Local Control Failure After Five-Fraction Stereotactic Radiosurgery Alone for Symptomatic Brain Metastasis From Squamous Cell Lung Carcinoma Despite 43 Gy to Gross Tumor Margin With Internal Steep Dose Increase and Tumor Shrinkage During Irradiation

Abstract

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.

Nineteen-Month Immunity to Adverse Radiation Effects Following 5-Fraction Re-radiosurgery With 43.6 Gy for Local Progression After Prior 3-Fraction Radiosurgery for Brain Metastasis From Pan-Negative Lung Adenocarcinoma

“…Re-SRS in the present case was performed with curative intent, as the last opportunity to eradicate the recurrent lesion, considering the possibility of long-term survival and the presumed radio-resistance of pannegative LAC [3,9,10]. The GTV marginal dose of re-SRS in the present case seems to be one of the highest in the world: the BED 10 of 81.6 Gy is equivalent to a single fraction of 24 Gy [3,7,9].…”

“…Re-SRS in the present case was performed with curative intent, as the last opportunity to eradicate the recurrent lesion, considering the possibility of long-term survival and the presumed radio-resistance of pannegative LAC [3,9,10]. The GTV marginal dose of re-SRS in the present case seems to be one of the highest in the world: the BED 10 of 81.6 Gy is equivalent to a single fraction of 24 Gy [3,7,9]. Matsuyama et al have reported the significance of a BED 10 of ≥80 Gy covering 1-2 mm outside a GTV in multi-fr SRS, to ensure excellent local control of BMs in non-small lung cancer (NSCLC) [11]; this scheme has hardly been followed up or validated since 2013, and no other facilities seem to perform SRS in accordance with this policy, especially in the re-irradiation setting [1][2][3][4].…”

“…Although the administration of bevacizumab and steroids may attenuate the AREs to some extent, the achievement of sufficient tumor necrosis would contribute to lesion stabilization. If the maximum response is only a partial one, it will eventually smolder due to regrowth unless controlled by systemic therapy [3,9,10].…”

“…If WBRT had been used earlier in the present case, the brain morphology and cognitive function would have been considerably different from those shown in Figure 9 (E-H). Given the variability of current SRS schemes, there is still much scope and necessity to reconsider the dose fractionation and distribution of SRS itself [3,4,8,9,12]. Focal irradiation with reservation of WBRT and an appropriate combination of systemic therapy will increasingly play a central role in the management of patients harboring limited BMs from NSCLC and even small-cell lung cancer [4,17], just as whole-organ irradiation is rarely performed for lung or liver metastases.…”

“…Focal irradiation with reservation of WBRT and an appropriate combination of systemic therapy will increasingly play a central role in the management of patients harboring limited BMs from NSCLC and even small-cell lung cancer [4,17], just as whole-organ irradiation is rarely performed for lung or liver metastases. The first step to its success is to ensure the long-term efficacy and safety of SRS, for which SRS should aim for complete local tumor eradication beyond a good partial response, especially for limited BMs, in either the first-line or re-irradiation setting [3,7,9]. In addition, flexible and appropriate dose fractionation should be used instead of sticking to a limited one [3,7,8].…”