Value Of Bookend Quantitative Perfusion And T1 Mapping In Clinical Management Of Cerebral Gliomas And Metastases After Radiotherapy

Glioma is the most common primary tumor in the brain,which is classified into grade I-IV according to the standards of the World Health Organization.Among them,high-grade glioma(grade III and grade IV)has a higher degree of malignancy,accounting for more than 70%of primary intracranial malignancy.For primary high-grade gliomas,surgical resection combined with radiotherapy and chemotherapy is the first-line treatment.However,due to the biological characteristics of infiltrative growth of high-grade glioma and the generation of radiation and chemotherapy resistance of tumor cells,most patients with high-grade glioma will relapse after radiotherapy.Brain metastasis is the most common intracranial malignant tumor,about 15-40%of patients with cancer will have intracranial metastasis.Radiotherapy is the first-line treatment for metastatic tumors,especially with the development of stereotactic radiotherapy technology,many patients benefit from conformal radiotherapy and gamma knife radiotherapy.However,due to the radiation resistance of tumor cells and the presence of in situ implantation,patients with metastatic tumors may also relapse after radiation therapy.Radiation not only kills tumor cells,but also causes unavoidable damage to normal brain tissue around the tumor,called radiation damage.Magnetic Resonance Imaging(MRI)is one of the important means of follow-up after radiotherapy for glioma and brain metastases,and plays an important role in making clinical management decisions.However,like tumor recurrence,radiation damage is also enhanced in postcontrast T1WI,therefore,conventional MRI plays a limited role in differentiating the recurrence and radiation damage of glioma and brain metastases after radiotherapy.Dynamic susceptibility contrast perfusion weighted imaging(DSC-PWI)is by far the most common used functional imaging sequence in the identification of tumor recurrence and radiation damage,however,the traditional DSC-PWI sequence has a relatively low image resolution and was not applicable for quantitative analysis,it impedes the dynamic and consistent assessments of the perfusion condition in post-radiotherapeutic lesionsBookend DSC-PWI is a new quantitative perfusion technology.The first part of this paper explored the advantages of Bookend DSC-PWI technology in the differential diagnosis between radiation necrosis and tumor recurrence of brain metastases after gamma knife radiotherapy.Correct diagnosis solves the problem of identification for the post-radiotherapeutic lesions,but it is only the first step of the clinical management for brain tumors after radiotherapy.Irradiation is the most common used method for the recurrent tumor after radiotherapy,but the enhancing areas of post-radiotherapeutic lesions are not always consistent with the true scale of the recurrent tumor.How to accurately define the regions of tumor in the post-radiotherapeutic lesions is the second step of clinical management.The second part of this paper explored the feasibility of customized radiotherapy based on the technology of Bookend DSC-PWI for the recurrent high-grade glioma,which solves the problem of the positioning of recurrent tumors.Although Bookend DSC-PWI technology has many advantages,but the inherent disadvantages of DSC-PWI such as artifacts,sensitive to hemorrhage,low resolution and required bolus effect,still exist.These shortcomings also limit its wider range of applications in the clinical management ofbrain tumors after radiotherapy.T1 Mapping technology can effectively solve the above problems,so the third part of this study explored the feasibility of post-contrast T1 Mapping technology in identification of recurrence and radionecrosis of brain metastases after gamma knife radiotherapy,which solves the problems of both identification and positioning.The three parts of this study were designed to solve the problems existing in the clinical manangement of brain glioma and metastases after radiotherapy step by step.Part I Absolute CBV for the Differentiation of Recurrence and Radionecrosis of Brain Metastases after Gamma Knife Radiotherapy:A Comparison with Relative CBVPurpose:This study aimed to investigate the efficiency of absolute cerebral blood volume(CBV)in the differentiation of tumor recurrence(TR)and radionecrosis(RN)in brain metastases(BM)and to evaluate the performance of absolute CBV compared to relative CBV(rCBV).Methods:Between March 2014 and October 2015,46 patients with BM underwent quantitative dynamic susceptibility contrast perfusion-weighted imaging(DSC-PWI)because new enhancement had been demonstrated in irradiated lesions after gamma knife radiotherapy.Written informed consent was obtained from each volunteer prior to the study,after the approval of the local ethical committee.All experiments were performed in compliance with the Helsinki Declaration.The patients were assigned to either the TR group or RN group on the basis of MR perfusion follow-up or histopathological outcome.Absolute CBV of lesions(CBVlesion)and contralateral normal appearing white matter(CBVNAWM)in both groups were obtained.Mean rCBV were calculated as CBVlesion/CBVNAWM,which was equal to rCBV using traditional DSC-PWI.Intergroup and intragroup differences were tested for significance using the two-tailed Mann-Whitney U test and Wilcoxon's paired test,respectively.Correlation between aCBV and rCBV values was obtained using Spearman's rank correlation coefficient.The interobserver reliability was calculated using the Fleiss intraclass correlation coefficient(ICC)using a two-way mixed model.Receiver operating characteristic(ROC)curve analysis was used to determine the optimum cut-off values for differential diagnosis of recurrence and radionecrosis.Results:CBVlesion of TR alone was significantly higher than the other parameters in both groups(p<0.001,separately).CBVlesion had smaller interobserver difference than CBVNAWMand rCBV(p<0.001,separately).Although CBVlesion significantly correlated with rCBV(r=0.914,p<0.001)and both had a similar specificity(96%)in differential diagnosis,CBViesion had a higher sensitivity(96.9%vs 90.9%)to predict the treatment outcome.The best cut-off value of CBVlesion was 2.18 ml/100g.Conclusions:Bookend DSC-PWI is a powerful method for the assessment of radiosurgically treated brain metastases.Absolute CBV has higher diagnostic efficiency than rCBV,which enables an absolute quantification of the regional CBV and prediction of tumor response.These advantages promote the intra-and inter-patient quantitative image comparison across different institutions.Pa rt II Bookend Dynamic Susceptibility Contrast Perfusion-Weighted Imaging-Guided Customized Gamma Knife Re-irradiation of Recurrent High-Grade GliomasPurpose:Precise re-irradiation of recurrent high-grade gliomas(rHGG)has always been challenging in the clinical management of cerebral gliomas after radiochemotherapy.Tradiontal re-irradiation would cover all the enhancing area non-selectively,resulting in a larger scale of radiation damage.This study aimed to explore the treatment effect of quantitative dynamic susceptibility contrast perfusion-weighted imaging(DSC-PWI)-guided gamma knife radiosurgery(GKR)on rHGG.Methods:Between January 2016 and July 2017,twenty-six consecutive patients were treated by quantitative DSC-PWI-guided GKR as salvage treatment for rHGG.Written informed consent was obtained from each volunteer prior to the study,after the approval of the local ethical committee.All experiments were performed in compliance with the Helsinki Declaration.The gross tumor volume(GTV)was defined as the high perfusion area on absolute cerebral blood volume maps,with a cutoff value of 2.2 ml/100 g,without the traditional method of covering all the enhancing area.The clinical target volume(CTV)encompassed the GTV by 3 mm.Overall survival(OS)and progression-free survival(PFS)were calculated by the Kaplan-Meier method.Prognostic factors were tested by the log-rank(Mantel-Cox)test.Results:With a median follow-up of 32 months,the median PFS after GKR was 8 months(95%CI:[6,12]);the one-year and two-year survival rates were 30.8%and 11.5%,respectively.The median OS was 25.5 months(95%CI:[18,40]);the one-year and two-year survival rates were 96.2%and 57.7%,respectively.Pathology grade and CTV were identified as prognostic factors for PFS.However,none of the parameters tested were independent prognostic factors for OS among these selected patients.No severe radiotoxicity was observed among all patients.Conclusions:Quantitative DSC-PWI-guided GKR is feasible for the treatment of rHGG and that these outcomes remain to be validated.Despite this,we think that carefully selected patients can benefit from this treatment method.Part ? Post-contrast T1 Mapping for Differential Diagnosis of Recurrence and Radionecrosis after Gamma Knife Radiosurgery for Brain MetastasisPurpose:Although Bookend DSC-PWI has many advantages in the clinical management of brain glimoas and metastases after radiotherapy,the inherent disadvantages of DSC-PWI were still unresolved.T1 Mapping has been comfirmed as a qualified quantative imaging method to solve the problems existing in the DSC-PWI as possible.We investigated the diagnostic efficiency of post-contrast T1 mapping in distinguishing recurrence and radionecrosis in brain metastases after gamma knife radiotherapy.Methods;Between March 2016 and June 2017,56 patients with brain metastases who underwent contrast-enhanced cerebral T1 mapping were recruited in this prospective study.Written informed consent was obtained from each volunteer prior to the study,after the approval of the local ethical committee.All experiments were performed in compliance with the Helsinki Declaration.The findings revealed new enhancement after gamma knife radiosurgery(GKR).The subjects were assigned to radionecrosis and recurrence groups on the basis of follow-up(median:11.5 months)and histopathological results.T1 values of lesions 5(T15min)and 60(T160min)min after administration of contrast agent as well as their difference(T1 differ)were compared between the two groups by the two-tailed Mann-Whitney U test.Receiver operating characteristic(ROC)curves were used to determine the optimum cutoff values for differential diagnosis.Spearman correlation analysis was used to explore the correlation between T1 differ and rCBV.Results:There were significant differences between the two groups in T15min,T160min and T1 differ values(p=0.012,p=0.004 and p<0.001,respectively).Relative to T15min and T160min,T1 differ exhibited greater sensitivity and specificity(p<0.001,respectively)in identifying radionecrosis.The optimum T1 differ value for differential diagnosis was 71.1 ms(AUC 0.97,95%CI[0.93,1.00]),with a sensitivity and specificity of 81.5%and 96.5%,respectively.T1 differ correlated with rCBV significantly(r=0.58,p<0.01).Conclusion:Post-contrast T1 mapping is optimal for differential diagnosis of radionecrosis and tumor recurrence.Among T1 parameters,T1 differ is the most powerful parameter for differential diagnosis.