br Patients and methods According
Patients and methods According to previous clinical experiences, lesions were treated with a dose of 3 x 9 Gy over three consecutive days [10,, , ]. Doses were usually prescribed to the 80% isodose line with a minimum 95% target coverage of the prescribed dose. The planned radiation dose was delivered by a linear accelerator (Varian Clinac 600 DBX or TrueBeam STx) by using dynamic conformal arc therapy or modulated arc therapy. Dexamethasone therapy was started by the first day of treatment at doses of 4 mg PO per day and generally discontinued within one week. Patients were examined every 1–2 months. At each visit, the neurological status and the severity of complications were scored according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.03 (NCI-CTCAE) . MRI scans were performed every 2–3 months, and responses determined according to the RANO criteria , with tumor measurements of all scans carried out by same radiologist (A.R.) Diagnoses of tumor progression or RN were determined on the basis of histologic findings (for patients who underwent surgical resection) or by imaging using MRI and 3,4-dihydroxy-6-(18)F-fluoro-l-phenylalanine (F-DOPA) PET-CT. In summary, tumor progression was defined as any increase of lesion on postcontrast T1-weighted images in at least two subsequent MRI scans if associated with: - a cerebral blood volume ratio (rCBV) >2.0 at dynamic susceptibility-weighted contrast-enhanced perfusion images (calculated by dividing the lesion CBV value by the mean CBV value in the normal white matter), and – maximum lesion to maximum background uptake ratio (SUVLmax/Bkgrmax) >1.59 at F-DOPA PET-CT. Shrinking or stable lesions over a period of at least 6 months associated with: - a rCBV <2.0 and – a SUVLmax/Bkgrmax <1.59 were diagnosed as RN. Following these criteria, the reported sensitivity and specificity of MRI and PET-CT are of 86.7% and 90%, and 92.3% and 68.2%, respectively .
Discussion Multi-fraction SRS has been increasingly used to treat large Dynasore metastases [, , , ]. Using SRS at doses of 24–35 Gy given in 3–5 fractions to either intact or resected brain metastases, retrospective studies have shown 1-year LC rates from 70% to 90%, with a variable risk of RN of 2% to 15% [, , ,17,, , , ]. Currently, there is no study comparing the outcome of single- or multiple-fraction SRS to the resection cavity. In Brown et al.  randomized trial, cavity volumes up to 14·3 cc received single SRS doses of 17–20 Gy, whereas larger cavities received radiation doses of 12 to 15 Gy. The 6-month and 12-month estimates of resection cavity control were 80.4% and 60.5%, resulting inferior to those observed with WBRT (87.1% and 80.6%, p = 0·00,068). Using similar doses of 16, 14, and 12 Gy for target volumes of ≤10 cc, 10.1–15 cc, and >15 cc, respectively, Mahajan et al.  observed 12-month LC rates of 43% in patients receiving surgery alone and 72% in those receiving surgery and SRS, (HR 0.46, 95%CI 0.24-0.88, p = 0.015). Notably, the rate of recurrence following resection and postoperative SRS was 44% for lesions ≥ 3 cm. The apparent better control of 85% at 1 year observed in our study may, at least in part, be explained by the higher BED12 of our regimen as compared with BED12 of single doses of 12–16 Gy, as used in Brown and Mahajan studies when treating large cavities [6,7]. The efficacy of different postoperative SRS schedules in terms of LC and toxicity needs to be evaluated in prospective trials. A few retrospective studies indicated that LC following surgery and SRS is superior to SRS alone [13,14]. In a series of 213 patients with 223 treated large brain metastases from different histologies receiving SRS alone or combined surgery and SRS, given either preoperatively or postoperatively, Prabhu et al.  found that surgery and SRS resulted in lower 1-year local recurrence rates (36.7% vs 20.5%; P = 007), although the treatment was associated with a higher rate of RN. Similar results have been reported in another retrospective study of 120 consecutive patients with melanoma brain metastases who received mfSRS (3 x 9 Gy) or surgery and postoperative mfSRS to the resection cavity at Rome University Sapienza; 1-year local failure rates were 28% and 12% (p = 0.02), respectively. The use of different treatment schedules and the inclusion of only “radiosensitive” NSCLC brain metastases may, at least in part, explain the different results observed in our study.