Local Recurrent Nasopharyngeal Carcinoma Research Articles

518 Local recurrence of nasopharyngeal carcinoma: re-irradiation, immunotherapy, surgery?

518 Local recurrence of nasopharyngeal carcinoma: re-irradiation, immunotherapy, surgery?

Patterns and Prognosis of Local Recurrence of Nasopharyngeal Carcinoma after Intensity-modulated Radiotherapy.

Objective: To investigate the patterns of local failure and prognosis in patients with locally recurrent nasopharyngeal carcinoma (rNPC) after primary intensity-modulated radiotherapy (IMRT). Methods: The data of 298 patients with locally rNPC after IMRT were retrospectively analyzed. Magnetic resonance images of the initial and recurrent tumors were reviewed and, for patients with extra-nasopharyngeal local recurrence, the gross tumor volume of local recurrence was transferred to the original IMRT plan for dosimetry analysis. Significant prognostic factors for overall survival (OS) were selected by multivariate Cox regression analysis. Results: The commonest recurrence sites were the nasopharynx (93%, 277/298) and skull base (53.7%, 160/298). Of the 21 patients with extra-nasopharyngeal recurrence (19 cases valid), 12 had in-field failures, 4 had marginal failures, and 3 had out-field failures. The ethmoid sinus (57.1%, 4/7) and nasal cavity (28.6%, 2/7) were the most frequent sites of marginal and out-field failures. After median follow-up of 37 months, the 3-year and estimated 5-year OS rates were 57.3% and 41.7%, respectively. Multivariate analysis showed that age, recurrence interval, plasma Epstein-Barr virus (EBV) DNA level, and recurrent T stage were independent prognostic factors for OS. Conclusions: Local failure after IMRT occurs most commonly in the nasopharynx and skull base. In patients with extra-nasopharyngeal recurrence, in-field failure remains the main failure pattern, and marginal and out-field failures mainly occur in the ethmoid sinus and nasal cavity. Elder age, shorter recurrence interval, detectable plasma EBV DNA, and advanced recurrent T stage are negative predictors of OS in patients with rNPC.

Normal tissue complication probability model of temporal lobe injury following re-irradiation of IMRT for local recurrent nasopharyngeal carcinoma.

We tried to establish the normal tissue complication probability (NTCP) model of temporal lobe injury of recurrent nasopharyngeal carcinoma (NPC) patients after two courses of intensity modulated radiotherapy (IMRT) to provide more reliable dose-volume data reference to set the temporal lobe tolerance dose for recurrent NPC patients in the future. Recurrent NPC patients were randomly divided into training data set and validation data set in a ratio of 2:1, All the temporal lobes (TLs) were re-contoured as R/L structures and named separately in the MIM system. The dose distribution of the initial IMRT plan was deformed into the second course planning CT via MIM software to get the deformed dose. Equivalent dose of TLs in 2Gy fractions was calculated via linear quadratic model, using an α/β=3 for temporal lobes. NTCP model that correlated the irradiated volume of the temporal lobe and? the clinical variables were evaluated in a multivariate prediction model using AUC analysis. From Jan. 2010 to Dec. 2020, 78 patients were enrolled into our study. Among which 26 (33.3%) developed TLI. The most important factors affecting TLI was the sum-dose d1.5cc of TL, while the possible clinical factors did not reach statistically significant differences in multivariate analysis. According to NTCP model, the TD5 and TD50 EQD2 dose of sum-dose d1.5cc were 65.26Gy (46.72-80.69Gy) and 125.25Gy (89.51-152.18Gy), respectively. For the accumulated EQD2 dose, the area under ROC shadow was 0.8702 (0.7577-0.9828) in model validation, p<0.001. In this study, a NTCP model of temporal lobe injury after a second course of IMRT for recurrent nasopharyngeal carcinoma was established. TD5 and TD50 doses of temporal lobe injury after re-RT were obtained according to the model, and the model was verified by validation set data.

Radiomic signatures reveal multiscale intratumor heterogeneity associated with tissue tolerance and survival in re-irradiated nasopharyngeal carcinoma: a multicenter study

BackgroundPost-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC.MethodsThis multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes.ResultsThe radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713–0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2–62.5% vs. 16.3–18.8%, P < 0.001). The signature significantly outperformed the clinical model (P < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07–6.75, P < 0.001) and all causes of deaths (HR 1.53–2.30, P < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity.ConclusionsWe present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.

Radiation-induced nasopharyngeal necrosis in locally-recurrent nasopharyngeal carcinoma patients after re-radiotherapy.

e18063 Background: Re-radiotherapy (re-RT) is the main treatment for locally recurrent nasopharyngeal carcinoma (lrNPC) patients, and commonly led to radiation-induced nasopharyngeal (NP) necrosis, which was lethal but rare study has focused on it. The aim of this study was to evaluate the cause and impact of radiation-induced NP necrosis in lrNPC patients who received re-RT. Methods: Totally 252 lrNPC patients who received re-RT between January 2013 and December 2020 were retrospectively collected. The inclusion criteria were as follows: (1) no NP necrosis before re-RT; (2) complete medical records, including treatment, clinical and dosimetric information; (3) conventional fractionated radiotherapy. All patients received intensity-modulated radiotherapy ± chemotherapy. Radiation-induced NP necrosis was diagnosed by magnetic resonance imaging and/or electronic nasopharyngoscopy. Dosimetric factors of the planning target volume of primary tumor (PTVp) were extracted from the dose-volume histogram (DVH), which was rescaled to an equivalent dose of 2 Gy per fraction (EQD 2 Gy) using a linear quadratic model. Logistic regression was used to identify the independent prognostic factors for generating the nomogram. Results: With a median follow-up of 44.63 months (inter-quartile range [IQR], 27.70 – 69.20 months), 47.6% of patients (120/252) occurred radiation-induced NP necrosis, which mostly happened within 1 year post re-RT (median [IQR], 5.83 [3.37 – 11.57] months). The 3-year overall survival was 83.0% vs 39.7% ( P＜0.001) in lrNPC patients with or without radiation-induced NP necrosis. Except for the fractionated dose, other dosimetric factors of PTVp were not significantly different between two groups, including D98 (dose to 98% of PTVp), D50, D2 and homogeneity index (Table). Furthermore, multivariate analysis showed that continuous variable age (HR [95%CI]: 1.04 [1.02 – 1.07], P = 0.003) and tumor volume (HR [95%CI]: 1.02 [1.01 – 1.03], P＜0.001), and fractionated dose &gt; 2.22 Gy (HR [95%CI]: 2.36 [1.32 – 4.21], P = 0.004) were independent factors in predicting radiation-induced NP necrosis, which yielded a C-index of 0.742 (95% CI, 0.682 - 0.803) for OS in the nomogram. Conclusions: The incidence of radiation-induced NP necrosis was high in lrNPC patients who received re-RT. Patients with older age, larger tumor volume or receiving fractionated dose over 2.22 Gy were more easily to suffer NP necrosis, which need to explore novel treatment strategies to improve patients’ survivals. [Table: see text]

Treatment of loco-regional recurrence of nasopharyngeal carcinoma in a non-endemic area: oncologic outcomes, morbidity, and proposal of a prognostic nomogram.

The study assessed outcomes and toxicities of different treatment modalities for local and/or regional recurrent nasopharyngeal carcinoma (NPC) in a non-endemic area. Patients treated with curative intent for recurrent NPC with salvage surgery, photon-based radiotherapy, proton therapy (PT), with or without chemotherapy, at different Italian referral centers between 1998 and 2020 were included. Adverse events and complications were classified according to the Common Terminology Criteria for Adverse Events. Characteristics of the patients, tumors, treatments, and complications are presented along with uni- and multivariate analysis of prognostic factors. A survival predictive nomogram is also provided. A total of 140 patients treated from 1998 to 2020 were retrospectively assessed. Cases with lower age, comorbidity rate, stage, and shorter disease-free interval (DFI) preferentially underwent endoscopic surgery. More advanced cases underwent re-irradiation, fairly distributed between photon-based radiotherapy and PT. Age and DFI were independent factors influencing overall survival. No independent prognostic effect of treatment modality was observed. No significant difference in the morbidity profile of treatments was observed, with 40% of patients experiencing at least one adverse event classified as G3 or higher. Recurrent NPC in a non-endemic area has dissimilar aspects compared to its endemic counterpart, suggesting the need for further studies that can guide the choice of the best treatment modality.

Unraveling the patterns and pathways of local recurrence of nasopharyngeal carcinoma: evidence for individualized clinical target volume delineation

BackgroundsDespite publication of international guidelines, there are notable controversial points of clinical target volume (CTV) delineation in nasopharyngeal carcinoma (NPC). Recently, scholars proposed a novel way of delineation of CTV in NPC—individualization of CTV delineation based on T classification and spread patterns, which yielded excellent long-term local control with limited late toxicities. The aim of this study was to clarify the anatomic patterns and pathways of local recurrence of NPC and provide a clinical reference for the delineation of CTV.MethodsA total of 869 patients with non-metastatic NPC were treated with intensity-modulated radiation therapy (IMRT) at our institution between 2009 and 2010. Among the 57 cases of local/locoregional recurrence, 52 cases with traceable radiotherapy plans and magnetic resonance imaging at the time of the first diagnosis of recurrence were included. Anatomical structures and gross tumor volume of local recurrence were contoured. The incidence of relapse of each anatomic structure, route of local recurrence, and their correlation were analyzed.ResultsLocally advanced disease had a significantly increased risk of recurrence in the posterior nasal cavity and a trend towards higher risk of recurrence in the clivus, lateral pterygoid muscle, and hypoglossal canal. Based on the incidence of local recurrence, we constructed a high-risk map for the early and locally advanced stages. Local recurrences were classified into five routes, where anterior extension accounted for the majority (30.8%), and caudal tumor extension pathway had the lowest incidence (5.8%). There was a significant correlation between the local recurrences of neural foramina and neighboring anatomical structures along each pathway. All cases relapsed at unilateral cavernous sinus, most at the same side of primary tumor. Based on our findings, we proposed some suggestions on delineations of CTV, based on T classification and local extension pattern.ConclusionsLocal recurrence of NPC varied according to T classification, followed a stepwise pattern, spread via neural foramina, and recurred at ipsilateral cavernous sinus. This provides meaningful clinical evidence for delineation of CTV, especially individualized delineation.

Prediction of outcomes in patients with local recurrent nasopharyngeal carcinoma: development and validation of a four-factor prognostic model integrating baseline characteristics and [18F]FDG PET/CT parameters

ObjectivesTo investigate the prognostic value of [18F]FDG PET/CT parameters in local recurrent nasopharyngeal carcinoma (lrNPC) and establish a prognostic tool for lrNPC patients based on these [18F]FDG PET/CT parameters.MethodsA total of 358 lrNPC patients seen from 2010 to 2019 at Sun Yat-sen University Cancer Center with complete baseline characteristics and [18F]FDG PET/CT data were retrospectively analyzed. Maximal standardized uptake value (SUVmax), SUVmean, SUVpeak, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and heterogeneity index (HI) for recurrent nasopharynx tumors were included. Cox regression analysis was performed to select candidate variables. Subsequently, a nomogram for predicting overall survival (OS) for lrNPC patients was developed and internally validated.ResultsMultivariate Cox analysis results suggested that age ≥ 47 years (hazard ratio (HR), 1.62 (1.18-2.24); p = 0.003)，with smoking history (HR, 1.41 (1.01–1.98); p = 0.046), recurrent T stage {[rT3 vs rT1/2: HR, 1.81 (1.04–3.12); p = 0.037]; [rT4 vs rT1/2: HR, 2.46 (1.32–4.60); p = 0.005]}, and TLG {[37.1–184.3 vs ≤ 37.1: HR, 2.26 (1.49–3.42); p < 0.001]; [>184.3 vs ≤ 37.1: HR, 4.31 (2.50–7.43); p < 0.001]) were independent predictors of OS. A 4-factor nomogram was generated to stratify patients into 3 risk groups. This novel model showed good discrimination with a high C-index (0.752, 95%CI: 0.714–0.790). In addition, the calibration curves showed good agreement between the predicted probabilities and actual observations and decision curve analysis (DCA) suggested that the nomogram was useful for clinical decision-making.ConclusionsOur study confirmed that [18F]FDG PET/CT parameters were valuable in predicting OS and PFS for lrNPC patients. The 4-factor prognostic model combing baseline patient characteristics with [18F]FDG PET/CT parameters for lrNPC patients had good discrimination, agreement, and clinical application potential.Key Points•[18F]FDGPET/CTparameters were valuable in predicting OS and PFS for lrNPC patients.• The novel 4-factor nomogram for lrNPC patients had good discrimination, agreement, and potential for clinical application.

Anatomic distribution of local recurrence of nasopharyngeal carcinoma in the Era of IMRT: Suggestion of modification of clinical target volume delineation.

e18060 Background: Target volume delineation in nasopharyngeal carcinoma (NPC) remains a challenge because of the narrow therapeutic margin. There are no-well established guidelines for clinical target volume (CTV) delineation with long-term follow-up. Current consensus continues to rely heavily on bony structure and experience from conventional two and three- dimensional radiation. The aim of our study, is to clarify different anatomic distribution of local recurrence of NPC based on various T stages and spread patterns, provide a high-risk map of local recurrence of NPC, and thus provide suggestion for modification of CTV delineation based on T stages and spread patterns. Methods: We retrospectively enrolled 869 patients with newly diagnosed nonmetastatic NPC treated with definitive IMRT in our institution. With a median follow-up of 54.4 months, 72 patients developed local failure. All the cases of local failure were reviewed and those of local residual disease were excluded. After that, 52 cases with tracaeble primary radiotherapy plans and MR imaging of local recurrence were included in this study. Gross tumor volume of local recurrence (GTVr) and normal structures were delineated in each recurrent patient on primary CT of radiotherapy. The overlap of normal structures with GTVr were analyzed, as well as the stepwise patterns of tumor spread in NPC, based on different T stages and relapsed risk (≥5%, ≥10%, ≥20%, etc). Results: The anatomic distributions of local recurrence of various primary T stages were compared between early and late stages of NPC. Of note, these structures were significantly highly involved in T3/4 cases, compared with T1/2 cases, including lateral pterygoid muscle, inferior orbital fissure，posterior ethmoid sinus，cavernous sinus as well as hypoglossal canal. As for tumor spread patterns of local relapse, most cases relapsed in the nasopharynx and retropharyngeal lymph node (38.5%), followed by anterior-lateral tumor extension (via nasal cavity-pterygoid process-pterygopalatine fossa, 17.31%), posterior tumor extension (via prevertebral muscle-clivus, 13.46%), anterior-superior extension (via nasal cavity-ethmoid sinus-sphenoidal sinus,13.46%), superior extension(via foramen lacerum-cavernous sinus, 11.54%), etc. Finally, we depicted a map of high-risk area based on different T stages and relapsed risk (≥5%, ≥10%, ≥20%). Conclusions: Comprehensive analysis of local recurrence distributions and tumor spread patterns in real-world IMRT provides important reference for modification of CTV delineation for primary NPC. Certain structures such as cavernous sinus and lateral pterygoid muscle are not routinely recommended in the delineation of high-risk CTV for T1-2 disease. Future individualized delineations should be based on relapsed risk and tumor spread patterns.

Long-term results of robotic-assisted nasopharyngectomy for recurrent nasopharyngeal carcinoma.

We have previously reported our early experience in robotic-assisted nasopharyngectomy. The current case series is a report of our experience in 33 robotic-assisted nasopharyngectomy. Prospective series of patients who underwent robotic-assisted nasopharyngectomy for local recurrent nasopharyngeal carcinoma from January 2010 to March 2019. Thirty-one patients underwent robotic-assisted nasopharyngectomy with two additional second procedure for positive margin. Median age is 55 years (29-85). Twenty-five patients had rT1 disease and six patients had tumor invaded sphenoid floor (rT3). Median operative time was 227 min and median blood loss was 200 ml. The median follow-up period for all patients were 38 months. Four patients had local recurrence. Five-year local control rate, overall survival, and disease-free survival are 85.1%, 55.7%, and 69.1%, respectively. Robotic-assisted nasopharyngectomy for recurrent nasopharyngectomy was showed to have a high local control rate. The operating time was comparable to open surgery.

Transoral robotic nasopharyngectomy for local recurrent nasopharyngeal carcinoma

Objective: To investigate the safety, efficacy, locally control and survival results of transoral Da Vinci robotic surgery for salvage treatment of locally recurrent nasopharyngeal carcinoma. Methods: This retrospective study included 33 patients with locally recurrent nasopharyngeal carcinoma (stage rT1-2, partial rT3) underwent transoral Da Vinci robotic surgery between October 2017 and January 2020. There were 20 males and 11 females, with an average age of (47.9±10.5) years. The lesions were localized in nasopharyngeal cavity in 14 cases, with extending to parapharyngeal space in 6 cases and the floor of sphenoid sinus in 13 cases. Transnasal endoscopy was used to assist surgery if necessary. SPSS 25.0 statistical software was used for statistical analysis. Results: Transoral robotic nasopharyngectomy was successfully performed in all cases without conversion to open surgery, of which 13 cases were combined with transnasal endoscopic surgery. The average operation time was (126.2±30.0) min, ranging from 90 to 180 min. The postoperative pathological margin was R0 (31 cases) and R1 (2 cases), with no tumor residue. Complications of surgery mainly included symptoms of headache, nasal dryness and velopharyngeal insufficiency without nasopharyngeal hemorrhage. Follow-up time was from 3 to 54 months. One case had tumor recurrence 11 months after operation, 1 case had ipsilateral cervical lymph node metastasis 27 months after operation, 2 cases had distant metastasis and 1 case died of nasopharyngeal hemorrhage 3 months after operation. The 1-year, 2-year and 3-year overall survival rates were 97.0%, 96.0% and 92.9%, respectively and the local recurrence free rates were 97.0%, 95.7% and 91.7%, respectively. Conclusion: Transoral robotic nasopharyngectomy is safe and feasible for local recurrent nasopharyngeal carcinoma in selected patients, with higher local control rate and quality of life.

Photoimmunotherapy for Local Recurrence of Nasopharyngeal Carcinoma: A Case Report

Photoimmunotherapy (PIT), developed by the National Cancer Institute, involves Cetuximab sarotalocan sodium infusion followed by laser irradiation. PIT exerts specific antitumor effects on a variety of carcinomas that express epidermal growth factor receptors. PIT is a new cancer treatment option approved by Japan ahead of other countries worldwide. As of 2022, PIT is indicated in “unresectable, locally advanced, or locally recurrent head and neck cancer, with priority given to standard treatments such as chemotherapy when available”. The conventional treatment for unresectable locally advanced or locally recurrent head and neck cancer is palliative. Whether photoimmunotherapy can be curative for unresectable locally advanced head and neck cancers depends on the case. Herein, we report a case of locally recurrent nasopharyngeal carcinoma, treated with photoimmunotherapy via the nasal cavity, along with a literature review. Preoperative simulation provided considerable information on device selection, numbers of devices, and availability of working space. As a result, a complete response was obtained following a cylindrical diffuser puncture. Cases of local recurrence of nasopharyngeal carcinoma are considered a good indication for PIT. However, since the follow-up period after treatment was short in this case, we will continue to conduct strict follow-ups and accumulate more cases.

Comparison of radiotherapy combined with nimotuzumab vs. chemoradiotherapy for locally recurrent nasopharyngeal carcinoma

BackgroundThe present study compared the effectiveness and toxicity of two treatment modalities, namely radiotherapy combined with nimotuzumab (N) and chemoradiotherapy (CRT) in patients with locally recurrent nasopharyngeal carcinoma (LR-NPC).MethodsPatients with LR-NPC who were treated with radiotherapy were retrospectively enrolled from January 2015 to December 2018. The treatment included radiotherapy combined with N or platinum-based induction chemotherapy and/or concurrent chemotherapy. The comparison of survival and toxicity between the two treatment modalities was evaluated using the log-rank and chi-squared tests. Overall survival (OS) was the primary endpoint.ResultsA total of 87 patients were included, of whom 32 and 55 were divided into the N group and the CRT group, respectively. No significant differences were noted in the survival rate between the N and the CRT groups (4-year OS rates, 37.1% vs. 40.7%, respectively; P = 0.735). Mild to moderate acute complications were common during the radiation period and mainly included mucositis and xerostomia. The majority of the acute toxic reactions were tolerated well. A total of 48 patients (55.2%) demonstrated late radiation injuries of grade ≥ 3, including 12 patients (37.5%) in the N group and 36 patients (66.5%) in the CRT group. The CRT group exhibited significantly higher incidence of severe late radiation injuries compared with that of the N group (P = 0.011).ConclusionRadiotherapy combined with N did not appear to enhance treatment efficacy compared with CRT in patients with LR-NPC. However, radiotherapy combined with N may be superior to CRT due to its lower incidence of acute and late toxicities. Further studies are required to confirm the current findings.

Salvage Re-irradiation with Intensity-modulated Radiotherapy, Chemotherapy Combined with Hyperthermia for Local Recurrence of Nasopharyngeal Carcinoma After Chemoradiotherapy.

A sufficient dose of radiation is difficult to administer in re-irradiation for local recurrence of cancer after radiotherapy because of the dose limitation to organs at risk. Re-irradiation cases also include radioresistant tumors that are difficult to control locally, and their prognosis is poor in general. The effect of re-irradiation using intensity-modulated radiotherapy (IMRT) has recently been reported to significantly reduce the dose to organs at risk, and the efficacy of hyperthermia has been reported for radioresistant tumors. We report a case of local recurrence after concurrent chemoradiotherapy treated with salvage re-irradiation using IMRT and chemotherapy combined with hyperthermia in a patient with nasopharyngeal carcinoma, and include a discussion of the literature.

Stereotactic radiation therapy for recurrent nasopharyngeal carcinoma

: Radiation therapy is the mainstay treatment modality for nasopharyngeal carcinoma. Recurrent disease affects about 10% of patients, and reirradiation is the most common treatment for recurrent nasopharyngeal carcinoma. Serious complications are not uncommon during the second course of radiation therapy because of the full-tolerance radiation dose applied to normal tissue. Catastrophic toxicity may be induced by treatment for recurrent nasopharyngeal tumor. Salvage surgery has a 3-year overall survival of 85.8% with a 5% incidence of late fatal toxicity. However, the surgical approach is still relatively new with limited information and experience regarding its optimal implementation. Another technique used for recurrent nasopharyngeal carcinoma is stereotactic radiation therapy (SRT), which delivers radiation to a specific target with a rapid dose fall-off to adjacent normal tissue that can reduce the risk of complications. Single-shot radiation therapy for nasopharyngeal carcinoma has a local control rate of up to 72% for 2 years, although there is a 10% chance of cranial neuropathy and temporal lobe necrosis. Conventional fractionated SRT has shown a 3-year control rate of 56% with complications of 11% nasopharyngeal necrosis and 8.3% nasal bleeding. Hypofractionation SRT with a large fraction dose has demonstrated a 5-year control rate of 78% with a 12.5% to 16% incidence of fatal complications. Local recurrent nasopharyngeal carcinoma with a limited volume should be treated with SRT. For reirradiation, the dose constraints in organs at risk (OARs) of recurrent nasopharyngeal carcinoma are critical. Despite the lack of data regarding SRT, the radiation doses of OARs in SRT may be converted to a biologically equivalent dose and summed with doses of primary radiation therapy for evaluation. Hypofractionation may have an optimal treatment response rate with acceptable complications. For recurrent nasopharyngeal carcinoma, SRT has shown certain therapeutic advantages, but conventional fractionation radiation therapy may still be the appropriate setting for reirradiation. Patients undergoing SRT should be counseled carefully before initiation of therapy, especially if the targets are close to a critical organ that may cause serious side effects. The treatment decision of recurrent nasopharyngeal carcinoma should be based on the patient’s overall condition and disease status.

Pretreatment 18F-FDG uptake heterogeneity can predict treatment outcome of carbon ion radiotherapy in patients with locally recurrent nasopharyngeal carcinoma.

Our study was to investigate the value of pretreatment 18F-FDG uptake heterogeneity to predict the prognosis of patients with locally recurrent nasopharyngeal carcinoma (LRNPC) treated by carbon ion radiotherapy (CIRT). Twenty-nine LRNPC patients who underwent whole-body 18F-FDG PET/CT scanning before CIRT were enrolled. Heterogeneity index (HI)-based 18F-FDG uptake, and the PET/CT traditional parameters, including SUVmax, MTV, and TLG were assessed. Receiver operator characteristics (ROC) determined the best cutoff value, and local recurrence-free survival (LRFS) and progression-free survival (PFS) were evaluated by the Kaplan-Meier method and log-rank test. And the predictive ability was evaluated by the ROC curve. Cox analyses were performed on LRFS and PFS. In this study, univariate analysis showed that HI was a significant predictor of LRNPC treated by CIRT. HI could be used to predict LRFS and PFS. Patients with HI (≥ 0.81) had a significantly worse prognosis of LRFS (12.25 vs. NR, p = 0.008), and of PFS (10.58 vs. NR, p = 0.014). The AUC and its sensitivity and sensitivity and specificity were 0.75, 84.21% and 70.00% for LRFS and 0.82, 80.95% and 75.00% for PFS, respectively. Multivariate analysis showed that HI was an independent predictor for the LFRS of LRNPC with CIRT. 18F-FDG uptake heterogeneity may be useful for predicting the prognosis of patients with LRNPC treated by CIRT.

Carbon Ion Radiation Therapy for Salvage Treatment of Locoregionally Recurrent Nasopharyngeal Carcinoma

Reirradiation for locally recurrent nasopharyngeal carcinoma (LR-NPC) after a definitive radiotherapy is challenging and usually associated with severe adverse-effects. The 2-year overall survival (OS) rates of LR-NPC patients treated with X-ray based intensity-modulated radiation (IMRT) ranged between 45%∼60%, depends on the stage at local recurrence. Carbon-ion radiotherapy (CIRT) offers both physical and biological advantages over IMRT. To report the outcomes of 205 LR-NPC patients treated with intensity-modulated CIRT. Patients with locoregionally recurrent, poorly or un-differentiated NPC (WHO type II or III) who underwent salvage therapy with CIRT at the Shanghai Proton and Heavy Ion Center (SPHIC) between May 2015 and June 2019 were included in this analysis. The CIRT doses were 50 to 69 Gray equivalent (GyE) (2.0-3.0 GyE/daily fraction), delivered via raster scanning technology. The 2-year OS, progression-free survival (PFS), local recurrence free survival (LPFS), regional progression-free survival (RPFS), distant metastasis-free survival (DMFS) as well as acute and late toxicities were analyzed. Prognostic indicators of the outcomes were analyzed for overall survival. Among the 205 patients included, 17 patients, 50 patients, 60 patients, and 78 patients, respectively, had recurrent American Joint Committee on Cancer stage I, stage II, stage III, and stage IVA/B disease. With a median follow-up of 18.4 (range, 2.0-74.6) months, the 2-year OS, PFS, LPFS, RPFS, and DMFS rates were 83.1%, 41.8%, 54.0%, 85.4%, and 94.8%, respectively. Favorable prognostic indicators that reached statistical significance included a longer disease-free interval (p=0.001), small volume of gross tumor (p=0.025), stage I-II (vs. stage III-IVB) disease (p < 0.001), lack of necrosis (p=0.023) and carotid artery encasement (p=0.017) before CIRT. No patient developed acute toxicity of grade ≥3 during CIRT. Late treatment-induced severe (grade 3-4) toxicities included mucosal necrosis (20.5%, including patients presented with mucosal necrosis prior to re-irradiation), xerostomia (0.5%), cranial neuropathy (0.5%), and temporal lobe necrosis (0.98%). Among patients experienced mucosal necrosis, grade 4 and 5 hemorrhage were seen in 3.4% (7 patients) and 5.8% (12 patients) with or without local disease progression. The treatment results of the 205 patients received salvage CIRT suggested that the new radiation technology substantially improved the survival outcomes and toxicities profile for LR-NPC, as compared to re-irradiation with photon-based IMRT. Further investigation that compares the efficacy and safety between CIRT vs. IMRT, preferably in prospective manner and with longer follow-up, are needed to confirm these findings.

Proton/heavy ion therapy in salvage of locally recurrent nasopharyngeal carcinoma

: Radiotherapy is the major modality for treating advanced local recurrence of nasopharyngeal carcinoma (NPC). However, as the nearby critical neurological structures have already absorbed a dose close to their maximum tolerance in the primary treatment, even state-of-the-art intensity modulated radiotherapy (IMRT) cannot achieve a satisfactory dose distribution, and re-irradiation is often associated with serious, or even fatal, late complication, as well as substantial local failure. Proton/heavy-ion therapy, with their superior energy deposition characteristics and biological effectiveness, have the potential to overcome these obstacles. The use of proton/heavy-ion therapy to treat re-current NPC dates back to the last millennium when such facilities were extremely rare and dose delivery technique was in its infancy (mainly passive-scattered beams from very limited directions were available). Over the last two decades there have been substantial technological development in proton/heavy-ion therapy, the facilities have become much more widely available, with proton therapy being accepted as a suitable mean for re-irradiation setting in general. The advancement in diagnostic technology and systemic treatment have also contributed significantly to the effectiveness of such highly conformal radiotherapy modalities. Many have applied proton/heavy-ion therapy in the extremely challenging recurrent NPC situation, with various degrees of success. This article provides a brief review of the basic principle of proton/heavy-ion therapy, the issues unique to their usage, studies on their application in treating recurrent NPC and their possible future development.

Establishment of a prognostic nomogram to identify optimal candidates for local treatment among patients with local recurrent nasopharyngeal carcinoma.

Thus far, there is no final conclusion on the treatment of local recurrent nasopharyngeal carcinoma (lrNPC) patients. Herein, we developed a nomogram which combined prognostic biomarkers to predict clinical outcome and guide individual treatment. From 2006 to 2016, 303 patients with lrNPC were retrospectively reviewed. Overall survival (OS) was the primary endpoint. The nomogram was established with the significant prognostic factors (P<0.05) selected by multivariate analysis using Cox regression model. Harrell Concordance Index (C-index), calibration curves, and decision curve analysis (DCA) were applied to evaluate this model. Four independent prognostic factors (age, hypertension, relapsed T (rT) stage, and Epstein-Barr virus DNA) identified from multivariable analysis were included into the nomogram. The C-index of the nomogram was 0.687. The calibration curves for 1-, 3-, and 5-year OS rate showed satisfactory agreements between the predicted and actual values. The decision curve analysis also exhibited a preferable net benefit of this model. All patients were subdivided into three risk groups based on the nomogram. Local treatment was associated with higher OS than palliative chemotherapy alone in the low (P<0.001) and intermediate-risk groups (P=0.001). However, no significant difference was observed between different treatment methods in the high-risk group (P=0.176). We established the nomogram for patients with lrNPC to predict OS and guide individual treatment, which showed satisfactory performance in accuracy, discrimination capability, and clinical utility.

Volumetric parameters derived from FLT-PET performed at completion of treatment predict efficacy of Carbon-ion Radiotherapy in patients with locally recurrent Nasopharyngeal Carcinoma.

The purpose of this study was to investigate the role of 3'-deoxy-3'-[18F]fluorothymidine (FLT)-PET for predicting the outcome of patients with locally recurrent nasopharyngeal carcinoma (LR-NPC) treated by carbon-ion radiotherapy (CIRT). Patients received FLT-PET/CT scan one-week prior to or after completion of CIRT were enrolled in the study. All patients were from prospective trials or treated using a standardized protocol. Time-dependent receiver operator characteristics (ROC) were used to determine the optimal cutoff values for FLT-PET parameters. Univariable and multivariable analyses of local progression-free survival (LPFS) were performed using Cox regression, to examine the prognostic value of FLT-PET parameters, including SUVmax, metabolic tumor volume (MTV) and total lesion thymidine (TLT). A total of 41 patients were enrolled. Elevated MTV and TLT were significantly associated with worse LPFS, in both univariable and multivariable analyses. ROC analysis revealed that both an MTV value higher than 8.6 and a TLT value higher than 14.9 were predictive of increased risk of developing local recurrence, the adjusted HRs were 5.59 (p=0.009) and 7.76 (p=0.002), respectively. In conclusion, FLT-PET was found to be a promising prognostic tool for LR-NPC patients and might play a role in the treatment guidance.