Early and Late Brain Toxicity after Prophylactic and Curative Whole-Brain Radiotherapy with or without Re-irradiation

Early and Late Brain Toxicity after Prophylactic and Curative Brain Abstract Brain metastases (BM) are the most frequent intracranial neoplasms in adults. Due to the development of the imaging diagnosis and the efficacy of complex oncology treatment, there is a significantly increased overall survival of patients with malignancies. On this background, clinical cases with brain metastases are also with increasing frequency. In addition to surgery, their treatment involves the application of various radiotherapeutic techniques with different radiation volumes and fractionation of the radiation dose. We present four clinical cases with early and late neurotoxicity after radiotherapy (RT) on the prevention or treatment of brain recurrences or metastases. The prophylactic whole-brain radiotherapy (WBRT) is a standard approach in the limited or advanced stage of small cell lung cancer (SCLC). In multiple brain metastases, radiotherapy is a major healing method, involving a self- WBRT, a WBRT with a boost in solitary brain metastasis or radio surgery of 1-4 metastases followed by a WBRT. The purpose of this article is to define preventive measures in defining and planning different radiotherapeutic approaches in order to minimize early and late brain toxicity.


Introduction
Brain metastases (BM) are the most frequent (between 10-15%) intracranial neoplasms in adult patients [1]. BM may spread from any primary site, most common in lung, breast and gastrointestinal neoplasms [2]. BMs represents a significant health problem as it is believed that 20% to 40% of cancer people will develop metastatic cancer in the brain during their illness [3]. The incidence of BM is increasing as a result of the growing elderly population, advances in detection with imaging techniques, and (systemic) cancer treatments that prolong life and allow BM to develop [4][5][6]. Most trials focusing on brain metastasis patients evaluated the efficacy of various treatment options through common endpoints such as survival, imagistic response rate, neurologic status or time to intracerebral recurrence [7][8][9]. In this article, we present four clinical cases with early and late neurotoxicity after radiotherapy (RT) on the prevention or treatment of brain recurrences or metastases. We will try to identify preventive measures in RT planning in order to minimize these early and late side effects brain radiotherapy.

Clinical Cases
First clinical case A 73-year-old patient after fibrobronchoscopy (FBS) with histologically and immunohistochemically (IHС) proven small cell lung cancer (SCLC) (T4 N1 M1/pleural) was presented. First-line CT of the lung after 6 cycles of Ch -Tumor lesion of the right lobe bronchus with infiltration of the pleura -without dynamics. No secondary changes are reported bilaterally. Mediastinum -without enlarged lymph nodes bilaterally. A small discrete effusion in the right pleura was reported. CT of the brain -No secondary changes in the brain parenchyma. Ventricular system -unexpanded ( Figure   1).

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Second clinical case
We present a 57-year-old woman with solitary intracranial plasmacytoma (SICP). Intensively modulated prophylactic wholebrain radiotherapy (WBRT) with DD 3 Gy up to TD 30 Gy / Biologically equivalent dose (BED) 38 Gy / 5 times per week was performed. The first local recurrence occured 1.5 years after the WBRT, and the second local recurrence occured 5 months after its       : CT of the brain -A parasagittal cystic lesion up to 14 mm in size in the right parietal supratentorial area with frontoparietal edema, most likely a necrotic brain tissue.

Discussion
Due to the development of the imaging diagnosis and the efficacy of complex oncology treatment, there is a significantly increased overall survival of patients with malignancies. On this background, clinical cases with brain metastases are also increasing. In addition to surgery, their treatment involves the application of various radiotherapeutic techniques with different radiation volumes and fractionation of the radiation dose.

Prophylactic whole-brain radiotherapy (PWBRT)
The whole-brain radiotherapy (WBRT) is conducted for two therapeutic purposes -preventive or prophylactic and curative.
PWBRT is a standard approach in the limited or advanced stage of small cell lung cancer (SCLC) in clinical remission after systemic chemotherapy (Ch) and local pulmonary radiotherapy (RT).
Without PWBRT, 60% of SCLCs develop brain metastases (BM), and they are reduced to 20% after it was performed [10]. PWBRT is also recommended for non-small cell lung cancer (NSCLC) [11][12][13][14][15], in which a significant reduction in BM of 18% to 8% without improved overall survival (OS) has been achieved [16] in contrast to SCLC, where OS is significantly increased [17,18]. The purpose of PWBRT is to destroy microscopic metastatic tumor cells in the brain before their clinical manifestation. Radiation brain effects after PWBRT are divided into acute, subacute and chronic [19]. Acute side effects occur during or one to two weeks after completion of PWBRT.
They are expressed by general fatigue, alopecia and symptoms associated with increased cerebral edema -headache, nausea, focal brain deficits, a pronounced mental change [20]. These acute symptoms gradually subside in a large proportion of patients. On MRI, diffuse cerebral edema is visualized [21]. Subacute symptoms

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Copy@ Lena Marinova develop immediately after the completion of RT or three months after its completion. They are relatively rare and limited, mainly to drowsiness syndrome and less commonly as leukoencephalopathy [20]. 3 months after 10x3Gy PWBRT, the condition of a 73-yearold SCLC patient, who underwent 6 courses of Ch (Cisplatin and Etoposide) deteriorated. CT and MRI visualize extensive cerebral edema in the left hemisphere, without brain metastases (Figure 3 & 4). In children with leukemia after PWBRT, there is a "radiation somnolence syndrome" characterized by somnolence often associated with headache, nausea, vomiting and sometimes fever.
The necessary treatment is the administration of corticosteroids, but it should be noted that these complaints may resolve spontaneously [22]. Somnolence is more common in children with PWBRT with concomitant chemotherapy (methotrexate/ intrathecal) [23]. Pathophysiologically, this somnolent syndrome is associated with transient demyelination of the white matter. On the other hand, it should be noted that leukoencephalopathy is considered a more severe manifestation of demyelination and may be fatal. These changes in white matter are much more common in adult patients with concomitant chronic cerebrovascular ischemia [20]. Symptoms are usually mild and stabilize or resolve. Imaging -CT and MRI with intravenous contrast varies from diffuse cerebral edema to increased accumulation of contrast [21]. In the presented adult patient it can be seen that against the background of antiedema medication treatment (Dexamethasone and Mannitol), the symptoms was not transient, on the contrary, they worsen ( Figure 3 & 4). Subacute encephalopathy usually begins two or three months after cerebral RT but may occur 2 weeks to 4 months after completion of PWBRT. It is usually seen in patients with SCLC after chemotherapy of the primary tumor. The pathogenesis of subacute encephalopathy is due to demyelination due to damage to the oligodendroglia with subsequent involvement of the myelin sheaths [22]. The progression of these changes leads to late effects manifested by radionecrosis [23][24][25]. Tissue necrosis is a distinct syndrome of radiation toxicity, thought to be the consequence of vascular endothelial cell damage, resulting in fibrinoid necrosis of small vessels and direct brain parenchymal necrosis. Occlusion of small blood vessels results in focal coagulative necrosis, capillary leakage, and demyelination of the surrounding brain parenchyma [26,27]. The relationship between PWBRT and late brain toxicity was analyzed in 264 patients with limited stage SCLC [28].

Curative whole-brain radiotherapy (WBRT)
Brain metastases represent a significant cause of cancer morbidity, occurring in around 30% of patients with a malignancy originating outside the central nervous system [29].
The management of intracranial metastatic disease is made complicated by the impermeability of the blood-brain barrier to many chemotherapeutic agents, rendering this region a 'sanctuary site' for malignancies, most commonly breast, lung, melanoma, and renal cell carcinoma [30]. WBRT was the historic standard of care prior to the widespread use of radiosurgery (RS) [31].
For patients with multiple brain metastases or presenting with uncontrolled primary tumor or multiple extracerebral metastases, WBRT is the treatment of choice, associated with corticosteroids as symptomatic treatment. Fractionation schedules are varied (30 Gy in 10 fractions, 20 Gy in 4 or 5 fractions), but none has proven superiority in terms of prolonging OS [32]. Still, it has been postulated that patients with a more favorable survival prognosis could benefit from a protracted radiotherapy (RT) regimen, whereas patients with a poorer prognosis should receive shorter course RT [33]. For the statistical analysis of these heterogeneous regimens, total doses were normalized to 2 Gy and the biologically equivalent dose (BED) was calculated, with a α/β ratio of 3, for long term toxicities in brain tumors [34]. There are different opinions about the radiation toxicity on the cognitive brain function after WBRT -no changes, reported adverse effects and even initial improvement [35][36][37][38][39][40]. However, the principle concern with WBRT, particularly in patients with a more favourable prognosis, is the negative impact on neurocognitive function and quality of life [41].
WBRT in brain metastases has been associated with subacute and late neurotoxicity, causing reduced cognitive function, including reduced memory [20]. The second clinical case is an extremely rare extramedullary brain plasmocytoma (EMBP) with intracranial localization [42]. Craniocerebral solitary plasmocytom may occur from the skull (the grain or cranial base), the solid brain sheath and less frequently in the brain parenchyma [43].
There are two forms of the solid craniocerebral plasmocytoma:

1.
Primary plasmocytom expanding from the cranial bones and 2.
There are publications for full cure after biopsy and local RT, as solitary plasmocellular neoplasms are extremely radiosensitive [49]. In EMBP after self-RT without surgery, increased OS has been reported [50]. RT up to TD 50 Gy for 5 weeks on the cranial base EMP achieves excellent healing output and local tumor control (LTC) over 85% [51]. Optimal treatment in most patients with EMBP is local RT up to TD 40-50 Gy with DD 1.8-2 Gy [52]. After operating in the clinical case with EMBP, the WBRT (10 fractions with DD 3Gy up to TD 30 -BED 38 Gy) was conducted, instead of local radiation in the tumor bed up to TD 50Gy. This is the reason for the first recurrence, that was operated. Subsequently, after one year, a second recurrence appears, which we irradiated locally up to TD 45Gy ( Figure 6). Although the total BED does not exceed 100Gy, due to the extremely radiosensitiv plasmocytoma, brain tissue necrosis develops (Figure 7/B).

Whole-brain radiotherapy with boost RT
Although different fractionation schedules of WBRT do not influence survival [32], it appears that escalating the dose to the metastatic lesions increases intracerebral control as well as OS, compared to WBRT alone [53,54]. WBRT with 3D conformal boost is a feasible technique which improves the quality of life (QOL) of patients with a reduced number of brain metastases, regardless of the fractionation regimen or the total dose administered to the metastatic lesions [34]. In the third clinical case, with NSCLC after WBRT with VMAT boost in the brain metastasis to can result in a chronic inflammatory response that influences hippocampal cell proliferation, which has stimulated interest in trials using anti-inflammatory agents to prevent radiation injury.
In addition, research has shown that damage to the hippocampus that is caused by radiation can lead to impairments in learning, (short-term) memory, and spatial processing [66,67]. By avoiding the hippocampal neural stem cells during WBRT, cognitive decline might be prevented or minimized [68].
In  [71]. In adult patients, the five-year progression-free survival rate ranges from 45% to 78% depending on the risk class [72][73][74]. In the young patient with a primary brain PNET, the bone marrow transplantation with stem cells was conducted, 1 year after which we diagnosed third local recurrence (Figure 13). For a period of   [76]. ii.
iii. The human brain contains areas with mitotically active cells that retain their ability to divide and differentiation in neural or glial brain cells throughout life [91]. They are known as neural stem cells, which are located in two specific brain areas in the subgranular zone in the dentate girus (part of the hippocampus) and the subventricular zone adjacent to the lateral part of the temporal horn and the occipital part of lateral ventricles [92,93]. These cells can migrate into the brain to the affected areas to settle in the neural cortical or white brain damage [94,95]. The preservation of neural stem cells during PWBRT and culture WBRT should affect the possibility of restoring induced brain damage from cranial RT and help keep the neurological function. A dosimetric reduction in these zones with intensive modulated WBRT is possible [96].
iv. Re-irradiation is frequently undertaken for isolated brain relapses. A meta-analysis of brain re-irradiation found no cases of necrosis if the TD lower than 100Gy (2 Gy daily fraction dose; α:β = 2 Gy) was [97]. In humans, there is evidence that the risk of myelopathy is low at radiation doses up to a median cumulative BED 135Gy, when the time interval between reirradiation is not shorter than six months and the dose for each course is <98Gy BED [98].
v. Large BM can be defined according to their diameter or volume, with lesions measuring either ≥2 or ≥3 cm in diameter or ≥ 4 cm3 [99][100][101][102][103][104][105] being considered in this category. The combination of surgery with post operative radiation either to the cavity or to the whole brain (WBRT), SRS alone or hypofractionated RT have been proposed to address these tumors [100][101][102][103][104][105][106]. Treatment can be administered using different delivery systems and is usually linear-accelerator based to avoid head frame fixation as patients are usually treated with multiple fractions. Hypofractionated RT is a viable alternative to WBRT for the upfront treatment of brain metastasis that are not amenable to radiosurgery or surgery, or in the postoperative setting [107].

Conclusion
Due to the development of the imaging diagnosis and the efficacy of complex oncology treatment, there is a significantly increased overall survival of patients with malignancies. On this background, clinical cases with brain metastases are also increasing.
In patients over 60 years of age with vascular changes, the daily There is evidence that the risk of myelopathy is low at radiation doses up to a median cumulative BED 135Gy, when the time interval between re-irradiation is not shorter than six months and the dose for each course is <98Gy BED.