Radiation Oncology/Toxicity/Brain

Normal tissue reactions Acute begin few hours after 1st treatment, progressively less severe with additional fractions mild headache, nausea Cause: radiation-induced permeability in blood-brain barrier Rx: corticosteroids Early-delayed begin 1-12 weeks after completion of RT, peak by 8 weeks, resolve spontaneously within 4 months transient, self-limited neurologic deterioration, somnolence, or focal encephalopathy headache, lethargy, exacerbation of neurologic symptoms, decline in long-term memory Cause: transient demyelination from damage to proliferating oligodendrocytes, plus changes in blood-brain barrier Rx: corticosteroids Late-delayed vary from asymptomatic white matter changes to cerebral atrophy, hemorrhagic vascular telangiectasia, neurobehavioral impairment, pituitary-hypothalamic dysfunction, radiation necrosis lassitude, personality changes, dementia, urinary incontinence, gait abnormalities Radiation necrosis: from 3 months, but usually 1-2 years after treatment. Very difficult to differentiate from tumor recurrence Rx: corticosteroids, surgical resection of necrotic area Radiation necrosis Studies External beam radiotherapy: Amsterdam; 2007 PMID 17555870 -- "Cerebral necrosis after 25Gy radiotherapy in childhood followed 28 years later by 54Gy radiotherapy." (Koot RW, Clin Neurol Neurosurg. 2007 Sep;109(7):607-12.) Case report. 34-year old with PCI 25 Gy in childhood. Then atypical meningioma treated with fractionated 54 Gy Outcome: 2 years later radiation necrosis, surgery confirmed Intergroup NCCTG/RTOG/ECOG (1986-1994) Randomized. 203 patients. Age >18. Included low grade astrocytoma, oligodendroglioma, or mixed oligoastrocytoma; pilocytic astrocytomas were excluded. Randomized to 50.4 Gy vs 64.8 Gy in 1.8 Gy/fx. RT technique: 2 cm margin around preoperative tumor volume, 1 cm margin for boost after 50.4 Gy. 5-years; 2002 PMID 11980997 — "Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study." (Shaw E et al. J Clin Oncol. 2002 May 1;20(9):2267-76.) Median F/U 6.4 years Toxicity: crude incidence of severe, life-threatening, or fatal radiation necrosis was 1% in low-dose vs. 6% in high-dose group (2-yr actuarial rates 2.5% vs. 5%). Radiation necrosis of brain stem leading to death recorded even at 50.4 Gy Washington University (1974-1976) 1985PMID 4070632 The risk of cerebral radionecrosis in relation to dose, time and fractionation. A follow-up study. (Marks JE, Prog Exp Tumor Res. 1985;29:210-8.) Brain necrosis: 18% incidence with doses > 64.8 Gy, compared to 0% with doses <57 Gy 1981 PMID 6260715 -- "Cerebral radionecrosis: incidence and risk in relation to dose, time, fractionation and volume." (Marks JE, Int J Radiat Oncol Biol Phys. 1981 Feb;7(2):243-52.) 152 patients with brain/pituitary tumors. Pathology done in 17% patients. Necrosis pathologically confirmed in 7 patients (5%), didn't vary with type of tumor. Median time to development 14 months (6 months - 2 years) Conclusion: no radiation necrosis <54 Gy in 30 fractions UCSF; 1980 PMID 7007303 -- "Therapeutic irradiation and brain injury." (Sheline GE, Int J Radiat Oncol Biol Phys. 1980 Sep;6(9):1215-28.) Review. >100 reported cases of injury in literature analyzed, 80 evaluated. Analyzed for acute reactions, early delayed reactions, leukoencephaly, and late delayed reactions 20 patients with dose <50 Gy, but 17 had daily fractions 2.5 - 37.5 Gy). If dose 52 Gy in 2 Gy/fx, rate <0.5%, necrosis becomes a risk at 50-60 Gy in 2 Gy/fx Radiosurgery: Cleveland / Case Western PMID 16226848 -- "12 Gy gamma knife radiosurgical volume is a predictor for radiation necrosis in non-AVM intracranial tumors." (Korytko T, Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):419-24.) Retrospective, 129 pts with 198 non-AVM tumors followed with MRI every 3-6 months. Symptomatic radiation necrosis correlated with 12 Gy volume. Risk of asymptomatic radiation necrosis did not relate to 12 Gy volume. Treatment MD Anderson; 2007 PMID 17236958 -- "Effect of bevacizumab on radiation necrosis of the brain." (Gonzalez J, Int J Radiat Oncol Biol Phys. 2007 Feb 1;67(2):323-6.) Retrospective. 15 patients with malignant brain tumors treated with bevacizumab (5mg/kg/2-week or 7.5mg/kg/3-week). Radiation necrosis in 8 patients. MRI studies reviewed Post-treatment MRI: abnormality reduction in all 8 patients. Average reduction in daily dexamethasone 8.6 mg Conclusion: Bevacizumab can reduce radiation necrosis, by decreasing capillary leakage and associated brain edema Review Fox Chase; 1995 PMID 7677836 -- "Radiation response of the central nervous system." (Schultheiss TE, Int J Radiat Oncol Biol Phys. 1995 Mar 30;31(5):1093-112.) Review of anatomical, pathophysiological, and clinical aspects of radiation injury to CNS Spine cord: 5% radiation myelopathy probably induced at 57 - 61 Gy without chemo Brain: necrosis rarely <60 Gy; neurocognitive lower Somnolence Syndrome Considered under category of early delayed encephalopathy Syndrome: somnolence (mild drowsiness to overwhelming exhaustion), low-grade fever, nausea/vomiting, and headache Symptoms reported in 1929 in children treated with low-energy X-rays for ringworm of scalp Syndrome described in 1973 in children treated with cranial RT for ALL Classically occurs after whole brain irradiation (after cranial RT for ALL (15-58%), and also after TBI) Doses as low as 12 Gy TBI have been reported to trigger it (PMID 10989470) Fractional dose (1.8 Gy/fx vs 1.0 Gy/fx) doesn't appear to impact incidence of clinical somnolence Also described after focal RT to pineal region for meningioma Etiology unclear, but hypothesized to be transient demyelination, possibly in the reticular activating system (RAS) Effects on long-term cognitive function are contradictory Prophylactic steroids can reduce incidence, and can be helpful in recovery. However, most children can improve spontaneously and completely without treatment Ankara (Turkey)(1994-1996) -- oral dexamethasone 2mg/m2 vs. 4 mg/m2 Randomized. 32 patients with high-risk ALL. Prophylactic cranial RT 18/10. Arm 1) oral dexamethasone 2 mg/m2 during RT vs Arm 2) oral dexamethasone 4 mg/m2. Tapered in 5 days after RT 1998 PMID 9756169 -- "Reduced incidence of the somnolence syndrome after prophylactic cranial irradiation in children with acute lymphoblastic leukemia." (Uzal D, Radiother Oncol. 1998 Jul;48(1):29-32.) Outcome: Somnolence syndrome low dose 64% vs. high dose 18% (SS). Most common symptom drowsiness. Median time-to-development 4 weeks, duration of symptoms median 7 days (2-14 days). In all cases, symptoms subsided completely and spontaneously Conclusion: Steroids at 4 mg/m2 during cranial RT can reduce incidence of somnolence syndrome ? Institution -- RT dose 1 Gy/fx vs. 1.8 Gy/fx Randomized. 97 children with ALL, receiving cranial RT. Same chemotherapy including IT-MTX. Arm 1) 18/18 (@1 Gy/fx) vs. Arm 2) 18/10 (@1.8 Gy/fx) 1984 PMID 6593316 -- "The somnolence syndrome in leukemic children following reduced daily dose fractions of cranial radiation." (Littman P, Int J Radiat Oncol Biol Phys. 1984 Oct;10(10):1851-3.) Outcome: Clinical somnolence 58% in both groups (NS) Conclusion: RT dose fraction does not appear to impact incidence of somnolence Radiation-induced moyamoya syndrome Snehal S Desai et al. Radiation-induced moyamoya syndrome. Int J Radiat Oncol Biol Phys. 2006 Jul 15;65(4):1222-7. (PMID: 16626890) ( DOI: 10.1016/j.ijrobp.2006.01.038) A PubMed search of English-language articles, with radiation, radiotherapy, and moyamoya syndrome used as search key words, yielded 33 articles from 1967 to 2002. Patients who received RT to the parasellar region at a young age (<5 years) are the most susceptible to moyamoya syndrome. The incidence for moyamoya syndrome continues to increase with time, with half of cases occurring within 4 years of RT and 95% of cases occurring within 12 years. Patients with NF-1 have a lower radiation-dose threshold for development of moyamoya syndrome. Paulo Almeida et al. Moyamoya Syndrome after Radiation Therapy: a Clinical Report. Eur J Case Rep Intern Med. 2019; 6(12): 001337. (PMID: 31893204) Radiosurgery See also: treatment-specific information at Radiation Oncology/CNS/Arteriovenous malformation