Stereotactic radiosurgery (SRS) with >5 fraction (fr) has been increasingly adopted for brain metastases (BMs), given the current awareness of limited brain tolerance for ≤5 fr. The target volume/configuration change and/or deviation within the cranium during fractionated SRS can be unpredictable and critical uncertainties affecting treatment accuracy, plus the effect of these events on the long-term outcome remains uncertain. Herein, we describe a case of two challenging BMs treated by 10 fr SRS with a unique dose-gradient optimization strategy, in which the large cystic tumor revealed an intriguing correlation of such inter-fractional change with late radiographic sequela, suggesting a dose threshold for attaining longterm local tumor control and being immune to symptomatic brain necrosis.A 63-year-old man presented with two cystic lesions located in the left parietal lobe (19.9 cm 3 ) and pons (1.1 cm 3 ) one month after surgery for esophageal squamous cell carcinoma. The principles for 10 fr SRS were as follows: (1) very inhomogeneous gross tumor volume (GTV) dose covered by 53 Gy, biologically effective dose with an alpha/beta ratio of 10 (BED 10 ) of ≥80 Gy; (2) moderate dose spillage margin outside the GTV boundary: 2-2.5 mm outside the GTV margin was covered by 37 Gy, BED 10 of ≈50 Gy; (3) concentricallylaminated, steep dose increase inside the GTV boundary: 2 mm inside the GTV margin was covered by ≥62 Gy, BED 10 of ≥100 Gy. At the completion of SRS, the parietal lesion showed significant shrinking and dorsomedial shifting with slight evisceration of the GTV, followed by marked regression of the parietal lesion within four months. At 13.5 months, a cystic change was noted at the dorsal part of the remnant. At 16.7 months, ventral enhancement gradually expanded without enlargement of the dorsal cystic component. On the T2-weighted images, the dorsal low-intensity remnant and ventral iso-intensity blurry-demarcated component were contrasting. Pathological examinations during and after lesionectomy at 17.4 months revealed necrosis only. At 30.5 months, the patient had a left visual field defect without recurrence. In contrast, the pons lesion showed no notable change during 10 fr SRS and nearly complete remission over six months with its sustainment without radiation injury at 30.5 months.Taken together, 10 fr SRS with a sufficient BED 10 can provide superior tumor response and safety for BM that is not amenable to ≤5 fr SRS. Although a very inhomogeneous GTV dose can contribute to early and adequate tumor shrinkage and subsequent local tumor eradication, significant tumor shrinkage during fractionated SRS (fSRS) inevitably results in unnecessary higher dose exposure to the surrounding brain, which could lead to late radiation injury requiring intervention. The optimum dose should be determined through further investigation, in consideration of the dynamic and unpredictable nature of the actual absorbed doses to both the tumor and the surrounding brain.

Purpose: Several factors, including the surrounding brain volume receiving specific doses, have hitherto been reported to correlate with brain radionecrosis (BR) after single or fractionated stereotactic radiosurgery (sSRS or fSRS) for brain metastases (BMs); however, those, especially for fSRS, have not yet been fully elucidated. Furthermore, the clinical outcome data of patients with BM treated with SRS using Vero4DRT are extremely limited. Therefore, this study aimed to demonstrate the incidence of BR requiring intervention (BRRI) and its highly correlated factors.Materials and Methods: Patients with BMs treated with sSRS or fSRS using Vero4DRT at Toyohashi Municipal Hospital between July 2017 and June 2021 were retrospectively reviewed, of whom patients were available for at least 20 weeks of magnetic resonance imaging follow-up from SRS were included, and analyzed. The prescribed dose fractionation schemes to the planning target volume (PTV) boundary included 24 Gy (sSRS), 35 Gy (5 fractions [fr]), 42 Gy (10 fr), and 30 Gy (3 fr), according to the tumor volume and location. The volume of the surrounding normal brain receiving 84 Gy (V84 Gy, biologically effective dose [BED 2 ] based on a linear-quadratic model with an alpha/beta ratio of 2, single-dose equivalent [SDE] to 12 Gy), V112 Gy (BED 2 , SDE to 14 Gy) for all lesions, and all irradiated volume, including gross tumor volume (GTV) receiving 81.6 Gy (81.6 Gy vol., BED 2 ) for fSRS were calculated, for which cerebrospinal fluid and bone volumes were cautiously excluded. The diagnosis of tumor progression or BR dominance was based on serial T1/T2 matching.Results: Sixty patients with 120 lesions (65 treated with sSRS and 55 treated with fSRS) were included in the final analysis, with a median follow-up period of 65 weeks. The local control rate at one year was 87.5%. The cumulative incidence of BRRI within two years was 11.5%. The risk of symptomatic BR was significantly higher for V84 Gy >10 cc (p <0.001) and V112 Gy >5 cc (p = 0.021). In the fSRS group, the cumulative incidence of Grade 3 BR and those requiring resection was significantly higher for 81.6 Gy vol. >14 cc (p = 0.003 and p = 0.004, respectively). The coexistence of viable tumor tissue and BR could not be ruled out for enlarging lesions after the nadir response, especially for fSRS, due to a lower BED 10 to GTV margin (<80 Gy, BED 10 ).Conclusions: Stereotactic irradiation with Vero4DRT provided efficacy and safety comparable to previous linear accelerator series, and most of the dose-volume thresholds for BRRI presented in this study were notably lower than those reported in previous studies. This study suggests that the indication of single and up to 5 frSRS should be limited to far smaller tumors than previously acknowledged to ensure long-term safety and efficacy.

Five-fraction (fr) stereotactic radiosurgery (SRS) is increasingly being applied to large brain metastases (BMs) >2-3 cm in diameter, for which 30-35 Gy is the commonly prescribed dose. Since 2018, to further enhance both safety and efficacy, we have limited the five-fr SRS to approximately ≤3 cm BMs and adopted our own modified dose prescription and distribution: 43 and 31 Gy cover the boundaries of the gross tumor volume (GTV) and 2 mm outside the GTV, respectively, along with a steep dose increase inside the GTV boundary, that is, an intentionally very inhomogeneous GTV dose. Herein, we describe a case of symptomatic BM treated with five-fr SRS using the above policy, which resulted in a maximum tumor response with nearly complete remission (nCR) followed by gradual tumor regrowth despite obvious tumor shrinkage during irradiation. A 71-year-old man who had previously undergone surgery for squamous cell carcinoma (SCC) of the lungs presented with right-sided hemiparesis attributed to the para-falcine BM (27 mm in maximum diameter, 5.38 cm 3 ). The BM was treated with five-fr SRS, with 99.2% of the GTV covered with 43 Gy and 59% isodose. Neurological symptoms improved during SRS, and obvious tumor shrinkage and mitigation of perilesional edema were observed upon completion of SRS. No subsequent anti-cancer pharmacotherapy was administered due to idiopathic pulmonary fibrosis (IPF). Despite a maximum response with nCR at four months, the tiny residual enhancing lesion gradually enlarged from 7.7 months to 22.7 months without neurological worsening. Although a consistent T1/T2 mismatch suggested the dominance of brain radionecrosis, 11 C-methionine positron emission tomography showed increased uptake in the enhancing lesion. Pathological examination after total lesionectomy at 24.6 months revealed viable tumor tissue. Post-SRS administration of nintedanib for IPF may have provided some anti-tumor efficacy for lung SCC and may mitigate the adverse effects of SRS. The present case suggests that even ≥43 Gy with ≤60% isodose to the GTV boundary and ≥31-35 Gy to the 2 mm outside the GTV are insufficient to achieve long-term local tumor control by five-fr SRS alone in some large BM from lung SCC.