Radiotherapy side effects: integrating a survivorship clinical lens to better serve patients

The Canadian Cancer Society estimated that 220,400 new cases of cancer would be diagnosed in 2019. Of the affected patients, more than 60% will survive for 5 years or longer after their cancer diagnosis. Furthermore, nearly 40% will receive at least 1 course of radiotherapy (rt). Radiotherapy is used with both curative and palliative intent: to treat early-stage or locally advanced tumours (curative) and for symptom management in advanced disease (palliative). It can be delivered systemically (external-beam rt) or internally (brachytherapy). Although technique improvements have drastically reduced the occurrence of rt-related toxicity, most patients still experience burdensome rt side effects (seffs). Radiotherapy seffs are local or locoregional, and manifest in tissues or organs that were irradiated. Side effects manifesting within weeks after rt completion are termed “early seffs,” and those occurring months or years after treatment are termed “late seffs.” In addition to radiation oncologists, general practitioners in oncology and primary care providers are involved in survivorship care and management of rt seffs. Here, we present an overview of common seffs and their respective management: anxiety, depression, fatigue, and effects related to the head-and-neck, thoracic, and pelvic treatment sites.


INTRODUCTION
The Canadian Cancer Society estimated that 220,400 new cases of cancer would be diagnosed in 2019. Of the affected patients, more than 60% will survive for 5 years or longer after their cancer diagnosis 1 . Furthermore, nearly 40% of cancer patients receive at least 1 course of radiotherapy (rt) 2 . Radiotherapy is used with both curative and palliative intent: to treat early-stage or locally advanced tumours (curative) and for symptom management in advanced disease (palliative).
Although technique improvements have drastically reduced rt-related toxicity 3 , most patients still experience burdensome rt side effects (seffs) 4 . Radiotherapy seffs are local or locoregional, and manifest in tissues or organs that were irradiated. Side effects manifesting during or within weeks after rt completion are termed "early seffs," and those occurring months or years after treatment are termed "late seffs" 4 .
In addition to radiation oncologists, general practitioners in oncology and primary care providers are involved in survivorship care 5 , including the management of rt-induced seffs. Here, we present an overview of common seffs and their respective management: anxiety, depression, fatigue, and effects related to the head-and-neck (hn), thoracic, and pelvic treatment sites.

SIDE EFFECTS AND THEIR MANAGEMENT Distress, Anxiety, and Depression
Studies have shown an increase in distress, anxiety, and depression in patients undergoing radiation 6,7 . Although such problems tend to decrease upon rt completion, a significant number of patients still manifest psychological

ESSENTIALS FOR PRACTITIONERS IN ONCOLOGY
This series is brought to you in partnership with the Canadian Association of General Practitioners in Oncology. a These authors share first authorship. effects after treatment 7 . Patients with pancreatic cancer and lung cancer appear particularly vulnerable, higher rates of depression being associated with those diagnoses 8 . Radiotherapy-induced hypothyroidism, especially in patients with hn cancer, and secondary vitamin B 12 malabsorption can contribute to psychological findings and should be ruled out 8 .
Regardless of stage of diagnosis or treatment intent, depression and anxiety affect approximately 20% and 10% of patients respectively 9 , but underrepresentation is a concern, given the lack of standardized distress screening programs across Canada 10 . Current guidelines therefore recommend that all patients be screened for distress at their initial post-treatment visit and at regular intervals thereafter, using validated tools such as the revised Edmonton Symptom Assessment System, the Distress Thermometer, or the Patient Health Questionnaire-2 10 . Screening should include an assessment of psychosocial needs and fear of recurrence, with referrals to appropriate resources being promptly made as required 10 . In patients diagnosed with depression, a multidisciplinary approach including both nonpharmacologic and pharmacologic interventions is encouraged 11 .

Fatigue
Cancer-related fatigue is defined as "a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer and/ or cancer treatment that is not proportional to recent activity and interferes with usual functioning" 12 .
Patients often describe fatigue as one of the most distressing adverse effects of treatment 12 . Regardless of treatment site, rt has been reported to cause acute fatigue in up to 80% of patients, and chronic fatigue can persist in up to 30% for months to years after treatment 13 . The cause for persistent fatigue is likely multifactorial, but it has been suggested potentially to be secondary to persistent immune system activation or to late effects on major organ systems 14 . Guidelines recommend screening for cancerrelated fatigue in all patients and taking prompt action for potential contributing factors such as anemia, pain, and cardiac or endocrine dysfunction 12 . Nonpharmacologic and pharmacologic treatments might aid in the management of cancer-related fatigue ( Table i).

Effects of HN RT
Approximately 80% of patients with hn cancer will receive at least 1 course of rt as part of their treatment 20 . A frequent early seff of hn rt is oral mucositis: acute inflammation or ulceration, or both, of the oral or oropharyngeal mucosal membranes. Oral mucositis can cause pain and negatively affect capacity to swallow, eat, and speak, which can be very distressing to patients 21 . Oral mucositis is graded on a scale of 1-4 based on severity; Table ii summarizes its management 22 .
Other common seffs of hn rt include alterations of taste, dysphagia, xerostomia, and hypothyroidism. The latter condition should be recognized because thyroid hormone can readily be replaced. Screening for thyroid dysfunction based on thyroid stimulating hormone levels should be performed every 6-12 months after rt 23 .
Alterations of taste occur in more than 70% of patients 24 . Taste dysfunction can be partial or complete, and typically occurs 4-5 weeks after rt start 25 . Taste recovery can occur as early as 1 month after rt, and most survivors experience a complete return of taste 6-12 months after rt 26 .
The risk of dysphagia in patients with hn cancer who receive rt is high, and its occurrence can negatively affect quality of life 27 . Radiotherapy-induced fibrosis can impair the swallowing musculature 28 and could lead to nutritional intake through enteral feeding. Radiotherapyinduced fibrosis is dose-and site-dependent 28 , and concomitant chemotherapy can further affect swallowing 29 . The mainstay of management is behav ioural swallowing interventions with exercise aids provided by speech-language pathologists 30 . Thus, early referral to a speech-language pathologist is warranted; interventions can be performed to prevent dysphagia onset (before or during treatment) or to minimize existing dysphagia (after treatment) 31 . For persistent and debilitating dysphagia, referral to an experienced gastroenterologist for endoscopic dilatation might be beneficial 31 .
Lastly, xerostomia results from salivary gland dysfunction causing hyposalivation and is associated with swallowing, speech, and oral health problems 20 . Despite technique advancements such as intensity-modulated rt, approximately 40% of patients still experience burdensome xerostomia 20 . Increasing existing salivary flow (or replacing lost salivary secretions) and maintaining oral health (including treating dental caries and possible infections) are the mainstays of management 32 . After rt, dental visits are recommended at least once every 6 months 23 . Treatment options depend on the presence or absence of residual gland function. If gland function remains, mechanical gland stimulation with sugar-containing gums or xylitol-or sorbitol-containing candy can be attempted 32,33 . Salivary flow can also be stimulated by cholinergic medications such as pilocarpine at a recommended dose of 5 mg 3 times daily 32,33 . In the absence of gland function or upon saliva stimulation failure, mouthwashes and saliva substitutes can be used 33 .
Notably, hn rt is also associated with other late seffs, including lymphedema and carotid artery stenosis (cas). Lymphedema presents as local swelling because of damage to the lymphatic system, which can affect swallowing, speaking, and body image. Lymphedema management includes lymph drainage and use of compression garments: referral to a certified lymphedema therapist is recommended 22 . If cas occurs after hn rt, the risk for cerebrovascular disease increases. The risk appears greater in patients with other cas risk factors, including smoking, dyslipidemia, diabetes, and coronary and peripheral artery disease 34 . In addition to carotid artery surveillance, screening and optimal management of cas comorbid conditions are therefore recommended 34 .

Effects of Thoracic RT
Common effects of thoracic rt include radiation-induced lung injury (rili) and radiation-induced heart disease. Radiation-induced lung injury is a known complication in patients with lung, breast, esophageal, thymic, and hematologic malignancies who have undergone thoracic rt 35 . It affects 5%-20% of patients and can lead to dyspnea and chronic lung fibrosis, which can negatively affect quality of life 36 .
Radiation-induced lung injury consists of an acute inflammatory phase, defined as radiation pneumonitis (1-3 months after rt), and a chronic fibrotic phase, also known as radiation fibrosis (6-24 months after rt) 37 . Although most patients receiving thoracic rt are at risk of developing rili, certain factors such as smoking history, chronic obstructive pulmonary disease, and interstitial lung disease might increase the risk 35,36 . Older age and selected chemotherapies, immunotherapies, and targeted therapies also predispose patients to a higher risk of radiation recall pneumonitis. "Radiation recall" is a phenomenon in which patients develop pneumonitis after active rt treatments have been completed 35 . Radiation pneumonitis often presents with dyspnea, dry cough, and sometimes fever. A physical exam could be normal, but rare signs include pleural friction rub and rales 37 . Given those nonspecific findings, rili must always be included in the differential diagnosis for these patients. Although investigations can guide its identification, radiation pneumonitis is a clinical diagnosis: treatment includes steroids in symptomatic patients 37 . Figure 1 summarizes rili assessment and management.
Radiation-induced heart disease can present years after rt completion and can manifest as valvular disease, pericardial disease, coronary artery disease, cardiomyopathy, or conduction abnormalities 38 . Although rt dose is the most significant risk factor, other traditional cardiovascular disease risk factors such as diabetes, hypertension, obesity, and smoking increase the risk 39 . Survivors should have an annual physician visit and scheduled screening for radiation-induced heart disease, together with targeted symptom investigation. Promotion of healthy lifestyle habits-including diet, regular exercise, weight control, and abstinence from smoking-are of utmost importance 40 . Moreover, a baseline echocardiogram 6-12 months after rt should be considered for high-risk survivors 40 . Lastly, adult survivors of childhood cancers should also receive periodic evaluation for cardiac toxicity and cardiology referral, typically 5-10 years after rt, especially for survivors exposed to a 35 Gy dose to the chest (or at least 15 Gy if they also received an anthracycline) 41 .

Recommendations b Suggestions c
• The panel recommends that benzydamine mouthwash be used to prevent oral mucositis in patients with head-and-neck cancer receiving moderate-dose radiation therapy (up to 50 Gy), without concomitant chemotherapy (I).
• The panel suggests that oral care protocols be used to prevent oral mucositis in all age groups and across all cancer treatment modalities (III).
• The panel recommends that sucralfate mouthwash not be used to prevent oral mucositis in patients receiving chemotherapy for cancer (I) or in patients receiving radiation therapy (I) or concomitant chemoradiation (II) for head-and-neck cancer.
• The panel suggests that 2% morphine mouthwash might be effective to treat pain from oral mucositis in patients receiving chemoradiation for head-and-neck cancer (III).
• The panel recommends that sucralfate mouthwash not be used to treat oral mucositis in patients receiving chemotherapy for cancer (I) or in patients receiving radiation therapy (II) for head-and-neck cancer.
• The panel suggests that 0.5% doxepin mouthwash might be effective to treat pain from oral mucositis (IV).
• The panel suggests that systemic zinc supplements administered orally might be of benefit to prevent oral mucositis in patients with oral cancer receiving radiation therapy or chemoradiation (III).
• The panel suggests that chlorhexidine mouthwash not be used to prevent oral mucositis in patients receiving radiation therapy for head-and-neck cancer (III).
• The panel suggests that misoprostol mouthwash not be used to prevent oral mucositis in patients receiving radiation therapy for head-and-neck cancer (III

Effects of Pelvic RT
Compared with other cancer sites, pelvic cancers more frequently involve treatment with rt. Pelvic rt can lead to gastrointestinal toxicity, sexual dysfunction, and fertility concerns. Pelvic radiation disease (prd) is defined as mild-tosevere transient or long-term gastrointestinal symptoms secondary to rt of a pelvic tumour. Patients have reported prd to have the greatest adverse effect on their quality of life 42 . Patients can present with up to 22 gastrointestinal symptoms, and given that each symptom can have more than one cause, symptoms should be investigated systematically 43 . Frequent seffs of pelvic rt are diarrhea, rectal bleeding, urgency, and fecal incontinence, all reported in up to 50% of patients 42,44 . In addition to pelvic rt, patientrelated risk factors for prd include diabetes, inflammatory bowel disease, collagen vascular disease, low body mass index, and smoking 45 . Table iii summarizes the proposed work-up and management for gastrointestinal symptoms linked to prd. Other pharmacologic (aminosalicylates, sucralfate, amifostine, corticosteroid enemas, bile acid sequestrants, famotidine, and selenium) and nonpharmacologic interventions (dietary modifications, green tea tablets, glutamine) currently have lower-certainty evidence of potential benefit 46 .
Sexual dysfunction after pelvic rt is typically multifactorial and negatively affects patients 47 . In men, erectile dysfunction is a common late seff, being reported in up to 50% of patients at 5 years after rt 48 . Bladder and bowel dysfunction can also occur and lead to decreased intimacy and self-esteem 49 . Phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, have been described as effective to treat rt-associated erectile dysfunction and should be considered for first-line treatment 47,49,50 . In women, seffs related to pelvic rt include vaginal dryness FIGURE 1 Clinical algorithm for the assessment and management of radiation-induced lung injury (RILI). Suspicion of RILI should be raised when a patient's physical examination findings correlate temporally (typically within 3 months) with completion of thoracic radiation. CBC = complete blood count; CT = computed tomography. Reprinted with permission (Elsevier) from Hanania et al. 35 .  51 . Experts recommend starting dilation 4 weeks after rt, at a frequency of 2-3 times weekly (1-3 minutes) for 9-12 months 52 . Referral to a trained physiotherapist for pelvic physiotherapy and education might facilitate dilator use and progress monitoring. Vaginal morbidity should be assessed before treatment, once every 3 months for the first 2 years after treatment, and then every 6 months thereafter 53 .
Water-based non-hormonal lubricants might help vaginal dryness during intercourse 54 . Sexual counselling before treatment start might be beneficial, and referral to a psychologist or sexual health specialist could be warranted if sexual concerns arise 49,55 . Fertility should be explored before treatment in patients who are considering pregnancy after treatment completion. A multidisciplinary approach involving reproductive endocrinologists, g y necologists, a nd maternal-fetal medicine specialists is recommended 56 . Women who have had pelvic rt can be at increased risk for spontaneous miscarriages, preterm labor, low birth weight, and placental abnormalities 56 . These survivors should be closely followed by a multidisciplinary team throughout pregnancy 56 .

SUMMARY
Radiotherapy treatments are associated with significant side effects that can negatively affect quality of life for cancer survivors. Although newer techniques in the field of radiation oncology have helped to reduce some of the adverse effects, further extensive research is needed to minimize rt-induced deleterious outcomes. All providers caring for cancer survivors, including general practitioners in oncology, should carefully assess and provide management for rt-related effects.

Key Points
n Radiation-induced side effects adversely affect quality of life for cancer survivors. n Screening and management of rt-induced early and late effects are crucial parts of the survivorship care agenda. n Family physicians and general practitioners in oncology are key providers in the management of comorbid conditions, promotion of healthy lifestyles, and treatment of rt-induced side effects.