Excessively Delayed Radiation Changes After Proton Beam Therapy for Brain Tumors: Report of Two Cases

Case 1

A 44-year-old woman with no significant medical history presented to our institution for a second opinion regarding a multiseptated mass in the right occipital lobe. Over the past year, she experienced persistent headaches, along with nausea, dizziness, and blurred vision while driving. Her headaches remained intractable despite the use of analgesic medications for the past month, prompting her to seek medical attention at a nearby hospital. At that time, her only neurologic abnormality was left homonymous partial hemianopsia with normal visual acuity.

Brain CT and MRI scans performed at the initial hospital showed an approximately 5-cm ovoid multiseptated mass with internal hemorrhage (Fig. 1A-C). To rule out a vascular abnormality, transfemoral carotid angiography was performed, which revealed no specific tumor staining or vascular abnormality except slightly decreased perfusion in the right occipital lobe.

Fig. 1
T1 (A), T2 (B and D), and T1 gadolinium-enhanced (C and E) MRI images preoperatively (upper row) and postoperatively, at 3 months before radiation therapy (lower row). (F) Proton beam therapy planning image (isodose line 100% represents 5,500 cGy delivered in 25 fractions).

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Craniotomy and tumor removal were performed at our institution after preoperative assessment, resulting in gross total resection with clear surgical margins (Fig. 1D and E). Final pathology results indicated the presence of cellular proliferation with hyalinized vasculature, consistent with astroblastoma, which was not graded according to the World Health Organization classification system but was assumed to be low grade (Fig. 2). The patient was discharged from the hospital with no acute complications or neurologic abnormalities.

Fig. 2
Photomicrographs of surgical specimens (hematoxylin & eosin, ×100) showing a low-grade glial neoplasm composed of radially arranged tumor cells with centrally located stromal blood vessels. Typical perivascular and pericellular hyalinization is observed.

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Three months after surgery, the patient underwent postoperative PBT at 5,500 cGy/25 fractions using two beam ports, covering the tumor margin as in the treatment of malignant glioma (Fig. 1F). After completing PBT, the patient attended regular outpatient follow-up evaluations to monitor for tumor recurrence and other abnormalities through symptom assessment and brain MRI. Follow-up MRI scans were scheduled beginning at 3 months post-RT and continuing at 6-month intervals for up to 2 years, then yearly until 5 years after surgery. Up to 3 years following RT, there were neither signs of local recurrence or radiation changes at the tumor bed nor other abnormalities outside the tumor resection cavity on MRI (Fig. 3A-C). However, at 4 years post-RT, new changes were identified on MRI suggesting radiation-induced changes or tumor recurrence (Fig. 3D-F). The existing tumor resection cavity had decreased in size, and there was linear enhancement around the cavity and accompanying perilesional edema showing T2/FLAIR high signal intensity but no evidence of diffusion restriction. The patient was asymptomatic and had no neurologic abnormalities except her preexisting visual field defect.

Fig. 3
T1 (A and D), T2 (B and E), and T1 gadolinium-enhanced (C, F, and H) MRI at 3 years post-radiation (upper row), 4 years post-radiation (middle row), and at 4 years and 3 months post-radiation (lower row). (G) MR perfusion shows decreased cerebral perfusion of the lesion, and (I) MRI shows slight decrease of enhancement of the lesion at 4 years and 9 months after PBT.

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To distinguish between tumor recurrence and delayed radiation changes, a perfusion brain MRI was performed 3 months later (Fig. 3G and H). It revealed reduced perfusion in the lesion, compared with surrounding normal brain tissue, and no growth of the enhancing lesion, indicating that the abnormalities likely represented asymptomatic delayed radiation changes, rather than recurrent tumor. A half-year later (4 years and 9 months after PBT) follow-up MRI showed a little, if any, decreased enhancement of the lesion (Fig. 3I) and we decided to have a year or more follow-up based on this assessment.

Case 2

A 50-year-old woman with no significant medical history, presented to our institution for a second opinion regarding a lobulated mainly cystic or necrotic mass in the right jugular fossa with infratemporal fossa extension on MRI. She had been experiencing headaches for the past several months since undergoing tooth implantation, which were eventually investigated with a brain MRI at another hospital. Neurologic examination at that time revealed no focal neurologic deficits.

Brain CT and MRI at the initial institution revealed an ovoid 4.5-cm mass producing widening of the jugular foramen and erosion of the petrous bone, with minimal intracranial involvement (Fig. 4A). The mass exhibited T2 high signal intensity, T1 isosignal intensity, and strong enhancement with gadolinium (Fig. 4B and C), findings highly suggestive of a paraganglioma or schwannoma. As the patient was asymptomatic, we recommended RT. Following consultation with our radiation oncologists, the patient underwent PBT of 6,000 cGy/25 fractions without histologic examination. Although we used two beam ports of posterior-anterior and right-anterior-oblique, the maximum dose to the brainstem was 6,140 cGy, and the relative volume of the brainstem receiving 5,400 cGy was 3.7% (Fig. 4D).

Fig. 4
Pretreatment brain CT (A) and MRI (B and C) images showing widening of the jugular foramen and a partially enhancing ovoid 4.5-cm extra-axial mass eroding the petrous bone. (D) Proton beam therapy planning image showing two ports were used for beam direction: posterior anterior (PA) and right anterior oblique (RAO) (isodose line 100% represents 6,000 cGy delivered in 25 fractions).

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After completing PBT, the patient was scheduled for regular outpatient follow-ups with brain MRI at 6 months and 1 year post-RT and yearly thereafter. Up to 2 years following PBT, there were neither signs of tumor progression nor radiation changes at the tumor bed or adjacent brain on MRI (Fig. 5A and B). However, new changes were identified on the follow-up MRI at 3 years post-PBT. A 1-cm round, enhancing lesion with perilesional edema showing T2 high signal intensity consistent with radiation-induced changes was observed, but there was no evidence of diffusion restriction at the ipsilateral middle cerebellar peduncle (Fig. 5C and D). At this time, the patient had no symptoms or neurologic deficits, and a follow-up MRI was scheduled in 6 months. However, 3 months later, the patient began to experience loss of sensation in the lower part of the right side of her face and decreased taste sensation. Despite the administration of corticosteroids, her symptoms worsened, and she developed a gait disturbance, dysphagia, and dysarthria 3 months later. Brain MRI at 3 years and 6 months after PBT revealed new enhancing lesions in the ipsilateral cranial nerve V entry zone, medulla, and middle cerebellar peduncle, with perilesional edema (Fig. 5E-H). The patient was treated with bevacizumab (7 mg/kg every 2 weeks) for presumed delayed cerebral RN. MRI after 2 cycles of bevacizumab showed reduced enhancement in the area of necrosis, but her symptoms were not improved. The patient was subsequently lost to follow-up.

Fig. 5
MRI images after proton beam therapy (PBT). A and B: MRI images at 2 years after PBT showing neither tumor growth nor radiation changes in adjacent brain tissue. C and D: MRI at 3 years post-PBT revealing T2 high-intensity signal changes in the adjacent cerebellum with central enhancement, suggestive of radiation-induced changes. E–H: MRI at 3 years and 6 months after PBT showing additional enhancing lesions with perilesional edema in the medulla and trigeminal entry zone, correlating with the patient’s developing symptoms.

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Chronologic patterns of radiation changes after brain irradiation

Radiation-induced changes are well-known complications following RT for brain tumors, and vascular damage has been proposed as an important mechanism of these changes [6, 7]. Radiation can increase vascular permeability and create hyalinization in small vessels through endothelial cell damage, leading to the development of cerebral parenchymal edema, hemorrhage and ultimately resulting in fibrinoid and necrotic changes [7]. The pathogenesis of RT-induced changes involves three main aspects: vascular injury secondary to endothelial cell damage; direct glial cell injury; and immune cell-related inflammation involving T-cell lymphocytes, macrophages, and cytokines [7, 8].

RT changes based on the time after treatment typically occur in three stages [1, 8]. Acute radiation changes appear during RT or within the first 1–2 months following completion of RT and are characterized by cerebral edema resulting from capillary damage. Subacute radiation changes refer to alterations occurring approximately 2–6 months after completing RT. The predominant mechanism at this stage is usually glial cell injury, with cell apoptosis secondary to oligodendrocyte damage and demyelination being crucial factors in this process. Chronic radiation changes manifest after 6 months following RT completion. Characteristically, these changes involve immune cell-mediated inflammation resulting from vascular and glial cell damage [7]. Infiltration of immune cells triggers chronic inflammation and necrosis through tissue ischemia. As acute and subacute RT changes are mostly reversible and transient, the true incidence and consequences of these changes are unclear. Furthermore, chronic RT changes may occur without preceding acute and subacute RT changes. Thus, it is difficult to know the chronologic changes or continuity of RT changes according to the time interval after RT.

In an earlier report from the 1980s in the era of CT imaging, RN was observed at various time intervals after RT, from 4 to 90 months post-RT [9]. Indeed, there are no specific definitions for when changes are considered “excessively delayed” after RT. However, the impact of previous radiation is generally thought to diminish after 3–5 years, especially when considering re-irradiation [10]. In most patients, cerebral RN after RT becomes apparent 1–2 years after treatment and continues to occur even beyond 5 years [11, 12]. Reports suggest that these changes are often associated with vascular insufficiency, hemorrhage, and continued cystic changes [6, 7]. However, patients like case 1 described here, in whom RT changes appeared suddenly on brain MRI at 4-year follow-up, are not well documented.

Risk factors for radiation changes include a higher dose per fraction, larger treatment volume, higher cumulative dose, and shorter time interval between courses of treatment (in cases of re-irradiation) [1, 13]. In a study by Andruska et al. [5], a large fraction dose of 30 Gy/5 fractions for brain metastasis resulted in a 15% incidence of RN, which occurred at a median of 6.9 months after treatment. In contrast, smaller fraction doses with a higher number of fractions (5,500–7,500 cGy/30–36 fractions) were associated with a 1.3% incidence of brainstem necrosis at a median of 28.5 months after intensity-modulated RT for nasopharyngeal cancer [14].

RT changes after PBT

There is increasing concern that the proton relative biological effectiveness (RBE) for injury to normal tissues may be significantly underestimated, leading to higher frequency and severity of toxicities than expected when analyzing dosimetric indices [15]. RBE in normal tissues downstream of the target could be higher than anticipated because linear energy transfer increases with increasing depth when protons decelerate. Data suggest that the average proton RBE can be considered 1.1–1.15 at the entrance of the spread-out Bragg peak, increasing to 1.35 at the distal edge of the peak and up to 1.7 in the distal fall-off [16].

In these cases, the prescribed radiation dose was higher in case 2 compared to case 1 (6,000 cGy/25 fractions and 5,500 cGy/25 fractions, respectively). Furthermore, while case 1 exhibited a delayed radiation change mainly in the cerebrum around resection cavity, which was directly exposed to a high dose, in case 2, a small volume of high-dose proton radiation was directed to the brainstem which is relatively radiosensitive. In the cerebrum, radiation-induced cerebral necrosis may not necessarily manifest as symptomatic lesion; however, when it occurs in the brainstem, it can immediately lead to critical symptoms and be potentially fatal.

As described in Fig. 4D, the brainstem was relatively close to the target, and the distal part of the right-anterior-oblique beam terminated at the surface of the right side of the brainstem, even though the use of multidirectional beams to reduce the risks of brainstem damage. This phenomenon in case 2 might be related to the uncertainty of RBE, which is a characteristic of PBT. Since RBE characteristics should be considered when performing PBT, we need a sufficient understanding of RBE and a suggestion of solution for RBE uncertainty to minimize injury to normal tissue. In recent years, there has been a consideration in proton therapy planning to minimize the formation of the distal part of the proton beam on critical organs at risk, such as the brainstem by altering the beam angle or utilizing lateral beam penumbra [17, 18]. This approach aims to reduce the risks associated with dosimetry aspects such as range uncertainty and increasing RBE.

The time to develop cerebral RN after PBT seems to vary according to previous reports. Cerebral RN after PBT (mean total cranial radiation, 54.0 Gy) was reported at a median of 5.0 months (range, 3–11 months) after RT in pediatric patients with brain tumors, although these patients received concomitant systemic chemotherapy, which is another risk factor for RN [19]. In 101 patients with skull base chordoma or chondrosarcoma treated with hyperfractionated (twice per day) PBT consisting of 78.4 Gy RBE (range, 60–95 Gy) in 56 fractions, cerebral RN began to appear more than 3 years after PBT, with the first RN observed at 44 months post-PBT [20]. As current evidence regarding proton RBE being limited, we need more clinical research including dosimetric analysis to determine the expected time and incidence of RN after PBT.

Conclusion

In this report, we present two patients with excessively delayed cerebral necrosis after PBT, challenging the conventional understanding of the temporal progression of radiation-induced effects. Follow-up MRI in both patients showed no RT-induced changes prior to 3 years, raising questions about the unique chronologic patterns of radiation changes after PBT. Further research is necessary to elucidate the specific risks and patterns associated with delayed RN after PBT.