| PART ⅠRadiation-induced lower cranial neuropathy after intensity-modulated radiotherapy for nasopharyngeal carcinoma:patient and treatment-related risk factorsObjective:This study retrospectively analyzed the occurrence and distribution of lower cranial neuropathy in patients with nasopharyngeal carcinoma(NPC)after intensitymodulated radiotherapy(IMRT)in our center,and analyzed the risk factors on lower cranial neuropathy,providing a basis for clinical identification and prevention of radiationinduced lower cranial neuropathy(RILCN).Materials and Methods:A retrospective review was conducted on patients with nonmetastatic NPC receiving IMRT in our center from January 2011 to December 2015,with complete medical records and follow-up records of at least half a year.After screening according to the inclusion criteria,a total of 893 cases were included in the analysis.The primary endpoint was the cumulative incidence of RILCN,and the second endpoint was RILCN-free survival.The cumulative incidence of RILCN was calculated using competing risk analysis,and the RILCN-free survival was calculated using the Kaplan-Meier method.The risk factors related to the cumulative incidence of RILCN were analyzed using the Fine-Gray test for univariate and multivariate analysis.COX proportional hazards model was used to identify the prognostic factors for RILCN-free survival.The restricted cubic splines(RCS)were used to evaluate the nonlinear correlation between continuous variables and outcomes.Results:The median follow-up time for the entire group was 96.1 months(range:6.3 to 133.0 months).A total of 138 cases developed RILCN,with a median latency of 61.6 months(range:6.5 to 119 months),of which the most common was the injury of Ⅻ branch alone(58.7%).The cumulative incidence of RILCN at 3,5,8,and 10 years were 2.8%,7.4%,15.4%,and 22.2%,respectively.The crude incidences of injuries of Ⅸ-Ⅹ,Ⅺ andⅫ branches were 5.9%,0.6%,and 12.8%,respectively.Among the patients with Ⅻbranch injury,45.6%were left-sided,36.8%were right-sided,and only 17.5%were bilateral.The 3,5,8,and 10-year RILCN-free survival rates were 88.7%,81.2%,69.7%,and 61.7%,respectively.Fine-Gray test univariate analysis showed that carotid sheath involvement,T stage,TNM stage,and GTV-P BED(total Biologically Effective Dose in the primary tumor/retropharyngeal lymph node region)were significantly correlated with the cumulative incidence of RILCN(all p<0.05),while multivariate analysis revealed that only GTV-P BED≥ 90.48 Gy(HR=2.189,95%CI=1.155-4.179;p=0.016)was an independent risk factor.COX univariate analysis showed that alcohol consumption,carotid sheath involvement,T stage,N stage,TNM stage,GTV-P BED,induction chemotherapy,adjuvant chemotherapy,and targeted therapy were significantly associated with RILCNfree survival(all p<0.05),while multivariate analysis revealed that only alcohol consumption(HR=1.335,95%CI=1.029-1.733;p=0.030),GTV-P BED(HR=2.139,95%CI=1.401-3.266;p<0.001)and adjuvant chemotherapy(HR=1.810,95%CI=1.190-2.752;p=0.006)are independent prognostic factors.RCS revealed a non-linear relationship between GTV-P BED and the cumulative incidence of RILCN,as well as RILCN-free survival(all p<0.001):The risk of endpoints continuously ascended with the increase of GTV-P BED,and ascendant rate gradually slowed after GTV-P BED exceeded 90.48 Gy.Conclusions:This study firstly investigated the incidence and distribution of RILCN in patients with NPC after receiving IMRT in a large number of cases series,and explored the risk factors of RILCN.The results showed that RILCN was not rare in the IMRT era,with the most common being the single hypoglossal nerve injury.The total dose of GTVP was an independent risk factor for RILCN.This study firstly confirmed that there was a non-linear correlation between the total dose of GTV-P and RILCN.In order to reduce the risk of RILCN after radiation exposure,further efforts to identify the optimal threshold point for dose limitation are warranted in the future.PART ⅡEstablishment and validation of a normal tissue complication probability(NTCP)model for predicting hypoglossal nerve injury after intensity-modulated radiotherapy in nasopharyngeal carcinomaObjective:Based on the previously constructed database of radiation-induced lower cranial neuropathy for nasopharyngeal carcinoma(NPC),the enrolled patients are divided into a training set and a validation set with radiation-induced hypoglossal neuropathy(RIHN)as the primary endpoint.The normal tissue complication probability(NTCP)model of RIHN is constructed and validated,and clinical factors are added to assess whether it can improve the discrimination and accuracy of the model,with a view to providing a reference for the prevention and risk prediction of RIHN.Materials and Methods:A total of 440 cases of the Pinnacle plan from 2012 to 2015 were recovered from our center’s plan backup database,and 423 cases were enrolled after careful screening.They were randomly(3:2)divided into a training set(n=256)and a validation set(n=167).The cumulative incidence of RIHN was calculated using competitive risk analysis.Dosimetric factors were selected by penalized regression and machine learning,with the area under the receiver operating curve(AUC)calculated.The dose-effect curve was plotted using logistic regression.Clinical factors were selected by the Fine-Gray test for univariate and multivariate analysis.A competitive risk model including clinical and dosimetric factors was established,and a nomogram was generated as a visualization of the model to predict the incidence of RIHN.Results:The median follow-up time for the entire group was 102 months(IQR:89.5 to 112.9 months).At the last follow-up,a total of 49 cases developed RIHN,with a median latency of 66.6 months(range:6.5 to 119 months)and unilateral injury predominating(83.7%).The cumulative incidence of RIHN at 3,5,8,and 10 years were 2.1%,5.4%,10.5%,and 1 7.5%,respectively.D1cc and aV75 were the most predictive dosimetric factors.The dose-effect curve plotted with D1cc indicated the tolerance dose for 5%probabilities to develop RIHN in 8 years(TD5/8)was 77.3 Gy(EQD2).The 8-year cumulative incidences of RIHN for D1cc≥ 77.3 Gy and<77.3 Gy were 16.9%and 5.6%,respectively(p=0.002).There is a non-linear correlation between aV75 and RIHN,with a reference point of 0.81 cm3.The risk of RIHN was significantly higher in patients with aV75 ≥ 0.81 cm3 compared to aV75<0.81 cm3(HR=4.57;95%CI=1.86～11.24;p=0.001).The Fine-Gray test showed that hypoglossal foramen involvement(HR=3.061,95%CI=1.253～7.477)and concurrent chemotherapy(HR=2.721,95%CI=1.001～7.395)significantly increased the risk of RIHN.A competitive risk model including hypoglossal foramen invasion,concurrent chemotherapy,D 1cc,and aV 75 was established,and a nomogram was generated to predict the cumulative incidence of RIHN at 8 years.The C-index of the training set and the validation set were 0.726 and 0.691,respectively,and the AUC values were 0.711 and 0.680,respectively.The median(71.8 points)of the total points calculated by the nomogram was used as a cut-off value to distinguish between high-risk and low-risk groups.The incidence of RIHN of the high-risk group was significantly higher than that of the low-risk group in the training set(8-year:15.5%vs 6.1%,p=0.003),and the result of the validation set was consistent(8-year:15.4%vs 2.9%,p=0.011).Conclusions:This study firstly developed and validated the NTCP model for RIHN in NPC.This study found that the cumulative incidence of RIHN significantly decreased when D1cc<77.3 Gy(EQD2)or aV75<0.81cm3,which could be considered as a potential dose constraint for hypoglossal nerves in NPC radiation plan.The Nomogram model combined with hypoglossal foramen invasion,concurrent chemotherapy,D1cc(EQD2),and aV75 has good predictive performance for RIHN after intensity-modulated radiotherapy,which contributes to identifying high-risk patients and intervention in advance.In the future,external data should be combined for validation.Part ⅢA prospective study on the optimization of antiemetic prophylaxis strategy for chemoradiotherapy-induced nausea and vomiting in head and neck squamous cell carcinomaObjective:Currently,there is sparse research reporting effective antiemetic prevention regimens for nausea and emesis caused by concurrent chemoradiotherapy(CCRT)in patients with locally advanced head and neck squamous cell carcinoma(LA-HNSCC).The purpose of this study was to evaluate the efficacy and safety of a triple antiemetic regimen including neurokinin-1 receptor antagonist(aprepitant),5-hydroxytryptamine-3 receptor antagonist(ondansetron),and dexamethasone in patients with LA-HNSCC receiving CCRT.Materials and Methods:The recruited patients were subjected to a unified antiemetic preventive regimen during intensity-modulated radiotherapy(IMRT)and concomitant triweekly cisplatin(100mg/m2 given evenly in three days)chemotherapy:oral aprepitant 125 mg once on day 1,then 80 mg once on days 2-5;intravenous ondansetron 8 mg once on day 1;and oral dexamethasone 12 mg once on day 1,then 8 mg on days 2-5.The primary endpoint was complete response(CR),defined as no emesis and no use of rescue therapy during concurrent chemoradiotherapy.The secondary endpoints were as follows:complete protection(CP,denoted as no emesis,no more than mild nausea,and no rescue therapy),nausea-free response,emesis-free response,and treatment-related toxicities.The Simon two-stage design was adopted to estimate the sample size.Pursuant to δ=0.2 andα=0.05,the expected CR rate was 80%.If the CR was less than 60%,the study protocol was declared invalid.In the first stage,17 patients were enrolled.If more than 13 patients achieved CR,26 patients would remain enrolled.Results:Between January 2018 and January 2020,a total of 43 patients with LA-HNSCC were enrolled including nasopharynx(n=23),oropharynx(n=9),hypopharynx(n=8),larynx(n=1),paranasal sinuses(n=2).The median age was 53 years old(range:18-66 years),and 86.0%were male.All patients completed IMRT as planned,with a median radiation dose of 69.96 Gy(53-73.92 Gy).All patients completed the first cycle of concomitant cisplatin chemotherapy,and 86.0%of patients completed the second cycle of concomitant cisplatin chemotherapy.All patients completed antiemetic treatment as planned.The overall CR rate of this study achieved 86.0%(95%CI:72.1%-94.7%),exceeding the expected CR rate.The CR rates of the first and second cycles were 88.4%(95%CI:74.9-96.1)and 89.2%(95%CI:74.6-97.0),respectively.The CP rate in the overall phase was 72.1%(95%CI:56.3%-84.7%),while the data of cycle 1 and cycle 2 were 76.7%(95%CI:61.4%-88.2%)and 86.5%(95%CI:71.2%-95.5%),respectively.The emesis-free response and nausea-free response in the overall phase were 88.4%(95%CI:74.9%-96.1%)and 60.5%(95%CI:44.4%-75.0%),respectively.Out of the five patients with emesis,grade 2 emesis occurred in three patients,the remaining two patients experienced grade 1 emesis,and all patients did not receive rescue antiemetics.Grade 1-2 toxicities that presented in at least 10%of patients included dermatitis,mucositis,dry mouth,leucopenia,anemia,hepatic dysfunction,fatigue,and appetite loss.The most frequent grade 3 toxicities were mucositis(20.9%)and leucopenia(14.0%).Grade 3 dermatitis,hepatic dysfunction,fatigue,and appetite loss were less than 5%,and no grade 4 or 5 treatment-related toxicity was observed.The toxicities presumably related to antiemetics were constipation(65.1%)and hiccups(16.3%),but both were grade 1-2.Conclusions:This study firstly adopted a triple antiemetic regimen consisting of aprepitant to prevent chemoradiotherapy-induced nausea and vomiting in patients with head and neck squamous cell carcinoma.The results show that the addition of aprepitant on the basis of ondansetron and dexamethasone effectively reduces the incidence of nausea and vomiting caused by concomitant chemoradiotherapy.Treatment-related toxicities are mainly mild to moderate and tolerable.Randomized phase Ⅲ studies are necessary to further define the potential role of neurokinin-1 receptor antagonist in chemoradiotherapy setting for head and neck squamous cell carcinoma. |
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