| Objective The current standard of care for locoregionally advanced nasopharyngeal cancer(NPC)is cisplatin-based induction chemotherapy followed by concurrent radio-chemotherapy.Improving treatment efficacy,minimizing treatment-related toxicities,and improving quality of life is crucial for NPC patients.The study was designed to identify and compare the value of Functional MRI parameters in predicting early response of primary tumor and regional metastatic lymph nodes to induction chemotherapy(IC)in NPC.Furthermore,to identify the efficacy of diffusion kurtosis imaging in tracking and monitoring the dynamic change of parotid glands,submandibular glands(SMG),sublingual glands,and acute xerostomia in NPC patients treated by induction chemotherapy plus concurrent chemoradiotherapy.To verify the clinical significance of sparing SMG for the amelioration of acute xerostomia using diffusion kurtosis imaging in NPC patients treated with helical tomotherapy(HT).Methods This study is a prospective observational study.(1)The study enrolled fifty-six consecutive NPC patients(totally 94 metastatic lymph nodes)treated with two cycles of IC from January 2021 to May 2021 in part 1 and part 2.Conventional diffusion-weighted imaging,diffusion kurtosis imaging,intravoxel incoherent motion,and dynamic contrast-enhanced magnetic resonance imaging protocols were performed before and after IC.Parameters maps(ADC,MD,MK,Dslow,Dfast,PF,Ktrans,Ve and Kep)of the primary tumor and metastatic lymph nodes were calculated by the Functool post-processing software.The target lesions were classified as responding group(RG)and non-responding group(NRG)according to Response Evaluation Criteria in Solid Tumors 1.1.The fMRI parameters were compared before and after IC and between RG with NRG.Logistic regression analysis and ROC were performed to further identify and compare the efficacy of the parameters.(2)The prospective study(part 3 and part 4)recruited 42 participants treated by IC followed by concurrent chemoradiotherapy.All patients underwent six times of DKI scans:before IC,before RT,in the middle of the RT course,immediately after RT,1-and 3-months post-RT.Mean diffusion coefficient(MD)and mean kurtosis(MK)of parotid gland,SMG,sublingual gland,saliva flow rate measured under resting(uSFR)and stimulated condition(sSFR),and xerostomia questionnaire(XQ)scores were recorded.The dynamic change of these parameters was recorded in the followed periods.All the patients were divided in SMG-spared group and SMG-unspared group according to whether SMG was spared.Comparisons between the SMG-spared and-unspared groups were analyzed using two-factor repeated-measures ANOVA for the group as the inter-subject factor and time as the intrasubject factor.Results1.Functional MRI in predicting response of primary tumor to induction chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma(1)Comparisons of the parameters before and after IC:the mean value of ADC,MD,MK,Dslow,Dfast,PF,Ve and Kep except for Ktrans changed significantly before and after IC.After IC,the mean values of ADC(p<0.007),MD(p<0.001),Dslow(p=0.001),PF(p=0.030)and Ve(p=0.003)significantly increased,while MK(p<0.001),Dfast(p=0.009)and Kep(p=0.003)values decreased dramatically.no significant difference was detected in Ktrans(p=0.130).(2)ADC-pre,ADC-post,ΔADC,MD-pre,ΔMD,ΔMD%,MK-pre,ΔMK,ΔMK%,Dslowpre in RG were different from that in NRG.Compared with NRG(ADC-pre:1386.25±198.23×10-6mm2/s,MD-pre:1121.00×10-6mm2/s,Dslow-pre:933.85±219.95×106mm2/s),ADC-pre(1119.58±144.06×10-6mm2/s),MD-pre(902.00×10-6mm2/s)and Dslowpre(724.50±23 5.92 × 10-6mm2/s)in RG were lower(p<0.001,p<0.001,p=0.002,respectively);while MK-pre(1052.25±122.02)were higher in RG than that in NRG(935.10±185.34)(p=0.017).(3)The areas under the ROC curves for the ADC-pre,MD-pre,MK-pre,Dslow-pre was 0.885,0.855,0.809,0.742,with the optimal cutoff value of 1210×10-6 mm2/s,1010×10-6 mm2/s,832×10-6,and 835×10-6 mm2/s respectively.The area of the ROC curves for the new fitted parameter PRE was 0.912,with the optimal cutoff value of 0.799,a sensitivity of 72.22%,a specificity of 95.00%,a positive predictive value of 96.3%and a negative predictive value of 65.5%.2.Functional MRI in predicting response of regional nodes to induction chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma(1)Comparisons of the parameters before and after IC:the mean value of ADC,MD,MK,Dslow,Dfast,PF,Ktrans except for Ve and Kep changed significantly before and after IC.After IC,the mean values of ADC,MD,Dslow significantly increased,while MK,Dfast,PF and Ktrans values decreased dramatically.no significant difference was detected in Ve and Kep.(2)PF-pre,PF-post,ΔPF%,Ktrans-pre,Ktrans-post in RG were different from that in NRG.The mean value of ΔADC%in RG showed an upward trend,while MK-post values showed a decreasing trend,but there were no significant differences compared with NRG(p>0.05).However,the other parameters derived from fMRI showed no significant differences between two groups.Compared with NRG(PF-pre:205.60±56.83×10-4、Ktrans-pre:925.81 ±311.04×10-3/min),PF-pre(263.71±68.44×10-4)and Ktrans-pre(1226.75 ±385.23 × 10-3-3/min)values in RG were higher statistically.(3)The areas under the ROC curves for the pretreatment PF,Ktrans and PRE(fitted by the two parameters)was 0.736,0.722,0.810 respectively,with optimal cutoff value of 222×104,934×10-3/min and 0.6624 respectively.3.Diffusion kurtosis imaging for evaluation of acute xerostomia in nasopharyngeal carcinoma patients treated by induction chemotherapy plus concurrent chemoradiotherapy(1)The mean dose of bilateral SMGs was the highest among the major salivary glands:mean dose of right SMG was 50.20Gy(22.82～64.77)and mean dose of left SMG was 47.89Gy(25.46～66.45)respectively.(2)At baseline,MD of PG was significantly lower while MK was higher compared to ipsilateral SMG and SLG(p<0.001 for all),MD and MK of SMG were similar with that of SLG(p>0.05).(3)At each time point(before IC,before RT,in the middle of the RT course,immediately after RT,1-and 3-months post-RT),sSFR was significantly higher than uSFR(p<0.05 for all).(4)MD of the bilateral salivary glands and XQ scores increased over time while MK,uSFR,and sSFR decreased.(5)After IC,significant differences were detected in MD and MK of bilateral SMG(p<0.05 for all).Compared with pre-IC,MD and MK of bilateral PG and MK of bilateral sublingual glands at post-RT,and uSFR,sSFR,and XQ scores showed no significant differences.(6)Compared with pre-RT,MD of bilateral PG,SMG,and SLG at mid-RT and post-RT were significantly increased while MK decreased(p<0.05 for all).There were also significant differences for uSFR,sSFR,and XQ scores between the time points of pre-RT,mid-RT,and post-RT(p<0.05 for all).After IC,uSFR and sSFR decreased while XQ scores increased.(7)Compared with time point of immediately after RT,no significant differences were detected in MD and MK of the bilateral PG,SMG,and SLG except for MK-PG-R(p=0.032)at 1m-RT.sSFR at 1-month post-RT decreased significantly(p=0.03)while no significant difference was detected in uSFR and XQ scores.(8)Correlations between the change ratio of DKI metrics from pre-RT to post-RT with dose of salivary glands:The change ratio of MD increased while the change ratio of MK decreased with the increasing dose of bilateral PG,SMG and SLG(except for MK of bilateral SLG).Moderate-strong correlations were detected in ΔMD-PG-R%,ΔMK-PGR%,ΔMD-PG-L%,ΔMK-PG-L%,ΔMD-SMG-R%,ΔMK-SMG-R%,ΔMD-SMG-L%,ΔMK-SMG-L%,and ΔMD-SLG-R%,with correlation coefficients(p<0.05 for all)ranging from 0.401 to 0.714.No significant correlation was found in ΔMK-SLG-R%,ΔMD-SLG-L%,ΔMK-SLG-L%(p>0.05).(9)Correlations between the change ratio of the DKI metrics with the change ratio of uSFR,sSFR,and XQ scores from pre-RT to post-RT:ΔuSFR%was correlated with ΔMDSMG%(p=0.01)、ΔMD-SLG%(p<0.001)、ΔMK-SMG%(p<0.001),with correlation coefficients of-0.39,-0.532,0.493 respectively.ΔsSFR%was correlated with ΔMD-PG%(p=0.001),ΔMD-SMG%(p=0.015),ΔMK-PG%(p<0.001),with correlation coefficients of-0.509,-0.221,0.524 respectively.ΔXQ%was only correlated with ΔMK-PG%(p=0.004),with correlation coefficients of 0.433.4.Sparing submandibular gland to alleviate acute xerostomia in patients with nasopharyngeal carcinoma treated with helical Tomotherapy:evaluation by diffusion kurtosis imaging(1)When sparing SMG,the dose of spared-SMG(32.50±4.07)and ipsilateral SLG(23.96±4.02)was lower compared to that of unspared glands(62.07±4.32,34.52±5.57,respectively)(p<0.001 for all).Mean dose of bilateral parotid glands showed no significant differences between two groups.(2)The interaction between group and time had statistically significant effect for MD of SMG and SLG(p=0.007 and 0.026 respectively),but not for MK of SMG and sublingual glands,MD and MK of parotid glands.(3)The simple effect of the group was statistically significant for MD-SMG and sublingual glands.As the pairwise comparison showed that MD-SMG and sublingual glands were lower in SMG-spared group than that of-unspared group at mid-HT,post-HT,1m-and 3m-HT.The simple effect of the time for MD-SMG and MD-SLG was also statistically significant at all time points(p<0.05 for all)(4)The main effect of the group was statistically significant for MK of SMG(p<0.001),and MK of spared-SMG was higher than that of unspared SMG.The main effect of the time was statistically significant for MK of SMG(p<0.001),and the value of MK of SMG decreased during followed periods.(5)The main effect of the group was not statistically significant for MK of SMG and sublingual glands,MD and MK of parotid glands,and no significant differences were detected in the groups(the main effect for the group,p value was 0.9,0.37,0.15,0.86,respectively).(6)The main effect of the group for uSFR and sSFR were significant(p=0.002 and 0.045 respectively)while no significant difference was detected for XQ(p=0.86).uSFR and sSFR in SMG-unspared group were lower than that in SMG-spared group.(7)There were significant differences in the effect of the time for all MD/MK of the salivary glands and uSFR,sSFR,and XQ between the SMG-spared and-unspared groups(p<0.001 for all).Conclusions The pre-treatment fMRI diffusion-related parameters ADC-pre,MD-pre and MKpre,and Dsiow-pre could be used to predict response of the primary tumor to IC,while perfusionrelated parameters PF and Ktrans showed promising potential in predicting early response of the regional lymph nodes to IC in NPC patients.Furthermore,diffusion kurtosis imaging is a promising tool for tracking and monitoring acute damage of parotid glands,SMG,and sublingual glands induced by IC followed by concurrent radio-chemotherapy in NPC patients.And sparing SMG is of great clinical significance in alleviating acute xerostomia for NPC patients treated by helical tomotherapy as evaluated from perspective of diffusion kurtosis imaging.fMRI can be used to predict response to induction chemotherapy plus concurrent chemoradiotherapy and evaluate associated xerostomia in locoregionally advanced NPC. |
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