Clinical Application Research Of Hypofractionated Radiation Therapy For Patients With Complex Brain Metastases

Part Ⅰ:A Phase Ⅱ Trial of Concurrent Temozolomide and Hypofractionated Stereotactic Radiotherapy for Complex Brain MetastasesPurpose:Complex brain metastases(BMs)remain the most challenges owing to poor intracranial control rates and inferior survival.Here we present results of a phase II trial from a single institution,to assess the feasibility and toxicity of concurrent Temozolomide(TMZ)combined with hypofractionated stereotactic radiotherapy(HFSRT)in patients with complex brain metastases.Materials and Methods:Complex BMs were defined as large lesions(the tumor volume≥6cm3),lesions within or close to eloquent locations(such as the motor areas,basal ganglion;thalamus and optic apparatus),or multiple BMs(≥3).All the patients were treated with concurrent HFSRT and TMZ(administrated orally at a dosage of 75 mg/m2/day for at least 20 days).HFSRT was administrated with 52 to 52.5 Gy in 13 to 15 fractions for large lesions;32 to 42 Gy in 4 to 7 fractions for lesions close to eloqurent locations;39 to 45 Gy in]3 to]5 fractions for lesions in brainstem and 20 to 24 Gy in 1 to 2 fractions for other small lesions.For large lesions,the radiation field would be shrunk if the tumor volume was reduced after 10 to 13 fractions.The primary endpoint was overall survival(OS),and secondary endpoints included brain metastasis-specific survival(BMSS),local control rate(LCR),intracranial progression-free survival(IPFS)and toxicities.Results:Fifty-four patients with pathologically proven primary cancer and complex BMs were enrolled between 2010 and 2015.Among them,35 patients(64.8%)had 43 large lesions and the median volume was 12.4 cm3,3 patients(5.6%)were with BMs close to eloquent structures and the other 16 patients(29.6%)were with multiple BMs.Disease control rate(DCR)at 2 to 3 months after concurrent chemoradiotherapy was 94.4%.The median follow-up time was 30.6 months(6.2-70.8 months).The 1 year OS,BMSS,LCR and IPFS were 64.6%,94.7%,95.9%and 70.4%,respectively.The median survival time was 17.4 months.Nineteen patients(54.3%)with 22 large lesions’ volume reduced greatly during treatment and got re-planned,and the median reduction rate was 47.4%(9.0-88.0%).Treatment-related grade 3-4 adverse events were rare and included one grade 3 hematological toxicity and two grade 3 liver dysfunction.Conclusions:The treatment of HFSRT concurrent with TMZ is safe and can significantly prolong survival time compared with historical control in complex BMs.More than 50 percent of patients with large lesions get re-planned due to the reduction of tumor volume.Large phase III randomized trials are warranted to verify our results.Part Ⅱ:Retrospective Study of Hypofractionated Stereotactic Radiotherapy Combined with Temozolomide for Large Brain MetastasesPurpose:A retrospective study was conducted to investigate the feasibility and safety of adding temozolomide(TMZ)to hypofractionated stereotactic radiotherapy(HFSRT)for large brain metastases.Materials and Methods:Between 2009 and 2017,84 patients with brain metastases of larger than 6 cm3 undergoing concurrent TMZ and HFSRT(CRT group,n= 42)or HFSRT alone(RT group,n= 42)were analyzed.The radiation dose was 52 Gy in 13 fractions or 52.5Gy in 15 fractions.Patients were re-evaluated by magnetic resonance imaging(MRI)after 10 to 13 fractions.The radiation field would be shrunk if the gross target volume(GTV)was reduced.The treatment outcomes were evaluated 2 to 3 months after HFSRT.Local recurrence-free survival(LRFS),intracranial progression-free survival(IPFS),progression-free survival(PFS),overall survival(OS)and brain metastasis-specific survival(BMSS)were analyzed with Kaplan-Meier method,log-rank test and Cox regression analysis.Toxicities were recorded according to Radiation Therapy Oncology Group(RTOG)Central Nervous System toxicities and Common Terminology Criteria for Adverse Events(CTCAE)version 4.0.Results:The median GTV of CRT and RT group was 16.9 cm3 and 15.7 cm3,respectively.During treatment,75.0%of the lesions in CRT group shrank greatly and got re-planned,compared with 34.0%in RT group(p= 0.001).The disease control rate after 2-3 months of treatment was 100%vs.97.6%,respectively.The median follow-up time was 16.1 months(range,2.1-105.7 months).The 1-year LRFS(p= 0.040),IPFS(p=0.022),PFS(p= 0.045),OS(p= 0.013)and BMSS(p= 0.006)of CRT group were significantly higher than RT group.The incidence of Grade 1-2 gastrointestinal toxicities of CRT group was higher than RT group(33.3%vs.26.2%,p= 0.006).No Grade 4-5 toxicities were seen in both groups.Conclusions:The addition of TMZ to HFSRT improves intracranial control and overall survival for patients with large brain metastases,with acceptable toxicities.Further studies with large sample sizes are warranted.Part Ⅲ:Helical Tomotherapy for Multiple Brain Metastases:Dosimetric and Clinical AnalysesPurpose:A retrospective study was conducted to analyze the dose distribution characteristics,and to evaluate the feasibility and toxicities of whole brain radiation(WBRT)with simultaneously integrated boost(SIB)by helical tomotherapy(HT)in the treatment of multiple brain metastases(BMs).Materials and Methods:From 2014 to 2017,43 patients with three or more BMs were analyzed.WBRT was delivered with 40 Gy in 20 fractions and SIB was 60 Gy in 20 fractions by HT.For some BMs larger than 6 cm3,gross tumor volume(GTV)was contracted by 2 mm to create Boost,which was given 66 to 70 Gy simultaneously.BMs located in brainstem were given 50 Gy in 20 fractions.Patients were reevaluated by magnetic resonance imaging(MRI)after 13 to 15 fractions.The radiation field would be shrunk if the gross target volume(GTV)was reduced.Target Coverage(TC),conformation index(CI),prescription isodose/target volume ratio(PITY)and homogeneity index(HI)was accessed.Clinical endpoints included local recurrence-free survival(LRFS),intracranial progresstion-free survival(IPFS),progression-free survival(PFS),overall survival(OS)and toxicities.Results:The median age was 61(36-81)years old.The median lesion number was 6(3-36)and median total volume of GTV was 8.74 cm3(0.37-120.3 cm3).Median Dmean of GTV was 63.1 Gy(50.2-72.6 Gy).There were 9 lesions located in brainstem,which received median dose of 52.5 Gy(51.3-53.3 Gy).Seventeen large BMs received simultaneously boost,with median volume of 12.15(6.79-34.18)cm3.Mean±standard deviation for GTV amounted to TC was 0.96 ± 0.028,CI 0.51±0.164,PITV 2.09±1.245,and HI 0.12 ± 0.066,respectively.TC and HI for whole brain were 0.95±0.033 and 0.43 ±0.161,respectively.25.6%of patients got re-planned and the dose of normal tissue reduced.The median follow-up time was 14.4 months(2.0-40.9 months).One-year LRFS,IPFS,PFS and OS were 95.7%、19.9%、39.4%and 85.6%,respectively.There were no grade 3-5 toxicities.Conclusions:Helical tomotherapy for WBRT and SIB shows excellent conformity and homogeneity,and it’s efficient and safe for patients with multiple BMs.Lesions that get shrunk during treatment should be re-planned to reduce the dose of normal tissue.