Fatigue is common during and after cranial radiotherapy (Table 1). In patients receiving WBRT, up to 95% of all patients experience excess fatigue and prospective studies have identified deterioration in validated fatigue scores from baseline to 1 month after WBRT.[24,25] However, fatigue is common with brain metastases in general and may be difficult to separate from treatment-related fatigue, as demonstrated in the QUARTZ trial, where 40% of patients who received WBRT vs. 44% of patients who received supportive care only reported tiredness.26) On the other hand, fatigue may be less common following SRS, reported by only 28% of patients compared to 95% of patients who underwent WBRT in one series.
The primary management of acute fatigue in patients undergoing brain radiotherapy is supportive care, including appropriate steroid taper, advising patients to take steroids earlier in the day (second dose no later than mid-afternoon) to avoid sleep disturbance, and other good sleep hygiene measures. Numerous studies demonstrate that aerobic and resistance exercise can mitigate cancer-related fatigue to an extent, and despite lack of data specifically in patients undergoing brain radiotherapy, we agree with the American Society of Clinical Oncology (ASCO) recommendations for 150 minutes of moderate aerobic exercise (including fast walking, cycling, or swimming) per week with an additional 2–3 sessions of resistance exercise (such as weightlifting), unless contraindicated for medical reasons.[27–31] Psychostimulants are not indicated for acute fatigue.
Alopecia and Dermatitis
Complete alopecia is common following WBRT and may be acute or chronic, typically beginning during WBRT or up to 1–2 weeks afterwards. Risk factors for alopecia include older age, radiation dose, volume, and receipt of chemotherapy. In most patients, hair regrowth occurs within 2–4 months after completion of radiation. However, in others, chronic alopecia (incomplete hair regrowth >6 months after treatment) may occur. Only patients who experience acute alopecia can develop chronic radiation-induced alopecia. In our experience, alopecia is uncommon following SRS, although patchy alopecia is possible with higher doses targeted to peripheral lesions.
In patients experiencing chronic radiation alopecia, one study found that topical minoxidil 5% BID improved hair regrowth in 82% of patients and given its favorable safety profile, is a reasonable option for interested patients. Patients with significant chronic alopecia can also be referred for hair prosthesis. Scalp-sparing radiation delivery techniques utilizing intensity-modulated radiation therapy (IMRT) have been developed which appear to both reduce the severity of acute alopecia and significantly reduce the likelihood of chronic alopecia.[33,36,37] It should be noted that despite a reduction in scalp radiation dose with IMRT, most patients will still experience acute alopecia with >50% hair loss and this technique should therefore be reserved for patients with an expected survival of >4–6 months or for those receiving IMRT for other indications (i.e., hippocampal avoidance).
Radiation dermatitis is highly associated with total radiation dose to the skin. Therefore, while erythema and dry desquamation of the scalp are possible with the range of radiation doses typically used for WBRT (20–37.5 Gy), moist desquamation is unlikely to occur. The management of radiation dermatitis of the scalp following cranial radiation is similar to other areas of the body. Patients should be counseled to use sunscreen, avoid sun exposure, and keep the area clean and dry. We typically use a gentle hydrophilic moisturizer (i.e., Aquaphor, Beiersdorf Inc., Wilton, CT, USA; Lubriderm, Johnson & Johnson, New Brunswick, NJ, USA) for grade 1 dermatitis and topical silver sulfadiazine with or without foam absorbent dressings (i.e., Mepilex, Mölnlycke, Gothenburg, Sweden) for grade 2 dermatitis with moist desquamation. Topical corticosteroids, such as hydrocortisone 1% applied once to twice daily, can be used to reduce irritation and itching.
Headaches, Vasogenic Edema and Nausea
Headaches are a common complaint during and after intracranial radiation therapy, including both WBRT and SRS. The pathogenesis is thought to be due to transiently increased vasogenic edema from an inflammatory response to tumor. In general, if headaches are mild, transient, and not associated with any new or progressive neurologic deficits, they can be managed conservatively with over-the-counter (OTC) analgesics such as acetaminophen.
On the other hand, more severe, persistent headaches and those associated with nausea, vomiting, and new or progressive neurologic deficits should prompt concern for vasogenic edema. Edema leading to increased intracranial pressure (ICP) can be a medical emergency and all patients should be evaluated for signs of elevated ICP and impending herniation, including but not limited to lethargy, nausea/vomiting, severe headache, focal neurologic deficits, cranial nerve palsies, papilledema, and respiratory depression. In the outpatient setting, the mainstay of treatment for vasogenic edema are systemic corticosteroids such as dexamethasone.
The optimal starting dose of dexamethasone depends on the severity of symptoms and underlying vasogenic edema.[39,40] In the emergency setting, a loading dose of 10 mg IV followed by 4 mg every 6 hours is commonly used. However, in the outpatient setting, a reasonable starting dose of dexamethasone is 2 to 4 mg PO BID. Clinical improvement typically occurs within 1–3 days, although improvement in vasogenic edema on imaging may lag by 1–2 weeks.[41–43] The optimal timing for steroid taper is variable and depends on the status of the underlying condition but should be considered after 7 days of therapy and performed slowly over the course of several weeks. For patients undergoing radiotherapy, we typically continue steroids at least until the end of treatment. Reductions in dose of 50% should occur no more frequently than every 3–4 days. Patients should be instructed to return to their previous dose if they experience rebound symptoms such as worsening headache or recurrent neurologic deficits.
In patients presenting with nausea temporally related to radiation therapy without other signs or symptoms, treatment with a 5-HT3 antagonist such as ondansetron, prescribed 8 mg every 8 hours as needed is reasonable. Cranial radiation is categorized as "low risk" for radiotherapy-induced nausea and vomiting and routine anti-emetic prophylaxis should be avoided.[44–46] If other signs or symptoms are present that may be explained by underlying vasogenic edema, corticosteroids with or without a 5-HT3 antagonist should be used as a first-line option.
Pseudoprogression describes an imaging finding on magnetic resonance imaging (MRI) which cannot reliably be differentiated from tumor progression on conventional MRI, typically characterized by increasing size, T1-weighted contrast enhancement, and peritumoral vasogenic edema of a treated tumor. There may be overlap between pseudoprogression and radiation necrosis, which is a pathologic diagnosis, but the two are distinct entities despite sometimes being used interchangeably in medical literature. Pseudoprogression is a radiation dose-dependent phenomenon, common following SRS but rare with WBRT alone, and owing to heterogeneous cohorts and definitions, has a reported incidence ranging from 9–31%. Typically, pseudoprogression occurs within 3 months of radiation treatment whereas radiation necrosis can occur months to years afterwards. Numerous studies have found MRI perfusion imaging to be helpful in differentiating pseudoprogression from tumor recurrence.[50–52] By definition, most cases of pseudoprogression resolve spontaneously over 2–3 months and if suspected, can be closely monitored with short interval follow-up MRI. Symptoms from increased vasogenic edema can be managed with steroid therapy as previously described. Progression of imaging changes on subsequent imaging should prompt evaluation for radiation necrosis and/or tumor recurrence.
Chin Clin Oncol. 2022;11(2):11 © 2022 AME Publishing Company