Timing Of Hypo-fractionated Radiotherapy And Prognostic Outcome Of Patients With Brain Metastases In Comprehensive Treatment Era

Part ⅠA phase Ⅱ trial of comprehensive treatment based on radiotherapy in leptomeningeal metastasisPurpose:To investigate the efficacy and security prospectively for patients with leptomeningeal metastases(LM)of comprehensive treatment based on radiotherapy.Materials and Methods:From 2014 to 2017,93 patients diagnosed with LM admitted to our hospital who underwent whole brain radiotherapy(WBRT)or craniospinal irradiation(CSI)with or without simultaneously boost were enrolled.The dynamic changes of enhanced magnetic resonance imaging,clinical signs and symptoms,cerebrospinal fluid cytology and liquid biopsy detection were recorded.The primary endpoint was overall survival(OS),the secondary endpoints were local control(LC),intracranial progress-free survival(IPFS),brain metastasis specific survival(BMSS)and toxicity.Results:The major primary diagnosis was non-small cell lung cancer.Subjects received WBRT with boost(40 Gy in 20 fractions(f)for WBRT and 60Gy in 20 f for boost),focal radiation to LM,WBRT and CSI(40 Gy in 20 f or 50Gy in 25 f for WBRT and 36 Gy in 20 f for CSI).20 patients were found tumor cells and were administrated intrathecal chemotherapy.63 patients used target therapy.The median follow-up time was 33.8 months.OS/LC/IPFS at 1 year were 62.4%/77.2%and 52.6%,respectively.The median survival time was 15.9 months,and the median brain metastasis-specific survival was 42.2 months.The results showed that independent factors improving LC included:the primary tumor was non-small cell lung cancer,receiving WBRT,no need for intrathecal-chemotherapy.The influencing factors prolonging OS time were:age≥ 55 years,without brain leptomeningeal metastases,extracranial metastases controlled,receiving WBRT,no need for intrathecal-chemotherapy.IPFS benefited in female patients.Treatment-related grade 3-4 adverse events were rare and included eight grade 3 hematological toxicity.Conclusions:Reasonable comprehensive treatment including precise radiotherapy,intrathecal chemotherapy and targeted agents were well tolerated and could extend the survival time of LM patients compared with historical controls.Part ⅡThe sequence of intracranial radiotherapy and systemic treatment with tyrosine kinase inhibitors for genedriven non-small cell lung cancer brain metastasesPurpose:The high intracranial efficacy of targeted therapeutic agents poses a challenge in determining the optimal sequence of local radiation therapy(RT)and systemic treatment with tyrosine kinase inhibitors(TKIs)in non-small cell lung cancer(NSCLC)patients with brain metastasis(BM).Therefore,we conducted a cohort study to elucidate the appropriate treatment strategy,either upfront RT or deferred RT including a toxicity assessment,in these patients.Materials and Methods:We retrospectively evaluated patients with gene-driven BMs from a single institution and divided them into deferred and upfront RT groups.Survival was estimated using a log-rank test.Intracranial progression was estimated using FineGray competing risks model.Cox proportional hazards regression was performed for multivariable analysis in the entire group and subgroups.Results:Among the 198 eligible patients,94(47.5%)patients first received target therapy followed by RT(deferred RT group),and 104 patients first received RT followed by target therapy(57,28.8%)or concurrent RT and target therapy(47,23.7%)(upfront RT group),respectively.The upfront RT group showed a lower intracranial progression risk with an adjusted sub-distribution hazard ratios of 0.41(95%Cl,0.30-0.57)than did the deferred RT group(median intracranial progression-free survival[iPFS],19.9 months vs.11.1 months;P<.001).The median overall survival(OS;43.2 months vs.49.1 months,P=0.376)and BM-specific survival(92.1 months vs.82.9 months,P=0.810)after salvage therapy were not significantly different between the upfront and deferred groups.Among patients with progressed extracranial disease,the deferred RT group showed significantly better OS than did the upfront RT group(44.0 vs.28.1 months,P=0.022).Grade 3-4 treatment-related adverse events were rare,and similar toxicities were observed between the two groups.Conclusions:Compared to the deferred RT group,the upfront RT group achieved longer iPFS and similar survival outcomes in most patients with gene-driven NSCLC BM,although patients with progression of extracranial disease might benefit from deferred RT.Both groups showed well-tolerated toxicities.Part ⅢDosimetric and clinical analysis of pseudo-progression vs.recurrence after hyper-fractionated radiotherapy for brain metastases based on enhanced Magnetic resonance imagingPurpose:The main challenge in follow-up duration of patients with brain metastases after stereotactic radiotherapy is to distinguish between pseudo-progression and tumor recurrence.The objective of this study is to retrospectively analyze the predictive factors.Materials and Methods:The study included 123 patients with enlarged brain metastases after hyper-fractionated radiotherapy in our center from 2009 to 2019,and the baseline clinical features,radiotherapy planning parameters,and enhanced magnetic resonance imaging before and after radiation therapy were analyzed.Survival was estimated using a log-rank test.Logistic regression was performed to compare the differences between groups.independent risk factors with P<0.05 and associated with recurrence was used to establish a predicting nomogram and validated by Bootstrap in internal cohort.Results:The median volume of lesions was 8.4 cc.The median follow-up time was 68.4 months(interquartile range,30.4-63.2 months).A total of 76(61.8%)patients were evaluated as pseudo-progression,47 patients(38.2%)were evaluated as tumor recurrence.The median time to tumor recurrence and pseudo-progression were 12.9 months(quartile range,8.7-19.6 months)and 18.3 months(quartile range,9.4-27.8 months)respectively.The 1-year local tumor control rate was 84.4%.Variables associated with tumor recurrence included:gross tumor volume>6 cc,biological effective dose<60 Gy,target coverage<96%and no targeted therapy.The area under curve value was 0.730 and mean absolute error in calibration curve was 0.041.Sixty-one patients received salvage therapy,including re-irradiation(n = 32,26.0%),surgical resection(n=22,17.9%)or systemic therapy(n=22,17.9%).The survival time in pseudo-progression and tumor recurrence groups were 66.3 months(95%CI,56.8-75.9 months)and 39.6 months(95%CI,29.2-50.0 months,respectively;P=0.001).Conclusions:Clinical and dosimetry features of hyper-fractionated radiation therapy based on enhanced brain magnetic resonance can help distinguish pseudo-progression from tumor recurrence after hyper-fractionated radiotherapy for brain metastases.Gross tumor volume,biological effective dose,target coverage,and having received targeted therapy or not were factors associated with the occurrence of tumor recurrence,and the individual risk could be estimated by the nomogram effectively.