The Usefulness of Pretreatment MR-Based Radiomics on Early Response of Neoadjuvant Chemotherapy in Patients With Locally Advanced Nasopharyngeal Carcinoma.

The aim of this study was to explore the predictive role of pretreatment MRI-based radiomics on early response of neoadjuvant chemotherapy (NAC) in locoregionally advanced nasopharyngeal carcinoma (NPC) patients. Between January 2016 and December 2016, a total of 108 newly diagnosed NPC patients who were hospitalized in the Cancer Hospital of the University of Chinese Academy of Sciences were reviewed. All patients had complete data of enhanced MR of nasopharynx before treatment, and then received two to three cycles of TP-based NAC. After 2 cycles of NAC, enhanced MR of nasopharynx was conducted again. Compared with the enhanced MR images before treatment, the response after NAC was evaluated. According to the evaluation criteria of RECIST1.1, 108 cases were divided into two groups: 52 cases for the NAC-sensitive group and 56 cases for the NAC-resistance group. ITK-SNAP software was used to manually sketch and segment the region of interest (ROI) of nasopharyngeal tumor on the MR enhanced T1WI sequence image. The parameters were analyzed and extracted by using AI Kit software. ANOVA/MW test, correlation analysis, and LASSO were used to select texture features. We used multivariate logistic regressions to select texture features and establish a predictive model. The ROC curve was used to evaluate the efficiency of the predictive model. A total of 396 texture features were obtained by using feature calculation. After all features were screened, we selected two features including ClusterShade_angle135_offset4 and Correlation_AllDirection_offshe1_SD. Based on these two features, we established a predictive model by using multivariate logistic regression. The AUC of the two features used alone (0.804, 95% CI=0.6020.932; 0.762, 95% CI=0.5560.905) was smaller than the combination of these two features (0.905, 95% CI=0.7240.984, p=0.0005). Moreover, the sensitivity values of the two features used alone and the combined use were 92.9%, 51.7%, and 85.7%, respectively, while the specificity values were 66.7%, 91.7%, and 83.3%, respectively, in the early response of NAC for NPC. The predictive model based on MRI-enhanced sequence imaging could distinguish the sensitivity and resistance to NAC and provide new biomarkers for the early prediction of the curative effect in NPC patients.

Optimal induction chemotherapeutic regimen followed by concurrent chemotherapy plus intensity-modulated radiotherapy as first-line therapy for locoregionally advanced nasopharyngeal carcinoma.

For patients with locoregionally advanced nasopharyngeal carcinoma (NPC), induction chemotherapy (IC) regimens based on TPF (docetaxel, cisplatin, and 5-fluorouracil), TP (docetaxel and cisplatin), and GP (gemcitabine and cisplatin) have shown excellent survival outcomes as the first-line therapy; however, no trials comparing the efficacy and safety of TPF, TP, and GP have been reported. We report 2 phase II trials comparing the treatment outcomes and side effects of 3 different IC regimens followed by concurrent chemoradiotherapy in locoregionally advanced patients with NPC.A total of 206 locoregionally advanced patients with NPC treated with a combination treatment from January 2012 to January 2014 were enrolled in the 2 studies. The patients received TPF-, TP-, and GP-based IC regimens every 3 weeks, followed by intensity-modulated radiotherapy and concurrent therapy with cisplatin every 3 weeks.After a median follow-up duration of 47 months (10-60 months), the 3-year local recurrence-free survival, regional recurrence-free survival, distant metastases-free survival, progression-free survival, and overall survival rates were 96.4%, 100%, 87.7%, 86%, and 94.7% in the TPF arm; 91.7%, 95.9%, 91.9%, 85.2%, and 92% in the TP arm; 98.6%, 100%, 89.0%, 87.6%, and 89.2% in the GP arm. The survival differences among the 3 arms were not statistically significant (P > .05). The multivariate analysis demonstrated that the IC regimen was not an independent prognostic factor for any survival outcomes. The patients in the TP arm experienced significantly lower grade 3/4 toxicities than the patients in the other 2 arms.TP-based IC regimen has similar efficacy compared with TPF- and GP-based IC regimens; however, TP-based IC regimen has a lower toxicity profile.

Survival without concurrent chemotherapy for locoregionally advanced nasopharyngeal carcinoma treated with induction chemotherapy plus intensity-modulated radiotherapy: Single-center experience from an endemic area.

Although induction chemotherapy (IC) combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy (CC) is the new standard treatment option in locoregionally advanced nasopharyngeal carcinoma (NPC), many patients fail to receive CC. The aim of this study was to investigate long-term survival outcomes and toxicities in these patients who are treated with IC before IMRT without CC.We retrospectively reviewed 332 untreated, newly diagnosed locoregionally advanced NPC patients who received IC before IMRT alone at our institution from May 2008 through April 2014. The IC was administered every 3 weeks for 1 to 4 cycles. Acute and late radiation-related toxicities were graded according to the acute and late radiation morbidity scoring criteria of the radiation therapy oncology group. The accumulated survival was calculated according to the Kaplan-Meier method. The log-rank test was used to compare the difference in survival.With a median follow-up duration of 65 months (range: 8-110 months), the 5-year estimated locoregional relapse-free survival, distant metastasis-free survival, progression-free survival (PFS), and overall survival rates were 93.4%, 91.7%, 85.8%, and 82.5%, respectively. Older age and advanced T stage were adverse prognostic factors for overall survival, and the absence of comorbidity was a favorable prognostic factor for PFS. However, acceptable acute complications were observed in these patients.IC combined with IMRT alone provides promising long-term survival outcomes with manageable toxicities. Therefore, the omission of CC from the standard treatment did not affect survival outcomes.

Addition of chemotherapy to intensity-modulated radiotherapy does not improve survival in stage II nasopharyngeal carcinoma patients.

In this study, we examined whether combining neoadjuvant chemotherapy (NAC) and/or concurrent chemotherapy (CC) with intensity-modulated radiotherapy (IMRT) improved survival in patients with stage II nasopharyngeal carcinoma (NPC). Two hundred forty-two stage II NPC patients were enrolled between May 2008 and April 2014 and received radical IMRT with simultaneous integrated boost technique using 6 MV photons; some patient groups also received chemotherapy every 3 weeks for 2-3 cycles. The median follow-up duration was 69 months for all patients. At the last follow-up, 18 patients had experienced treatment failure; locoregional relapse among the IMRT alone, NAC+IMRT, NAC+CCRT, and CCRT occurred in 3, 3, 4 and 5, respectively; distant metastases in 0, 0, 2 and 1, respectively, and there was a statistically significant difference among four groups (P=0.019). The 5-year locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) rates for all patients were 94.7%, 98.7%, 92.9%, and 93.4%, respectively. Five-year LRRFS, DMFS, PFS, and OS were similar among the IMRT alone, NAC+IMRT, NAC+CCRT, and CCRT treatment groups. Univariate and multivariate analyses revealed that a combined regimen was not an independent prognostic factor for any survival outcome. However, patients who received IMRT plus chemotherapy experienced more acute adverse events than those who received IMRT alone. Thus, the addition of NAC and/or CC to IMRT did not improve survival outcomes, but was associated with higher incidences of acute treatment-associated toxicities than IMRT alone in patients with stage II NPC.

Long-Term Use of Nimotuzumab in Combination With Intensity-Modulated Radiotherapy and Chemotherapy in the Treatment of Locoregionally Advanced Nasopharyngeal Carcinoma: Experience of a Single Institution.

In this retrospective review of a single institution's experience, the efficacy and safety of the long-term use of nimotuzumab in combination with intensity-modulated radiotherapy (IMRT) and chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma (NPC) were studied. Between August 2008 and March 2014, 39 newly diagnosed patients with stages III-IV NPC were treated with IMRT, chemotherapy, and nimotuzumab. Twenty patients were diagnosed with stage III (51.3%), 14 with stage IVA (35.9%), and 5 with stage IVB (12.8%) disease. All patients received at least one cycle of cisplatin-based induction chemotherapy followed by IMRT and more than nine cycles of nimotuzumab at 200 mg/week. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group. Accumulated survival was calculated according to the Kaplan-Meier method. The log-rank test was used to compare survival differences. With a median follow-up of 46 months (range, 22-86 months), the estimated 3-year local recurrence-free, regional recurrence-free, distant metastasis-free, progression failure-free, and overall survival rates were 92.1%, 89.7%, 82.5%, 77.6%, and 86.8%, respectively. Univariate analysis showed that clinical stage and the cycle of induction chemotherapy were related with prognosis. The median cycle for the addition of nimotuzumab was 12 weeks. Grade 3 radiation-induced mucositis was observed in 15.8% of the treated patients. No skin rash or infusion reaction was observed, which is distinctly different from what was reported in patients treated with nimotuzumab. The major toxicities observed were grades I-II mucositis and leukocytopenia. Long-term use of nimotuzumab plus IMRT showed promising outcomes in terms of locoregional control and survival, without increasing the incidence of radiation-related toxicities in patients.

Gemcitabine/cisplatin induction chemotherapy before concurrent chemotherapy and intensity-modulated radiotherapy improves outcomes for locoregionally advanced nasopharyngeal carcinoma.

Addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CC) is an encouraging first-line treatment strategy for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We evaluated the clinical efficacy and toxicity of addition of gemcitabine plus cisplatin (GP) IC to intensity-modulated radiotherapy (IMRT) and CC for patients with locoregionally advanced NPC. At a median follow-up duration of 48 months (10-59 months), 4-year local relapse-free survival (LRFS) was 86.9%, regional relapse-free survival (RRFS) was 90.6%, distant metastasis-free survival (DMFS) was 79.8%, progression-free survival (PFS) was 77.0%, and overall survival (OS) was 81.9%. Univariate analysis revealed that T stage, N stage, clinical stage, and CC correlated with OS, while N stage and clinical stage correlated with PFS. In multivariate analysis, T4 was a prognostic indicator of poor OS and PFS, and N3 was a prognostic indicator of poor OS. Having received ≥ 2 cycles of IC was prognostic of better RRFS. During IC, grade 3-4 thrombocytopenia occurred in 10 patients, and grade 3-4 leukocytopenia was observed in 16 patients. Two patients developed mild liver dysfunction. These findings indicate that GP-based IC followed by CC has promising efficacy with acceptable toxicities.

Association of the neoadjuvant chemotherapy cycle with survival outcomes in patients with locoregionally advanced nasopharyngeal carcinoma: a propensity-matched analysis.

Neoadjuvant chemotherapy (NAC) is widely used to treat locoregionally advanced nasopharyngeal carcinoma (NPC). To determine the optimal number of NAC cycles, we assessed the effect of NAC cycle on survival outcomes of locoregionally advanced NPC patients receiving NAC before concurrent chemotherapy and intensity-modulated radiotherapy. Clinical data from 1,188 non-metastatic NPC patients were retrospectively reviewed. All received ≥2 cycles of NAC added to concurrent chemoradiotherapy. Propensity score matching (PSM) was used to identify paired patients according to various covariates. In total, 297 pairs were selected. After a median follow-up time of 57 months (range: 7 to 104 months), the 5-year locoregional relapse-free survival, distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival rates in patients treated with 2 cycles vs. 3 to 4 cycles of NAC were 91.3% vs. 87.2% (P=0.149), 93.3% vs. 88.5% (P=0.043), 88.7% vs. 81.7% (P=0.037), and 94.0% vs. 92.6% (P=0.266), respectively. On multivariate analysis, 2 cycles of NAC were associated with improved DMFS (hazard ratio, 0.499; P=0.038) and PFS (hazard ratio, 0.585; P=0.049). NAC cycle was an independent prognosticator of DMFS and PFS in univariate and multivariate analyses. Thus, 2 cycles of NAC appear sufficient, as additional cycles were not associated with added survival benefit for locoregionally advanced NPC.

Addition of 5-fluorouracil to first-line induction chemotherapy with docetaxel and cisplatin before concurrent chemoradiotherapy does not improve survival in locoregionally advanced nasopharyngeal carcinoma.

Although a multicenter, randomized study indicated that induction chemotherapy (IC) with docetaxel/cisplatin/fluorouracil (TPF) before concurrent chemoradiotherapy (CCRT) improves survival outcomes, it remains unclear whether TPF is the best IC regimen for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Our aim was to compare the efficacy and toxicities of TPF vs. docetaxel/cisplatin (TP) IC followed by CCRT in patients with locoregionally advanced NPC. One hundred thirty-two patients with locoregionally advanced NPC received 21-day cycles of IC with either TPF or TP. Both were followed by intensity-modulated radiotherapy concurrent with the cisplatin treatment every 3 weeks. Three-year rates of locoregional relapse-free survival, distant metastasis-free survival, progression-free survival, and overall survival were respectively 96.4%, 87.7%, 86.0%, and 94.7% for patients in the TPF arm patients and 90.3%, 91.9%, 85.2%, and 92.0% for patients in the TP arm. There were no differences in survival between the two arms. Multivariate analysis revealed the IC regimen was not an independent prognostic factor for any survival outcome. However, patients in the TP arm experienced fewer grade 3/4 toxicities. In sum, IC with docetaxel and cisplatin is associated with similar efficacy and less toxicity than the TPF regimen. Addition of fluorouracil to docetaxel plus cisplatin IC is therefore not recommended for patients with locoregionally advanced NPC.

Outcome and long-term efficacy of four facio-cervical fields conformal radiotherapy for nasopharyngeal carcinoma.

PURPOSE: To evaluate the outcomes of 255 patients with nasopharyngeal carcinoma (NPC) treated with four facio-cervical fields conformal radiotherapy (4F-CRT). RESULTS: In one patient's 3 different RT treatment modalities, the 4F-CRT techniques resulted in sharper of the dose-volume histograms (DVHs) for primary gross tumor volume (PGTVnx) and planning target volume (PTVnx), similar to the intensity modulated radiation therapy (IMRT). The median follow-up duration was 43 months. Locoregional relapse and distant metastases as the first treatment failure events occurred in 32 (32/255, 12.5%) and 20 (30/255, 11.8%) patients, respectively. The 3-year and 5-year local control, disease-free survival, and overall survival rates were 83.3%, 82%, 83.8%, and 76.1%, 73.2%, 76.3% respectively. Univariate analysis displayed that clinical stage, T-stage, N-stage, and tumor response were related to prognosis. Multivariate analysis indicated that age, T-stage, N-stage, and combined chemotherapy were independent prognosticators. The incidence of grade 1-2 acute mucositis and leukocytopenia were 93.7% and 91.0%, respectively, with no cases of grade 4 toxicity detected. MATERIALS AND METHODS: From November 2007 to December 2011, 255 patients with histologically diagnosed, non-metastatic NPC were enrolled into this study and received 4F-CRT. Magnetic resonance imaging scans of the nasopharynx were performed on every patient. All patients received definitive radiotherapy with 6 MV X-rays using conventional fractions at 2 Gy daily, 5 fractions per week, and 231 patients with stage IIb-IV received concurrent chemotherapy and cisplatin-based adjuvant chemotherapy. The accumulated survival was calculated according to the Kaplan-Meier method; the log-rank test was used to compare survival differences. Multivariate analysis was performed using Cox's proportional hazard model. CONCLUSIONS: Compared with the conventional treatment plans, the 4F-CRT plan delivered more dose to cover the tumor volume and reduces the doses of the normal tissues including the parotid gland, TMJs and so on. The long-term efficacy of 4F-CRT is satisfactory and its toxicities are tolerable.

Optimization of the margin expanded from the clinical to the planned target volume during intensity-modulated radiotherapy for nasopharyngeal carcinoma.

During the radiotherapy process, the emergence of set-up errors is nearly inevitable. Because set-up errors were not detected and corrected daily, planned target volumes were formed by expanding the clinical target volume according to each unit's experience. We optimized the margins of clinical and planned target volumes during administration of intensity-modulated radiotherapy for nasopharyngeal carcinoma. A total of 72 patients newly diagnosed with non-metastatic nasopharyngeal carcinoma and treated with Tomotherapy were prospectively enrolled in the study. For each patient, one megavoltage computed tomography scan was obtained after conventional positioning, online correction, and daily tomotherapy delivery. The interfraction set-up errors were determined using a planning CT based on the registered scan. The mean interfraction errors were -2.437±2.0529 mm, 0.0652±2.3844 mm, 0.318±1.8314 mm, and 0.197±1.8721° for the medial-lateral, superior-inferior, and anterior-posterior directions, and the direction of rotation, respectively. The total MPTV in the three directions was 7.53 mm, 1.83 mm, and 2.08 mm, respectively. The 3-mm margins in the superior-inferior and anterior-posterior directions uniformly expanded from the clinical target volume should be sufficient, and the marging in the medial-lateral direction was up to 7.5 mm. These results suggest that personalized MPTV may be adopted for intensity-modulated radiotherapy planning.

Addition of 5-fluorouracil to docetaxel/cisplatin does not improve survival in locoregionally advanced nasopharyngeal carcinoma.

Addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) is a potentially effective approach for treating locoregionally advanced nasopharyngeal carcinoma (NPC). In this study, we compared the efficacy and toxicity of IC regimens consisting of docetaxel plus cisplatin with (TPF) or without (TP) 5-fluorouracil followed by CCRT in these patients. Clinical data from 245 propensity score-matched pairs of newly diagnosed non-metastatic NPC patients who received either TPF or TP IC before CCRT were retrospectively reviewed. After a median follow-up of 60 months, 5-year locoregional relapse-free, distant metastasis-free, progression-free, and overall survival rates were 95.6%, 94.7%, 90.4%, and 92.9% in TPF arm patients and 96.7%, 94.2%, 91.7%, and 91.0% in TP arm patients, respectively. There were thus no differences in survival between the two arms. Multivariate analysis revealed that IC regimen was not an independent prognostic factor for any of the survival outcomes. However, patients who received TP experienced lower incidences of grade 3/4 toxicities than those who received TPF. These results indicate that omission of 5-fluorouracil from TPF-based IC did not affect survival outcomes, but was associated with reduced toxicity, in patients with locoregionally advanced NPC.

An analysis on set-up errors by data of mugavoltage fan-beam computed tomography during intensity-mod-ulated radiotherapy for nasopharyngeal carcinoma / 实用医学杂志

Objective To explore the inter-fraction setup errors and affecting factors from data of daily fan-beam megavoltage computed tomography(MVCT). Methods A total of 37consecutive NPC patients treated with tomotherapy were hospitalized during the period of February 2015 to September 2015. For each patient,one MVCT scan was obtained after conventional positioning ,online correction and tomotherapy delivery daily ,and the scans were put into the planning computed tomography to determine inter-fraction setup errors. The MPTV was calculated with the equation:MPTV=2.5∑+0.7σ(∑:systematic error;σ:random error). Results The average absolute errors of the inter-fraction were(2.102 ± 0.0406)mm,(1.490 ± 0.0348)mm,(1.306 ± 0.335)mm and(1.392 ± 0.0384)° at three dimensions. The total MPTV accounting for inter-error was 3.4675 mm,2.9795 mm,and 2.8885 mm. Gradual increases in both inter-fraction three-dimensional displacement were observed with time and treatment(P < 0.05). Univariate analysis revealed that weight loss and retraction of neck lymph nodes were affecting factors of set-up errors. Conclusions 3 mm margins uniformly expended from clinical target volume to planning target volume may not be suitable. The personalized margin should be adopted for the design of IMRT planning. Displacement increases as a treatment course is prolonged.

Analysis of inter-fraction setup error of nasopharyngeal carcinoma treated with tomotherapy with mugavoltage computed tomography / 中国医师杂志

Objective To evaluate the inter-fraction setup error during the treatment with megavoltage computed tomography (MVCT) and provide theoretical basis for clinical target volume-planning target volume (CTV-PTV) margins for nasopharyngeal carcinoma (NPC) patients treated with tomotherapy.Methods Thirty-seven consecutive NPC patients treated with tomotherapy were prospectively enrolled for the study between February 2015 and September 2015.For each patient,one MVCT scan was obtained after conventional positioning,online correction and tomotherapy delivery daily,and the scan was registered to the planning CT to determine inter-fraction setup error.The expanding margin for PTV (MPTV) was calculated with the recipe:MPTV =2.5∑ + 0.76 (∑:systematic error;6:random error).Results The average absolute errors of the inter-fraction were (2.102 ± 0.040 6) mm,(1.490 ± 0.034 8) mm,(1.306 ± 0.335) mm and (1.392 ± 0.038 4) ° in the three dimensions.Gradual increases in both inter-fraction three-dimensional displacement were observed with time and treatment (P ＜ 0.05).The total MPTV ac counting for inter-error were 3.467 5 mm,2.979 5 mm and 2.888 5 mm.Conclusions Tomotherapy irradiation technology personalized MPTV should be adopted for the design of tomotherapy plan.Displacement increased as a function of time.