Oral Pharyngeal Mucosa: Early (Acute) Side Effects

Presentation

1. Mucositis

   • Starts approximately 1–2 weeks after commencing RT

   • Oral discomfort → injected mucosa → patch ulceration → confluent mucositis at about the fourth to fifth weeks

   • Plateaus for approximately 1–2 weeks

   • Recovery starts close to the end of the treatment course

   • Complete mucosal healing usually occurs within 2–3 weeks after RT completion

   • Concomitant chemoradiation can be associated with a severe and long-lasting mucositis

2. Oral/mucosal candidiasis

   • The most common infection of the oropharynx in patients who have received radiotherapy

   • May exacerbate the symptoms of mucositis

3. Bacterial infection

   • May also occur, but less common than candidiasis

   • Usually occurs early in the course of head and neck irradiation

Management

1. Mucositis

   General:

   • Minimize exposure to mechanical or chemical irritants (such as poorly fitting dentures, alcohol, and chewing tobacco)

   • Baking soda or saline (0.9% sodium chloride for irrigation) oral rinses: 1 tsp baking soda or 1 tsp table salt in 1 quart (~946 mL) of water. Gargle a minimum of 3 times per day and after all meals

   • Use a water flosser (eg, Waterpik) to remove sticky materials from the mucosa

   • Sucralfate suspension 1000 mg/10 mL orally 3–4 times daily, or

   • Other mucosal coating products (with emollient properties to soothe irritated tissues but without an anesthetic component). These rinses relieve the pain of oral lesions by adhering to injured tissue of the oral mucosa and protecting it from further injury while providing a moist wound environment necessary for healing:

     • Gelclair bioadherent oral gel (polyvinylpyrrolidone, sodium hyaluronate, and glycyrrhetinic acid): mix Gelclair with 1–3 tbsp (15–45 mL) tap water (it may also be used undiluted): Swish the product around the oral cavity or gargle with it for at least 1 minute. Use as needed. The product is usually expectorated, but is harmless if swallowed

     • Biotene Mouthwash (glucose oxidase, lactoperoxidase, and lysozyme): Administer by swishing the product around the oral cavity or gargling with it for at least 30 seconds, and then expectorate. Use as needed

     • RadiaCare (Carrington) Oral Wound Rinse: mix the powder with the specified amount of water. A usual dose is approximately 1 tbsp (15 mL) that should be swished or gargled in the mouth for about 1 minute (safe if swallowed). Repeat 4 times per day or as needed

     Analgesia:

   • Topical anesthetics

     • Viscous lidocaine 2%/simethicone liquid/with or without diphenhydramine liquid (12.5 mg/5 mL) in a 1:1:1 mixture, 1 tbsp (15 mL) every 4–6 hours as needed

     Note: This may be swallowed, but the lidocaine component can numb the hypopharynx, increasing the risk of aspiration

     • Topical morphine rinse, 1 tbsp (15 mL) of a 2% morphine solution every 3 hours, 6 times per day, swished in the mouth or gargled and then expectorated

       • 15 mL of a 2% solution contains 300 mg morphine and should NOT be swallowed

     Note: Topical morphine has been shown to be superior to other topical anesthetics in a small, randomized trial. It has better pain control with decreased duration of functional imparment¹⁵

   • Oral or parenteral opioids: Medication for pain control is used as needed: Oxycodone, hydromorphone, fentanyl, or morphine. See Chapter 52

     Note: Systemic opioids are mostly used to control pain associated with mucositis

2. Oral/mucosal candidiasis

   • Topical antifungal agents: Continue treatment for at least 48 hours after perioral symptoms resolve and cultures no longer demonstrate growing yeast

     • Nystatin suspension 500,000–1,000,000 units (5–10 mL) orally 4 times per day

     • Clotrimazole troche 10 mg slowly dissolved in the mouth 5 times per day for 14 consecutive days

     Notes:

     1. Patients with esophageal candidiasis require systemic antifungal treatment

     2. Topical antifungal agents such as nystatin require contact with the affected area, and results among patients may be inconsistent

   • Oral antifungal agents:

     • Fluconazole 200 mg orally on day 1, followed by fluconazole 100 mg per day orally for 13 days on days 2–14

3. Bacterial infection

   • Antibiotics that provide good anaerobic coverage:

     • Amoxicillin with or without clavulanic acid orally every 12 hours until symptoms resolve, typically 7–10 days (co-amoxiclav: amoxicillin 825 mg + clavulanic acid 125 mg)

     • Metronidazole 500 mg orally every 6 hours

   • A culture should be obtained if a patient fails to benefit from antimicrobial therapy or if there are systemic symptoms, such as fevers/chills, etc. Culture directed therapy should then be initiated based upon isolate sensitivities

Oral and Oral Pharyngeal Mucosa: Late (Chronic) Side Effects

Presentation

1. Pallor, telangiectasia, thinning of mucosa

2. Persistent ulceration of soft tissue

   • Can be very painful

Management

1. Pallor, telangiectasia, thinning of the mucosa

   • Maintain meticulous oral hygiene

2. Persistent ulceration of soft tissue

   • Analgesia: Adequate pain control, may need opioids

     • Morphine, hydromorphone, oxycodone, or fentanyl. See Chapter 52

   • Exposed bone needs prompt attention

   • Hyperbaric oxygen may promote soft tissue and bony healing. If bone remains exposed, surgical repair with or without planned hyperbaric oxygen is needed to prevent osteomyelitis

Salivary Glands and Taste Buds: Early (Acute) Side Effects

Presentation

1. Acute sialadenitis

   • Tenderness and swelling of the salivary glands

   • May occur within hours after the first RT session and subside within a few days

2. Xerostomia

   • Progressive thickening of saliva with decrease in salivary output within the first 2–3 days

3. Loss of taste

   • Common side effect of head and neck RT

   • Return of taste, with or without some degree of permanent impairment 4–6 months after completion of RT

Management

1. Acute sialadenitis and xerostomia

   General:

   • Hydration during RT is essential, especially in symptomatic patients

   • Oral rinses with any of the following products, 3–4 times per day:

     • Baking soda 1 teaspoonful in 1 quart (~946 mL) of water

     • Guaifenesin

     • Carbonated drinks (sugar and alcohol-free)

   • Papain

     Note: All these have been tried with variable results

   • Pilocarpine 5–10 mg/dose orally 3–4 times/day up to a total daily dose of 30 mg

     Note: Compared with placebo, pilocarpine maintains significantly better salivary function in patients undergoing RT, although quality of life is not different¹⁶

     Prevention:

   • Radioprotector for the salivary gland during postoperative RT for head and neck cancer: Amifostine 200 mg/m² by intravenous infusion over 3 minutes 15–30 minutes before daily RT.¹⁷ An alternate route of administration is 1000 mg subcutaneously 20 minutes before daily RT, which may be a better tolerated method of delivery¹⁸

Salivary Glands and Taste Buds: Late (Chronic) Side Effects

Presentation

1. 1. Permanent xerostomia

   • Occurs in patients who receive high doses of RT to both parotid glands

Management

1. Permanent xerostomia

   • Mixed results have been achieved with either:

     • Artificial saliva products may be used as often as needed to moisten and lubricate the mouth and throat in xerostomia (products are available in spray and moistened swab forms), or

     • Pilocarpine 5–10 mg/dose orally 3–4 times/day up to a maximum daily dose of 30 mg

   • Surgery may present a possible option. A prospective study by Jha et al. evaluated the efficacy of surgical transfer of a submandibular gland to the submental space in order to protect the transferred gland prior to initiation of RT. At a median follow-up of 14 months, 81% experienced minimal to no xerostomia, with the remaining 19% having moderate/severe xerostomia. There were no surgery-related complications¹⁹

Pharynx and Esophagus: Early (Acute) Side Effects

Presentation

1. Pharyngitis/esophagitis

   • Dysphagia and odynophagia occur in the second or third week of RT; resolve 2–3 weeks after completion of RT

   • Characterized by somatic pain when swallowing

   • Severe oropharyngitis → intermittent aspiration. Silent aspiration occurs in >60% of patients²⁰

Management

1. Pharyngitis/esophagitis

   General:

   • Soft diet to maintain nutritional intake

   • Sucralfate suspension 1000 mg/10 mL orally 3–4 times per day

   • Biotene Mouthwash (glucose oxidase, lactoperoxidase, and lysozyme): Swish the product around the oral cavity or gargle with it for at least 30 seconds, and then expectorate. Use as needed

   • Gelclair bioadherent oral gel (polyvinylpyrrolidone, sodium hyaluronate, and glycyrrhetinic acid): Mix Gelclair with 1–3 tbsp (15–45 mL) tap water (or may be used undiluted); swish the product around the oral cavity or gargle with it for at least 1 minute. The product is usually expectorated, but is harmless if swallowed

   • RadiaCare (Carrington) Oral Wound Rinse: Mix the powder with the specified amount of water. A usual dose is approximately 1 tbsp (15 mL), which should be swished or gargled in the mouth for about 1 minute (safe if swallowed). Repeat 4 times per day or as needed

     Analgesia:

   • Topical anesthetics

     • Viscous lidocaine 2%/simethicone liquid/with or without diphenhydramine solution (sugar-free and alcohol-free, 12.5 mg/5 mL) in a 1:1:1 mixture, 1 tbsp (15 mL) swished around the oral cavity or gargled and then expectorated every 4–6 hours as needed

     • Note: This product may be swallowed, but the lidocaine component can numb the hypopharynx, increasing the risk of aspiration

     • Topical morphine rinse, 1 tbsp (15 mL) of a 2% morphine solution every 3 hours, 6 times daily, swished around the oral cavity or gargled and then expectorated

       • 15 mL of a 2% solution contains 300 mg morphine and should NOT be swallowed

         Note: This has been shown to be superior to other topical anesthetics in a small, randomized trial. Better pain control with decreased duration of functional impairment⁵

   • Oral or parenteral opioids: For pain control to maintain comfort: Morphine, oxycodone, hydromorphone, fentanyl. See Chapter 52

     Note: Systemic opioids are often used to control pain associated with pharyngitis/esophagitis

     Prevention in patients at risk for severe mucositis, pharyngitis, and esophagitis:

   • Placement of a feeding tube before starting RT is recommended

   • Note: Many patients who receive chemotherapy and radiation concurrently become dependent on enteral tube feeding for nutritional support. Most patients will eventually regain swallowing ability, however, as many as 20% of patients treated with concurrent chemoradiation may still be PEG tube dependent after 1 year²¹

   • Recent data suggest that the radiotherapy dose to the pharyngeal constrictor muscles as well as the glottic and supraglottic larynx have the greatest deleterious effects in the development of esophagitis. Eisbruch et al. demonstrated, using IMRT, that the dose to these structures could be limited to <50 Gy without compromising tumor coverage. This approach reduced the dose to these critical structures by 20% on average when compared to conventional 3D-conformal techniques²²

     Rehabilitation:

   • Speech and swallowing therapy aid in recovery

Pharynx and Esophagus: Late (Chronic) Side Effects

Presentation

1. Soft-tissue changes, including pallor, telangiectasia, and fibrosis, which may lead to stricture formation

2. Persistent inability to swallow

3. Chronic aspiration

Management

1. Strictures

   • Surgical dilation

2. Persistent inability to swallow

   • Speech and swallowing therapy

   • Severe cases that persist despite speech and swallowing therapy may require a permanent feeding tube

3. Chronic aspiration

   • Nothing by mouth with nutritional support via a permanent feeding tube

   • Severe cases may need a laryngectomy for airway protection

Lungs: Early (Acute) Side Effects

Presentation

1. Dry, nonproductive cough. Likely caused by transient injury to the airway mucosa soon after completing RT

Management

1. Dry, nonproductive cough

   • Symptomatic treatment, including cough suppressants, bronchodilators, and humidification

Lungs: Subacute Side Effects

Presentation

1. Radiation pneumonitis (RP)

   • Uncommon side effect, usually seen 1–5 months after RT

   • Can be lethal if it involves sufficient lung volume

   • Acute symptoms of RP: Dry cough, low-grade fever, congestion, dyspnea, pleuritic chest pain, and, rarely, hemoptysis

   • Findings on imaging studies: Classically, the changes generally correspond to the RT portal; however, these changes do not correlate with clinical severity of the presentation. Additionally, a sporadic form of radiation pneumonitis has been previously described. In this syndrome, unirradiated lung may show changes on the chest x-ray. This is believed to represent an immune mediated hypersensitivity pneumonitis²³

   • Relevant predictive factors

     • Poor performance status²⁴

     • Ongoing smoking may decrease the frequency of radiation-induced pneumonitis²⁵

     • Comorbid pulmonary disease may increase risk

     • The greater the lung volume irradiated the greater the risk

Notes:

1. Risk starts when >22% of total lung volume is exposed to 20 Gy,¹¹ RP is generally not seen if <22% of total lung volume is exposed to 20 Gy compared with an 8% frequency when 22–31% of lung is exposed to 20 Gy²⁶

2. RP is a clinical diagnosis of exclusion. Typical imaging findings in the absence of clinical symptoms does not warrant the diagnosis of RP

3. No solid data to indicate that chemotherapy used in combination with thoracic radiation (as in lung or esophageal cancer) leads to increased RP. However, if one uses chemotherapy agents that have known toxicity to lung, such as bleomycin, mitomycin, or cyclophosphamide, the risk increases dramatically

Management

1. Radiation pneumonitis (RP)

   Prevention:

   • Limit the lung volume exposed to <22% of total lung volume and <20 Gy²⁶

     General:

   • Superinfection: Use antibiotics including penicillin-based, cephalosporin, macrolides, or fluoroquinolones. See Chapter 47

   • Supplemental oxygen as needed

   • Inhaled corticosteroids, such as fluticasone or fluticasone + salmeterol

     • Fluticasone Inhalation Aerosol (Flovent HFA) 44 mcg per metered dose, 2 puffs for a total of 88 mcg by oral inhalation twice daily, or Fluticasone Inhalation Aerosol Powder (Flovent Diskus) 100 mcg by oral inhalation twice daily

     • Fluticasone propionate/salmeterol xinafoate (Advair Diskus) 250/50 (250 mcg microfine fluticasone propionate + 50 mcg salmeterol base) by 1 oral inhalation twice daily

       • Care must be taken to gargle with salt water after each inhalation to prevent oropharyngeal fungal infection

   • Corticosteroids: Prednisone 30–60 mg/dose orally every day for 2–3 weeks, followed by a dose and administration schedule gradually decreasing (tapering) toward discontinuation

     • Reduce daily dose by 5–10 mg/day each week or every other week, depending on a patient's symptoms

     Note: Initiate corticosteroids only when symptoms are associated with hypoxemia. It is often very difficult to taper steroids in the setting of RP because of persistent symptoms. The rate of tapering should depend on the response of the patient

Lungs: Late (Chronic) Side Effects

Presentation

1. Pulmonary fibrosis

   • May occur anywhere from several months to years after radiation

   • May or may not be preceded by radiation pneumonitis. Usually develops silently in radiated area

   • Most patients are asymptomatic when small volumes of the lung are affected

   • If a sufficient or significant amount of lung is involved → dyspnea → progressive cor pulmonale. This process is irreversible

     Note: Occurs nearly always in the radiated area. In general, consider the area of the lung that receives >30–35 Gy as functionless and likely to develop fibrosis.²⁷ Therefore, it is prudent for the radiation oncologist to select patients and to minimize lung exposure to radiation

Management

1. Pulmonary fibrosis

   • Supportive care

   • Supplemental oxygen

   • Bronchodilators

     • Ipratropium bromide inhalation aerosol (18 mcg/actuation) 4 times per day. Additional doses may be given as required to a maximum of 12 inhalations/24 hours, or

     • Ipratropium bromide inhalation solution 0.02%. The usual dose is 500 mcg by nebulization every 6–8 hours

   • Prevention

     Note: It has been reported that amifostine is effective in reducing acute severe esophagitis and pneumonitis in persons with locally advanced non–small cell lung cancer treated with chemoradiation.^28,29 Although, a recent RTOG report failed to confirm objective improvement in esophagitis, patient self-assessment showed statistically improved swallowing function with amifostine³⁰

Heart: Early (Acute) Side Effects

Presentation

1. Cardiac damage

   • Uncommon when <30% of the heart receives <40 Gy

2. Acute pericarditis

   • Rare

Management

1. Pericarditis

   • Observation

   • Nonsteroidal antiinflammatory agents: Aspirin, ibuprofen, naproxen, or indomethacin

   • Steroids: Prednisone 30–60 mg/dose orally daily for 2–3 weeks, followed by a dose and administration schedule gradually decreasing (tapering) toward discontinuation

     • Reduce daily dose by 5–10 mg either each week or every other week, depending on a patient's symptoms

Heart: Late (Chronic) Side Effects

Presentation

1. Pericarditis

   • May develop 6 months to years after RT

   • Presentation: Chest pain, dyspnea, fever, and abnormalities on ECG

   • Pericardial effusion with tamponade may develop

2. Cardiomyopathy or pancarditis

   • Uncommon but can occur if RT + cardiotoxic chemotherapy such as doxorubicin is administered

3. Other cardiac effects of uncertain etiology: Coronary artery disease, valvular defects, conduction abnormalities

Management

1. Pericarditis

   • Pericardiocentesis and pericardiotomy are necessary for impending tamponade; both visceral and parietal pericardium must be removed

2. Cardiomyopathy or pancarditis

   • Avoid cardiomyopathy by adjusting anthracycline dosages and meticulously designing radiation portals. Special care should be taken when treating a patient with left-sided breast cancer as they may be at increased risk. In the Stockholm trial, a 6.8% incidence of excess cardiac morbidity was reported with left-sided tumors treated with deep tangent fields. The average volume of heart receiving at least 25 Gy in that study was 25%, whereas with conformal techniques, this can be reduced to 6% or less³¹

Esophagus: Early (Acute) Side Effects

Presentation

1. Esophagitis: Sensation of food getting stuck while swallowing (contrast with somatic pain that occurs when swallowing with pharyngitis from head and neck RT)

2. Gastroesophageal reflux disease (GERD)

3. Colonization by Candida species

Management

1. Esophagitis

   General:

   • Soft diet to maintain nutritional intake

   • Sucralfate suspension 1000 mg/10 mL orally 3–4 times per day

     Analgesia:

   • Topical anesthetics

     • Viscous lidocaine 2%/simethicone liquid/with or without diphenhydramine liquid (12.5 mg/5 mL) in 1:1:1 mixture, 1 tbsp (15 mL) every 4–6 hours as needed

     Note: This may be swallowed, but the lidocaine component can numb the hypopharynx, increasing the risk of aspiration

     • Topical morphine rinse 1 tbsp (15 mL) of a 2% morphine solution every 3 hours, 6 times daily, swished in the mouth or gargled and then expectorated

       • 15 mL of a 2% solution contains 300 mg morphine and should NOT be swallowed

     Note: Topical morphine has been shown to be superior to other topical anesthetics in a small, randomized trial. Better pain control with decreased duration of functional impairment¹⁵

   • Oral or parenteral opioids: For pain control to maintain comfort: Morphine, oxycodone, hydromorphone, fentanyl. See Chapter 52

     Note: Systemic opioids are often used to control pain associated with pharyngitis/esophagitis

     Prevention in patients at risk for severe mucositis, pharyngitis, and esophagitis:

   • Placement of a feeding tube before starting RT is recommended

   • Note: Many patients who receive chemotherapy and radiation concurrently become dependent on enteral tube feeding for nutritional support. Most patients will eventually regain swallowing ability

   • Recent data suggests that the radiotherapy dose to the pharyngeal constrictor muscles as well as the glottic and supraglottic larynx have the greatest deleterious effects in the development of esophagitis. Eisbruch et al. demonstrated with the use of IMRT, the dose to these structures can be limited to <50 Gy without compromising tumor coverage. This approach reduced the dose to these critical structures by 20% on average when compared to conventional 3D-conformal techniques²²

     Rehabilitation:

   • Speech and swallowing therapy aid in recovery

2. GERD

   • Antacids and proton pump inhibitors

3. Colonization by Candida species

   • Topical antifungal agents: Continue treatment for at least 48 hours after perioral symptoms resolve and cultures return to normal

     • Nystatin suspension 500,000–1,000,000 units (5–10 mL) orally 4 times per day

     • Clotrimazole troches 10 mg dissolved slowly in the mouth 5 times per day

     Notes:

     • Patients with esophageal candidiasis require systemic antifungal treatment

     • Topical antifungal agents such as nystatin and clotrimazole require contact with the affected area and results among patients may be inconsistent

   • Oral antifungal agents: Fluconazole 200 mg orally on day 1, followed by fluconazole 100 mg per day orally for 13 consecutive days on days 2–14

Esophagus: Late (Chronic) Side Effects

Presentation

1. Persistent esophagitis

2. Stricture

3. Chronic ulceration

4. Fistula

Management

1. Persistent esophagitis

   • Symptomatic relief, supportive care, similar to management of acute esophagitis

2. Stricture

   • Esophageal dilation

3. Chronic ulceration

   • Surgical intervention may be needed

Stomach: Early (Acute) Side Effects

Presentation

1. Nausea and vomiting

   • Occurs frequently with gastric RT. Resolves after the completion of RT

2. Acute gastritis with ulceration

   • 2–3 weeks after the start of RT. Resolves after the completion of RT

Management

1. Nausea and vomiting

   • Antiemetics before RT:

     • Ondansetron 4–8 mg orally 30–60 minutes before RT. For intractable nausea: 4–8 mg orally twice daily continually

       • Outpatients who are not able to retain swallowed medications may benefit from oral disintegrating tablet or oral soluble film formulations

     • Granisetron 2 mg orally 30–60 minutes before RT. For intractable nausea: 1 mg twice daily continually if needed

       • Outpatients who are not able to retain swallowed medications may benefit from a transdermal patch formulation

     • Tropisetron 5 mg/day either as needed, or, if administered prophylactically, start use 1 day before initiating RT, then 1–2 hours before each RT fraction, and after completion of RT once daily for 7 days

       • In the United States, tropisetron has not received FDA approval for use outside a clinical trial

     • Metoclopramide 40 mg orally 30–60 minutes before RT. For intractable nausea: 20–40 mg 4-times daily, continually

     • Prochlorperazine 20 mg orally 30–60 minutes before RT. For intractable nausea 5–20 mg orally every 4–6 hours, continually

     • Lorazepam 1 mg orally 30–60 minutes before RT. For intractable nausea: 0.5–1 mg orally every 6–12 hours, continually

     • Dronabinol 10 mg orally 30–60 minutes before RT. For intractable nausea 2.5–10 mg orally every 6 hours, continually

     • Chlorpromazine 50 mg orally 30–60 minutes before RT. For intractable nausea: 25–50 mg orally every 4–6 hours, continually

2. Nausea and vomiting and acute gastritis with ulceration

   • Smaller daily RT fraction sizes

Stomach: Late (Chronic) Side Effects

Presentation (a few months to years after the completion of RT)

1. Dyspepsia, chronic gastritis

2. Persistent ulceration

3. Gastric outlet obstruction

4. Perforation

Management

1. Dyspepsia, chronic gastritis

   • H₂-blockers

     • Ranitidine HCl 150 mg orally 2 times per day, or 300 mg orally at bedtime, or

     • Famotidine 40 mg orally at bedtime, or 20 mg orally 2 times per day, or

     • Cimetidine 300 mg orally 4 times per day, or 400 mg orally 2 times per day

   • Proton pump inhibitors:

     • Rabeprazole sodium 20 mg orally daily, or

     • Esomeprazole magnesium 20 mg orally daily, or

     • Lansoprazole 15 mg orally daily, or

     • Pantoprazole sodium 30 mg orally daily

     Note: The proton pump inhibitors doses and schedules vary by indication. Dose adjustment and duration of administration must be tailored to individual patients

   • Sucralfate suspension (1000 mg/10 mL) 1500 mg orally 3–4 times per day

2. Persistent ulceration, gastric outlet obstruction, and perforation

   • Urgent referral for surgical evaluation. In the event of bleeding ulceration, endoscopy with argon laser coagulation may provide temporary control³²

Small and Large Intestine: Early (Acute) Side Effects

Presentation

1. Fatigue, nausea, vomiting, early satiety, anorexia, and diarrhea

2. Enteritis

   • Crampy abdominal pain and watery diarrhea

3. Proctocolitis

   • Occurs 2–3 weeks after the start of pelvic RT

   • Frequent bowel movement with or without watery diarrhea; rectal urgency; and tenesmus

4. Proctitis

Management

1. Fatigue, nausea, vomiting, early satiety, anorexia, and diarrhea

   • Antidiarrheal medications

     • Psyllium fiber 1 tsp in 8 oz water orally 3–4 times per day

     • Cholestyramine 1000 mg orally 1–4 times per day as needed

     • Loperamide 4 mg orally at the first onset of loose stools, followed by loperamide 2 mg orally every 2 hours around the clock until the patient is diarrhea-free for 12 hours

     • Diphenoxylate-atropine 2 tablets orally after each bowel movement

       • The commercially available combination product contains diphenoxylate 2.5 mg hydrochloride + atropine sulfate 0.025 mg per tablet

       • The maximum dose of diphenoxylate per 24-hour interval is 20 mg

     • Octreotide acetate injection 100–500 mcg/dose subcutaneously 2 or 3 times daily, doubling the dose at 3- to 4-day intervals until maximum control of symptoms is achieved

       • Maximum total daily octreotide dose is 1500 mcg

     Note: Octreotide has been shown to be more effective compared with conventional treatments mentioned above in the control of radiation induce diarrhea³⁴

     • Oral sucralfate has been shown to reduce acute and late toxicity from pelvic irradiation in a prospective study³³

2. Enteritis and proctocolitis

   • Low-residue diet

3. Mild proctitis

   • Topical anesthetic products (eg, pramoxine cream, lotion, gel, spray, foam, wipes) externally to the affected area up to 5 times daily

   • Hydrocortisone-containing preparations, including creams, lotions, gels, suppositories, and aerosol foam

     • Creams, lotions, gels, and aerosol foam products often include an applicator for rectal administration

     • Apply topically by insertion into the rectum twice daily as needed

4. Severe proctitis

   • Mesalamine rectal suppositories 1000 mg inserted rectally twice daily

     • Retain in the rectum for 1–3 or more hours to increase exposure, and, potentially, beneficial response

     • Response may occur within days, but the usual duration of use is 3–6 weeks, depending on symptoms and endoscopic findings

   • Mesalamine rectal enema 4000 mg/60 mL instilled into the rectum once daily and retained for approximately 8 hours

     • Response may occur within days, but the usual duration of use is 3–6 weeks, depending on symptoms and endoscopic findings

   • Glucocorticoid retention enemas

     • Hydrocortisone Rectal Suspension retention enema 100 mg in 60 mL of an aqueous suspension once daily at bedtime

       • The enema should be retained for at least 1 hour, and preferably during hours of sleep. Overcoming the urge to evacuate may be facilitated by concurrent use of sedatives and antidiarrheal medications

       • Instructions for use often recommend patients lie on their left side during administration and for 30 minutes afterward to improve fluid distribution throughout the left colon

     • Prednisolone retention enema 20 mg/100 mL of prednisolone (as sodium phosphate) in an aqueous solution once daily at bedtime

       • Instructions for use as for Hydrocortisone Rectal Suspension (above)

     • Sucralfate Suspension 3000 mg as a retention enema in 15–30 mL water for 10–20 minutes once daily from the start of RT, until 2 weeks after RT is completed

   Note: In the United States, rectal use is “off-label” for both prednisolone and sucralfate, which are not marketed in the United States in formulations intended for rectal administration. Instead, the liquid products formulated for oral use are used as an enema

Small and Large Intestine: Late (Chronic) Side Effects

Presentation

1. Radiation injury to small bowel

   • Malabsorption of fat, diarrhea, persistent bleeding, ulceration, perforation, and fistulas

   • Small bowel obstruction: Uncommon, occurs 1–5 years after RT. Obstruction may be preceded by episodic, crampy, abdominal pain

2. Radiation injury to colon

   • Strictures, persistent painless bleeding, ulceration, tenesmus, obstipation, diarrhea, and rectal urgency

3. Rectovaginal fistulas may occur because of a high local RT dose from a brachytherapy implant

Management

1. Radiation injury to small bowel: Malabsorption

   • Lactase enzyme (eg, Lactaid) orally with dairy products

   • Pancreatic or lactase enzyme preparations: Pancrelipase—start with 400 units lipase/kg per meal orally and titrate to 2500 units lipase/kg per meal orally

   • Note: In some patients, enteric-coated pancrelipase enzyme tablets may not dissociate as intended and may pass through the bowel intact

     Note: Administer pancrelipase with meals or snacks. Individualize dosage by giving the number of tablets or capsules that optimally minimizes steatorrhea. Adjust doses slowly; monitor symptoms and response

     • Select products with a high lipase content to avoid steatorrhea

     • Do not crush or chew enteric-coated products or the enteric-coated contents of opened capsules

     • Capsules may be opened and shaken onto a small quantity of soft food that is not hot and does not require chewing

     • Pancrelipase should be swallowed immediately without chewing to prevent mucosal irritation

     • Ingested doses should be followed with a glass of juice or water to ensure complete ingestion

     • Avoid mixing pancrelipase with foods that have a pH >5.5, which can dissolve enteric coatings

   • Parenteral nutrition can improve outcome and delay surgery in some patients³⁵

2. Radiation injury to small bowel, colon, and rectovaginal fistulas

   • Surgical intervention for persistent symptoms should be considered as a last resort

Liver: Early (Acute) Side Effects

Presentation

1. Acute hepatitis: This is initially heralded by a relatively silent period, because more extensive radiation injury is required before the onset of clinically significant acute inflammation of hepatic tissues. Usually, symptoms occur subacutely

Management

1. Acute hepatitis:

   • Expectant

Liver: Subacute to Late (Chronic) Side Effects

Presentation

1. Radiation-induced liver disease (RILD)

   • The incidence of these severe toxicities is related to dose and treatment volume

   • The risk of liver damage is increased in patients who receive >30 Gy to the whole liver

     • Liver dose <30 Gy; the incidence is <5%

   • Volume of liver irradiated plays a significant role. Some studies suggest if <25% of the liver is irradiated, there may be no dose-dependent risk of RILD³⁶

   • Development of anicteric ascites 2–4 months after RT

   • Venoocclusive disease of the lobular central veins occurs

     • Vague to intense right upper quadrant discomfort

     • Ascites

     • Jaundice occurs later; alkaline phosphatase level >> bilirubin and other LFTs^37,38

   • Computed tomography findings: Low-density changes

2. Combined-modality-induced liver disease (CMILD) occurs with bone marrow preparative regimens

   • Occurs early, usually within 4–6 weeks after RT

   • Venoocclusive disease of the lobular central veins:

     • Vague to intense right upper quadrant discomfort

     • Ascites

     • Jaundice occurs early; bilirubin >> alkaline phosphatase

   • There are no imaging findings in CMILD patients

Management

1. Radiation-induced liver disease (RILD) and combined-modality-induced liver disease (CMILD)

   • No specific therapy exists for treatment of RILD or CMILD

   • No proven benefit to anticoagulants or corticosteroids

   • Conservative management of ascites using diuretics, including spironolactone

Urinary Bladder: Early (Acute) Side Effects

Presentation:

Usually begins 2 weeks after starting RT

1. Cystitis with dysuria

2. Urinary frequency and urgency

3. Obstructive urinary symptoms

Management

1. Dysuria

   • Topical analgesics

     • Phenazopyridine hydrochloride 200 mg orally 3 times daily

     • NSAIDs:

       • Ibuprofen 200 mg orally 3–4 times per day as needed

       • Naproxen 220 mg orally 1–2 times per day as needed

2. Urinary frequency and urgency

   • Antispasmodics

     • Oxybutynin chloride 5 mg orally 2–3 times per day as needed

     • Flavoxate hydrochloride 100–200 mg orally 3–4 times per day as needed

     • Hyoscyamine sulfate 0.125–0.30 mg orally 3–4 times per day as needed

3. Obstructive urinary symptoms

   • Terazosin hydrochloride start 1 mg orally at bedtime; titrate as needed over 4–6 weeks to a maximum of 20 mg/day

   • Doxazosin mesylate start 1 mg orally once a day; titrate as needed over 4–6 weeks to a maximum of 8 mg/day

   • Tamsulosin hydrochloride start 0.4 mg orally once a day; increase to 0.8 mg daily after 1–2 weeks

   • Finasteride 5 mg orally once daily

Urinary Bladder: Late (Chronic) Side Effects

Presentation

1. Persistent dysuria

2. Persistent frequency and urgency

3. Obstructive urinary symptoms

4. Hematuria or hemorrhage caused by telangiectasia or ulceration

5. Decreased bladder capacity

6. Urethral stricture, especially in patients with a history of transurethral resection of the prostate

7. Fistula

8. Sphincter insufficiency is less common; injury to ureters is rarely seen

Management

1. Persistent dysuria, frequency, urgency, and obstructive symptoms:

   • Symptomatic relief is the goal

   • Use agents recommended for acute management, as above

2. Hematuria or hemorrhage:

   • May require cystoscopy with bladder irrigation

   • Intravesical treatment with prostaglandins or silver nitrate can be used

   • Embolization of the hypogastric arteries may be a consideration

3. Severely decreased bladder capacity:

   • May require cystectomy

Kidneys: Early (Acute) Side Effects

Presentation

1. Acute radiation nephropathy

   • Rarely symptomatic

   • Symptoms are similar to those with nephropathy of other causes

   • Note: Renal damage is rarely reversible

Management

1. Acute radiation nephropathy

   • Limit the volume of kidney irradiated

   • TD 5/5 (5% incidence at 5 years) is 20 Gy if both kidneys are irradiated

Kidneys: Late (Chronic) Side Effects

Presentation

1. Chronic radiation nephropathy–chronic renal failure

   Note: The incidence of renal toxicity is dose-and volume-dependent. With increased volume irradiated and increased radiation dose, there is an increased risk of renal toxicity

   • When both kidneys are irradiated to 20 Gy, the rate of renal failure is 5% at 5 years

   • When both kidneys are irradiated to 28 Gy, the rate of renal failure is 50% at 5 years

   Note: Renal damage is rarely reversible. Progression to chronic radiation nephropathy can occur ≈1–2 years after completion of RT. Associated symptoms include:

   • Hyperreninemic hypertension

   • Nephrotic syndrome

Management

1. Chronic radiation nephropathy–chronic renal failure

   • Limit the volume of kidney irradiated. TD 5/5 (5% incidence at 5 years) is 20 Gy if both kidneys are irradiated

   • Low-protein diet and salt restriction may reduce kidney workload

   • For end-stage renal disease, dialysis or transplantation is needed

Testis and Erectile Function: Early (Acute) Side Effects

Presentation

1. Azoospermia, oligospermia, and hormonal changes

   • Can occur even in patients receiving low-dose testicular RT

   Note: Sperm count may recover; however, recovery may take months or years after RT

Management

1. Azoospermia and oligospermia

   • Sperm banking before starting RT is recommended in men with fertility concerns

Testis and Erectile Function: Late Side Effects

Presentation

1. Erectile dysfunction

   • Can occur with high RT dose to the prostate

   • Radiation dose to the penile bulb appears to be a predictive factor for erectile dysfunction³⁹

Management

1. Erectile dysfunction:

   • Sildenafil citrate 25–100 mg orally once daily 1 hour before sexual activity

   • Vardenafil hydrochloride 5–20 mg orally once daily 1 hour before sexual activity

   • Tadalafil 5–20 mg orally once daily 1 hour before sexual activity

   • Local therapy (consult a urologist):

     • Alprostadil (prostaglandin E₁) for intracavernosal injection or pellets for intraurethral insertion

     • Urethral implants

Vulva: Early (Acute) Side Effects

Presentation

1. Skin reactions

   • Vulvar reactions to radiation are essentially skin reactions but are more severe because of the location

Management

1. Skin reactions

   • Attention to personal hygiene

   • Topical steroids for symptoms of pruritus: Hydrocortisone cream 1–2.5%; apply locally twice daily

   • Topical antibiotics may be necessary if signs of infection are present: Triple antibiotic ointment (polymyxin B sulfate + neomycin sulfate + bacitracin zinc) apply twice daily to affected area

   • A treatment break from RT may be warranted if confluent grade 4 (moist desquamation) reaction occurs

   • Areas of moist desquamation may be treated topically with an aqueous solution of gentian violet (crystal violet) 1% which has an antimicrobial effect, but it dries and stains the dermis and may cause irritation and interfere with wound healing⁴⁰

Vulva: Late (Chronic) Side Effects

Presentation

1. Skin atrophy

2. Ulceration

3. Fibrosis with associated dyspareunia

4. Pruritus

5. Pain

6. Telangiectasia

7. Pigmentation changes

8. Hair loss

Management

1. Atrophy of the skin

   • Topical estrogen or testosterone creams:

     • Estradiol gel 0.06% (eg, EstroGel) metered-dose pump 1.25 mg (1 metered application) topically to intact skin once daily, at the same time each day

     Note: The recommended area of application is the arm, from shoulder to wrist

     • Estrace cream topically once daily

   • Maintaining dose of radiation delivered to the vulvar region to 180 cGy/fraction or less may minimize the likelihood of long-term vulvar complications

2. Persistent ulceration

   • Surgical intervention

3. Fibrosis with narrowing of the introitus

   • Daily use of a dilator

Vagina: Early (Acute) Side effects

Presentation

1. Vaginitis

2. Vaginal candidiasis

Management

1. Vaginitis

   • Vaginal douching with water or a 1:10 mixture of 1 part hydrogen peroxide with 9 parts water 2–3 times daily

2. Vaginal candidiasis

   • Miconazole nitrate

     • Intravaginal suppositories: Insert 1 suppository intravaginally once daily at bedtime for 1 day (1200 mg/suppository), for 3 consecutive days (200 mg/suppository) or for 7 consecutive days (100 mg/suppository)

     • Intravaginal cream: Insert 1 applicator-full intravaginally once daily at bedtime for 3 consecutive days (4% miconazole cream) or 7 consecutive days (2% miconazole cream)

     • Topical cream: Apply to affected areas daily (morning and evening) for up to 7 consecutive days, or as needed

   • Clotrimazole

     • Intravaginal suppositories: Insert 1 suppository intravaginally once daily at bedtime for 3 consecutive days (200 mg/suppository) or for 7 consecutive days (100 mg/suppository)

     • Topical cream: Apply to affected areas twice daily (morning and evening) for up to 7 consecutive days or as needed

   • Nystatin

     • Vaginal tablets: Insert 2 tablets using an applicator, high in the vagina daily for 2 weeks (100,000 units/tablet)

     • Topical cream: Apply to affected external areas 2–3 time daily until healing is complete

     • Topical powder: Apply to affected external areas 2–3 times daily until healing is complete

   • Fluconazole 150 mg orally for 1 dose

Vagina: Late (Chronic) Side Effects

Presentation

1. Adhesion, dyspareunia, fibrosis

2. Ulceration, fistula formation

3. Atrophy

4. Telangiectasia

Management

1. Adhesion formation and fibrosis

   • Daily vaginal dilation to prevent adhesion formation and fibrosis

   • Topical estrogen creams to promote healing and prevent atrophy and dyspareunia

     • Estradiol gel 0.06% (eg, EstroGel) metered-dose pump 1.25 mg (1 metered application) topically to intact skin once daily, at the same time each day

     Note: The recommended area of application is the arm, from shoulder to wrist

     • Estradiol vaginal cream (eg, Estrace) topically once daily

2. Persistent ulcer or fistula

   • Tumor recurrence must be ruled out

   • Surgical intervention may be necessary

Uterine Cervix and Uterus: Early (Acute) Side Effects

Presentation

1. Ulceration of the uterine cervix

   • Unavoidable with RT for curative treatment of cervical cancer

   • May present with persistent clear watery discharge

Management:

1. Ulceration of the uterine cervix

   • Personal hygiene is essential to prevent super-infection

   • Vaginal douching with water or a 1:10 mixture of 1 part hydrogen peroxide and 9 parts water 2–3 times per day

   • If ulceration persists, the patient may require surgical intervention

Uterine Cervix and Uterus: Late (Chronic) Side Effects

Presentation

1. Hematometra

   • Rare complication caused by residual functioning endometrium and a stenotic cervical os

2. Cervical ulceration

   • Necrosis of the cervix (or uterus) can be seen with high-dose brachytherapy used in the treatment of gynecologic cancers

Management

1. Hematometra

   • Cervical os dilation and surgical debridement may be necessary

Ovaries; Late (Chronic) Side Effects

Presentation

1. Permanent menopause develops in premenopausal women who receive high-dose RT to the ovaries

2. Sexual dysfunction with dyspareunia frequently follows treatment for pelvic malignancies. The causes are both physical and psychological

Management

1. Permanent menopause

   • When fertility is an issue, one can surgically move ovaries out of the RT portal before starting RT

   • To reduce hot flashes: Venlafaxine extended release 37.5 mg orally once daily⁴¹

2. Sexual dysfunction with dyspareunia

   • Attention to personal hygiene

   • Hormone replacement therapy. Many commercial preparations are available. Consult a gynecologist before initiation

   • Lubrication and daily dilation of the vagina may aid in prevention of dyspareunia

Brain: Early (Acute) Side Effects

Presentation

1. Increased intracranial pressure (ICP) caused by RT-induced edema with the first few fractions of RT leads to:

   • Nausea

   • Vomiting

   • Increased headache

   • Changes in mental status (less commonly seen)

   • Worsening of neurologic signs (less commonly seen)

   • Seizures (less commonly seen)

Management

1. Increased ICP

   • Dexamethasone 10 mg orally or intravenously as a loading dose, followed by 4–6 mg intravenously or orally 4 times per day. The dose can be tapered after symptoms have stabilized for 3–4 days

     Note: A fast tapering schedule with a reduction in dose of 50% every 3–4 days is recommended if a patient has been receiving dexamethasone less than 1 week

Brain: Subacute Side Effects

Presentation

1. Somnolence syndrome

   • Often noted ≈1–4 months after cranial RT

   • Characterized by drowsiness, fatigue, nausea, irritability, anorexia, apathy, and dizziness without focal neurologic abnormalities

   • Resolves spontaneously within 2–5 weeks

   Note: Focal neurologic signs seen after RT may be related to intralesional or local reaction, such as edema, demyelination, or bleeding into a tumor

Management

1. Somnolence syndrome may be alleviated by corticosteroids

   • Dexamethasone 10 mg orally or intravenously as a loading dose followed by 4–6 mg intravenously or orally 4 times per day. The dose can be tapered after symptoms have stabilized for 3–4 days

     Note: May need a slow taper depending on a patient's symptoms

   • Methylphenidate may be used with some efficacy after whole brain radiotherapy. Dose is usually started at 10 mg twice daily and then increased to 30 mg twice daily as tolerated with 2-week intervals between increases in dose⁴²

Brain: Late (Chronic) Side Effects

Presentation

1. Focal necrosis of the brain

   • Occurs 6 months to several years after RT

   • Occurs in 1–5% of patients who received ≥60 Gy to the brain

   • Associated with focal symptoms as well as symptoms associated with increased ICP

   • Abnormalities can be seen on CT scan or magnetic resonance imaging

   • A void of metabolic activity on PET (positron emission tomography) scan can confirm the clinical diagnosis

2. Leukoencephalopathy

   • Diffuse white matter injury

   • Characterized by lethargy, seizures, spasticity, paresis, ataxia, dementia, or even death

   • More severe forms are seen in patients who received combined chemotherapy and RT

   • The incidence of leukoencephalopathy has been reported to be as high as 45% when RT and intravenous or intrathecal methotrexate were given together and <1% when RT is given alone⁴³

3. Neuropsychological and intellectual deficits

   • Memory deficits and learning disabilities can be seen in children 6 months after RT

   • Global IQ decline can be observed 1–2 years after RT⁴⁴

   • Risk factors for more severe deficits,⁴⁵ include:

     • Young age when exposed to RT

     • High RT doses

     • Large volume of brain irradiated

4. In adults, memory loss, confusion, dementia, ataxia, and psychomotor retardation can also be seen

5. RT-induced glioma

   • Well documented in pediatric medical literature

   • 15-year cumulative risk is estimated to be 2.7%⁴⁶

Management

1. Focal necrosis

   • May be alleviated by corticosteroids: Dexamethasone 10 mg orally or intravenously as a loading dose, followed by 4–6 mg intravenously or orally 4 times per day. The dose can be tapered after symptoms have stabilized for 3–4 days

     Note: May need a slow taper, depending on a patient's symptoms

   • Symptomatic treatment with anticonvulsant drugs

   • Surgical resection may be needed

2. Leukoencephalopathy

   • Supportive care

3. Neuropsychological and intellectual deficits

   • A phase II study conducted by Shaw et al. suggests that 6 months of treatment with donepezil improved long-term cognitive function, mood, and health-related quality of life with minimal toxicity. Patients were treated with 5 mg for the initial 6 weeks and then 10 mg for the remaining 24 weeks

Spinal Cord: Early (Acute) Side Effects

Presentation

1. Demyelination

   • Transient radiation effects on the spinal cord may be seen within 2–4 months after RT

   • Incidence is as high as 15% after mantle RT for Hodgkin disease

   • Presumed to be the result of the transient demyelination within the RT portal⁴⁷

   • Lhermitte sign: Electric-like shock radiating down the spine to the extremities with flexion of the neck

   • Spontaneous resolution expected within 6 months. No relationship to late injury reported

Management

1. Demyelination

   • Symptoms may be alleviated by corticosteroids: Dexamethasone 10 mg orally or intravenously as a loading dose followed by 4–6 mg intravenously or orally 4 times per day. The dose can be tapered after symptoms have stabilized for 3–4 days

     Note: May need a slow taper, depending on a patient's symptoms

   • Gabapentin 100–600 mg orally 3 times per day can be used for pain

Spinal Cord: Late (Chronic) Side Effects

Presentation

1. Chronic progressive radiation myelitis (CPRM)

   • Rare but devastating late effect. Symptoms start 9–15 months after RT is completed

   • Caused by intramedullary vascular damage that progresses to hemorrhagic necrosis or infarction and extensive demyelination with white matter necrosis

   • Presents with progressive paresthesias, sensory changes, and weakness

   • Risk of developing CPRM varies directly with:

     • Radiation fraction size

     • Length of the cord treated

     • Total dose: A cord dose of 45 Gy in 1.8- to 2-Gy daily fractions has <0.2% chance of developing CPRM⁴⁸

   • The majority of patients die of secondary complications

Management

1. CPRM

   • High-dose corticosteroids: Dexamethasone 10 mg orally or intravenously 4 times per day. The dose can be tapered slowly after symptoms have stabilized or improved for several days

   • Use of hyperbaric oxygen may lead to remission

Endocrine System: Early (Acute) Side Effects

Presentation

1. Hyperthyroidism

   • Thyrotoxicosis has rarely been reported after mantle or cervical RT for Hodgkin disease

   • Subsequently evolves into hypothyroidism

2. Diffuse, symmetric thyroid enlargement resembling Hashimoto thyroiditis has been reported but is a rare reaction to RT

Management

1. Hyperthyroidism

   • Antithyroid agents may be needed, such as methimazole or propylthiouracil. In addition, a β-blocker may also be needed. Consult an endocrinologist for help in management

Endocrine System: Late (Chronic) Side Effects

Presentation

1. Hypothyroidism

   • Late RT effect, 1–2 years after RT

   • As high as 63% at 10 years after treatment of head and neck region and thorax⁴⁹

   • Can also be seen in patients who receive a moderate dose to the pituitary that leads to the decreased production of thyroid stimulating hormone

   • Risk factors

     • Dose: Some studies show a relationship between dose and RT-induced hypothyroidism

     • Age: Young children tend to be more susceptible

     • Chemotherapy: Some studies show chemotherapy increases the risk of hypothyroidism when used in combination with moderate doses of RT

2. Thyroid cancer

   • A late effect of radiation exposure

   • Risk after RT is about 1.7% in adults⁵⁰

   • Risk is increased in children and young adults⁵¹

Management

1. Hypothyroidism

   • TSH and thyroxin (T₄) levels should be measured every 6 months after head and neck and upper thoracic RT

   • If hypothyroidism develops, treat accordingly