PurposeTo evaluate the prognostic value of treatment related decline of peripheral absolute lymphocyte count (ALC) in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) after preoperative radiation therapy (RT) with or without chemotherapy.MethodsThis post-hoc analysis was performed using data of 222 patients from a phase III, randomized controlled trial in LA-HNSCC. ALCs were measured before, during, and after RT. The ALC decline was defined as the difference between pre-treatment ALC and the nadir ALC observed during RT. Optimal cut-off values for hematologic and nutritional indices were determined by ROC analysis. Survival outcomes were estimated using Kaplan-Meier analysis and compared with the log-rank test. Prognostic factors were identified using LASSO regression and multivariable Cox models. A nomogram was constructed based on independent prognostic variables.ResultsWith a median follow-up of 132.0 (IQR: 104.17-151.73) months, no significant difference was observed in the 10-year overall survival (OS) and progression-free survival (PFS) between treatment groups. Lymphopenia during RT occurred in 197 patients (88.7%), including grade 3 in 112 (50.5%) and grade 4 in 10 (4.5%). An ALC decline > 0.74×109/L was independently associated with poorer OS and PFS. The nomogram integrating T stage, N stage, ALC decline, and neutrophil-to-albumin ratio (NAR) yielded a C-index of 0.66, a 5-year AUC of 0.738, good calibration, and favorable net benefit on DCA.ConclusionTreatment-related ALC decline is an independent adverse prognostic factor in LA-HNSCC. A nomogram incorporating ALC decline performs favorably in individualized survival prediction.

PURPOSE:This study aims to compare clinical features, treatment responses, radiosensitivity, and failure patterns between childhood and adult nasopharyngeal carcinoma (NPC) patients in the era of intensity modulated radiation therapy. METHODS AND MATERIALS:A retrospective review was conducted on 140 childhood NPC patients, aged <21 years, treated at a single institution between January 2004 and November 2019. A propensity score matching method was used to select 280 matched adult NPC patients in a 1:2 ratio. Comparative analysis was performed between the childhood and adult cohorts. RESULTS:Childhood NPC is associated with more advanced clinical stages, heightened radiosensitivity, and improved prognostic outcomes compared to adult NPC. The 5-year rates for overall survival (OS), progression-free survival (PFS) were significantly higher in the childhood group compared with the adult group: 83.1% versus 71.9% (P = .001) for OS, 71.6% versus 60.9% (P = .023) for PFS, but significantly lower for locoregional relapse (LRR): 3.1% versus 12.6% (P = .002). Childhood NPC exhibited heightened radiosensitivity, and high locoregional control can be achieved even in cases that showed no response to induction chemotherapy, which is unlike in adults. In children receiving induction chemotherapy, no significant differences were found in OS (84.0% vs 75.7%, P = .289), PFS (75.2% vs 57.7%, P = .123), LRR (4.4% vs 3.8%, P = .656), and distant metastasis (22.4% vs 38.5%, P = .122) between those with complete/partial response and those with stable/progression disease. Late recurrence after 2 years was less frequent in children than in adults (13.6% vs 29.2%, P = .039), and a higher proportion of childhood patients were successfully salvaged (42.1% vs 21.7%, P = .015). CONCLUSIONS:Childhood NPC often presents at an advanced stage but has a favorable prognosis with excellent locoregional control. Children's heightened radiosensitivity allows for potential dose reduction. Given the risk of late effects, individualized treatment and follow-up strategies are warranted for young patients.

BACKGROUND AND PURPOSE:To establish predictive models for radiation-induced hypoglossal neuropathy (RIHN) in patients with nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS:Data from 423 NPC patients receiving IMRT-based treatment were retrospectively reviewed. They were randomly (3:2) divided into a training set (n = 256) and a testing set (n = 167). Dosimetric variables were selected by penalized regression and machine learning, with area under the receiver operating curve (AUC) calculated. Clinical variables were selected by the competitive risk analysis. A competitive risk model including clinical and dosimetric variables was performed, and a nomogram was generated as a visualization of the model to predict the incidence of RIHN. RESULTS:During a median follow-up of 102 months (IQR: 89.5 to 112.9 months), the cumulative incidence of RIHN at 3, 5, and 8 years were 2.1 %, 5.4 %, and 10.5 %, respectively. D1cc and aV75 were the most predictive dosimetric variables. The dose-effect curve plotted with D1cc indicated the tolerance dose for a 5 % probability of developing RIHN in 8 years (TD5/8) was 77.3 Gy (EQD2). The restricted cubic spline between aV75 and RIHN indicated a volume threshold of 0.81 cm3. A competitive risk model including hypoglossal canal involvement, concurrent chemotherapy, D1cc, and aV75 was established, with the C-index of the training set and testing set being 0.726 and 0.691, respectively. The nomogram-defined high-risk group had the higher RIHN incidences in the training and testing sets. CONCLUSIONS:This study identified the most critical dosimetric predictors, which is expected to become a feasible dose constraint for hypoglossal nerves in radiation plan. Combining dosimetric and clinical predictors, we further proposed and validated the first nomogram model to quantify the risk of RIHN, contributing to identifying high-risk patients and early intervention. Further multicenter studies are needed to validate or complement our findings.

Background:There is an unmet clinical need for the locoregional recurrent head and neck squamous cell carcinoma (HNSCC). Moreover, little data regarding the therapeutic survival outcomes are available for the unresectable recurrent setting that did not receive radiotherapy during the initial course of treatment. Objectives:To investigate the survival outcomes of radiation-naïve recurrent HNSCC who were treated with first-line immunotherapy-based systemic therapy in combination with radical locoregional radiotherapy. Design:This is a retrospective study. Methods:From January 2019 to December 2023, locoregional recurrent HNSCC patients receiving immune checkpoint inhibitor (ICI)-based systemic therapy plus locoregional radiotherapy as first-line treatment in our institution were selected. Median follow-up was 16.4 months. Results:A total of 23 patients with recurrent HNSCC met the inclusion criteria and were finally analyzed. The median time to progression from the beginning of initial course of treatment was 9.3 months. Nineteen patients (82.6%) harbored recurrent stage IV (rIV) disease according to AJCC eighth edition, and 17 (73.9%) patients were assessed unresectable. For overall cohort, the median progression-free survival (PFS) and locoregional progression-free survival (LRPFS) were 17.0 months and 27.2 months, while the median overall survival (OS) and distant metastasis-free survival (DMFS) were not reached. The 1-year OS, PFS, LRPFS, and DMFS were 100%, 79.5%, 79.5%, and 100%, respectively. Twenty patients obtained objective response during the treatment course, achieving the 1-year duration of response (DOR) of 75.3%, and the median of 16.7 months. Combined positive score (CPS) ⩾ 20 was unveiled to be correlated with significantly favorable PFS compared with CPS < 20 or unknown (1-year PFS: 100% vs 50.0%, p = 0.035). Conclusion:This study presented promising survival and tumor control with durable response in recurrent HNSCC, supporting the use of radical RT as the first-line treatment in addition to ICI-based systemic therapy, in particular for patients with CPS ⩾ 20.

PURPOSE:To provide a comprehensive analysis of conditional survival (CS) and dynamic failure hazards in oral cavity squamous cell carcinoma (OCSCC), enhancing prognostic understanding and facilitating more individualized treatment strategy and surveillance. METHOD:Patients with non-metastatic OCSCC undergoing surgery between 1999 and 2018 were retrospectively analyzed. Overall survival (OS), disease-free survival (DFS), conditional OS (COS), and conditional DFS (CDFS) were calculated. Annual hazards, including death, progression, and stage-specific risks, were estimated using Kernel-based methods. RESULTS:Among 700 patients (median follow-up: 97.6 months), the 5-year OS and DFS were 68.3 % and 62.0 %, respectively. The 5-year COS improved from 71 % after one year to 86 % after five years, while the 5-year CDFS increased from 76 % to 87 %. Annual hazard rates for death and progression peaked in the first two years post-surgery, with death hazard declining from 9.8 % to 3.3 % and progression hazard decreasing from 20.0 % to 2.9 % by the fifth year. Stage-specific death hazards peaked at varying timings: the second year for stages I/II, the third year for stage III, and the first two years for stage IV. Progression hazards peaked in the first year for all stages, with stage IV showing the highest risk at 32.0 %, decreasing to ∼ 4 % by the fourth year. CONCLUSION:This study provides an updated overview of CS and dynamic failure hazards in OCSCC, particularly emphasizing the high progression hazard in stage IV patients during the first year. These findings support tailored treatment strategies and rigorous early surveillance to improve outcomes.

Dynamic response to therapy is strongly associated with cancer outcomes. We aim to develop the response-adapted individualized risk index (RAIRI) as an individual prognostic approach and predictive biomarker for adjuvant chemotherapy (AC) benefit in nasopharyngeal carcinoma (NPC) based on pretreatment clinical characteristics, longitudinal cell-free Epstein-Barr virus DNA, and MRI-based tumor regression measurements collected during treatment. Using Bayesian joint model, we developed and validated RAIRI, a dynamic and multidimensional model, with 2148 patients in training, internal validation, external validation, and RCT cohorts (ClinicalTrials.gov NCT02958111 2016-11-04 and NCT02143388 2014-05-18). RAIRI predictions were refined over time using serially collected longitudinal data. RAIRI demonstrated accurate calibration and high prognostic accuracy, superior to conventional models. In RCT cohort, RAIRI identified approximately 70% of low-risk patients who did not benefit from AC, whereas the high-risks experienced substantial benefits from AC. Therefore, RAIRI could provide real-time updated quantitative survival estimates for individuals and facilitate personalized AC selection.

Currently, there is little evidence supporting the use of early endpoints to assess primary treatment outcomes in nasopharyngeal carcinoma (NPC). We aim to explore the relationship between 24-month progression-free survival (PFS24) and subsequent overall survival (sOS) as well as loss of lifetime (LoL) in NPC patients. sOS is defined as survival from the 24-month point or progression within 24 months leading to mortality. LoL represents the reduction in life expectancy due to NPC, compared to the general population matched by age, sex, and calendar year. The standardized mortality ratio (SMR) is defined as the ratio of observed mortality to expected mortality. The study included 6315 patients from nonendemic and endemic regions of China. Among them, 5301 patients (83.9%) achieved PFS24, with a 5-year sOS of 90.2% and an SMR of 1.0. Over a 10-year period following treatment, the mean LoL was only 0.01 months/year. For most subgroups, patients achieving PFS24 exhibited comparable sOS and LoL with the general population. However, patients failing to achieve PFS24 showed significantly worse outcomes, with 5-year sOS of 21.9%, SMR of 23.7, and LoL of 6.48 months/year. These notable outcome disparities highlight the importance of PFS24 in NPC risk stratification, patient monitoring, and study design.

BACKGROUND:Regional failure (RF) in oral cavity squamous cell carcinoma (OCSCC) is associated with poor outcomes, yet its detailed pattern and its relationship with corresponding neck management strategies remain inadequately defined. This study aims to provide insights for optimizing neck management in OCSCC patients through a comprehensive analysis of RF patterns. METHODS:A retrospective review was conducted on patients with OCSCC who underwent radical surgery with or without postoperative radiotherapy (PORT) between 2015 and 2018. Detailed mapping of the initial metastasis and RF patterns was performed and correlated with the corresponding neck management approaches. RESULTS:A total of 147 patients and 294 necks were included in the analysis. RF was identified as the predominant pattern of failure (5-year rate: 19.8%), with pN+ being the most notable risk factor for regional failure-free survival (RFFS). Compared to the Surgery group, the Surgery+PORT group demonstrated a significantly lower RF rate beyond the dissected region (6.5% vs. 20.0%, p = 0.03) and a numerically lower RF rate beyond the upper neck (5.2% vs. 12.9%, p = 0.10). In dissected necks, RF at level IV accounted for 47.3% of all RF occurrences. The "dissected and irradiated" necks exhibited a lower RF rate than the "dissected-alone" necks (8.7% vs. 13.4%), particularly at level IV (2.2% vs. 8.5%) and Vb (1.1% vs. 3.7%). When compared to the "untreated" necks, the "irradiated-alone" necks showed reduced RF at almost all levels. CONCLUSIONS:The significant rate of RF in the lower neck warrants particular attention in OCSCC management. Prophylactic irradiation to the lower neck may play a critical role in enhancing regional control and improving patient outcomes.

Euclidean and vertical distances in per-LN level and per-patient level for all distribution patterns of metastatic LNs.

Neuroendocrine neoplasm is a rare cancer of head and neck. This study aimed to evaluate clinical features, treatment outcomes, and prognostic factors of neuroendocrine neoplasm of head and neck treated at a single institution. Between Nov 2000 and Nov 2021, ninety-three patients diagnosed with neuroendocrine neoplasms of head and neck treated at our institution were reviewed retrospectively. The initial treatments included chemotherapy (induction, adjuvant, or concurrent) combined with radiotherapy in 40 patients (C + RT group), surgery followed by post-operative RT in 34 (S + RT group), and surgery plus salvage therapy in 19 patients (S + Sa group). The median follow-up time was 64.5 months. 5-year overall survival rate (OS), progression-free survival rate (PFS), loco-regional relapse-free survival free rate (LRRFS) and distant metastasis-free survival rate (DMFS) were 64.5

Dynamic therapy response is strongly associated with cancer outcomes. This study aimed to evaluate the significance of longitudinal Epstein-Barr virus (EBV) DNA and radiological tumor regression in risk stratification and response-adaptive treatment in locally-advanced nasopharyngeal carcinoma (LA-NPC). In total, 1312 patients from two centers were assigned to the training and validation cohorts. Based on the multipoint examination of EBV-DNA and tumor response, four post-induction chemotherapy, four mid-radiotherapy, and four post-radiotherapy subgroups were established. Then seven phenotypes were further generated according to different permutations and combinations. These phenotypes were subsequently congregated into four response clusters, which reflect distinct biological treatment responses. The four response clusters correlated with an evident 5-year progression-free survival in both the training and external validation cohorts (5-year: training cohort 91.1 %, 82.8 %, 30.6 %, and 10.0 %; external validation 94.4 %, 55.6 %, 40.0 %, and 12.7 %) had superior prognostic performance compared to TNM staging and nomogram model (concordance index: training cohort-0.825 vs. 0.603 vs. 0.756 and external validation-0.834 vs. 0.606 vs. 0.789). Importantly, the response clusters exhibited an excellent capability in selecting candidates who can benefit from adjuvant chemotherapy. In conclusion, risk stratification based on the dynamic assessment of both radiological and biological responses can significantly enhance prognostic insights and shed light on individualized treatment modifications in LANPCs.

Diagram of the study patients identification.

The impact of T stage on nodal drainage distance.

The impact of Epstein-Barr virus (EBV) DNA copies on nodal drainage distance.

The number and percentage of caudally located LNs included in each maximum diameter (MD) range.

AbstractPurpose: To determine the potential nodal drainage distances of nasopharyngeal carcinoma (NPC) by investigating spatial distribution of metastatic lymph nodes (LN). Experimental Design: Patients with NPC harboring at least two ipsilateral metastatic LNs were enrolled. LN spreading distances were analyzed in nonrestricted direction, cranial-to-caudal direction, and between the two most caudal LNs. Euclidean distance (ED) and vertical distance (VD) between any two LNs were computed. The nearest-neighbor ED and VD covering 95% of LNs or patients (p95-ED and p95-VD) were considered drainage distances, and were further validated by independent internal and external cohorts with recurrent LNs. Results: In all, 5,836 metastatic LNs in 948 patients were contoured. Corresponding to the three scenarios, per-LN level, the p95-EDs were 2.83, 3.28, and 3.55 cm, and p95-VDs were 2.17, 2.32, and 2.63 cm, respectively. Per-patient level, the p95-EDs were 3.25, 3.95, and 3.81 cm, and p95-VDs were 2.67, 2.81, and 2.73 cm, respectively. In internal validation, over 95% of recurred LNs occurred within ED of 2.91 cm and VD of 0.82 cm to the neighbor LN, and the corresponding distances in external validation were 2.77 and 0.67 cm, respectively. Conclusions: In NPC, the maximum LN drainage distance was 3.95 cm without considering the direction. Specifically, in cranial-to-caudal direction, the sufficient vertical drainage distance was 2.81 cm, indicating that a 3-cm extension from the most inferior node may be rational as caudal border of the prophylactic clinical target volume (CTV). These findings promote in-depth understanding of nodal spreading patterns, uncovering paramount evidence for individualized CTV.

Background:The survival rates of patients with nasopharyngeal carcinoma (NPC) have improved significantly, but there is no consensus on whether they can be considered cured. We aimed to determine whether a statistical cure could be achieved for patients with NPC in the contemporary therapeutic landscape. Methods:This retrospective multicenter study enrolled 6315 patients with nonmetastatic NPC from nonendemic and endemic regions of China from 2007 to 2020. We applied mixture and nonmixture cure models to estimate the cure probabilities and cure times by incorporating background mortality for the general population, matching by gender, age, and diagnosed year. Findings:With death as the uncured event, the probability of patients with NPC achieving a life expectancy at par with the general population was 78.1%. Considering progression as the uncured event, the likelihood of patients attaining a life expectancy without progression equivalent to that of the general population was 72.4%. For individuals, the probabilities of achieving cure were conditional and time-dependent, requiring approximately 7.1 and 4.7 years with 95% certainty, respectively. The corresponding cure times for uncured patients were 8.9 and 6.8 years, respectively. The cure probability was correlated with age, Eastern Cooperative Oncology Group score, TNM staging, Epstein-Barr virus DNA copies, and lactate dehydrogenase. The correlation was excellent between 5-year overall survival/progression-free survival and cure fractions. Interpretation:Statistical cure is potentially achievable among patients with NPC undergoing contemporary treatment modalities. The results hold significant potential implications for both clinical practice and patient perspectives. Funding:National High Level Hospital Clinical Research Funding; Beijing Xisike Clinical Oncology Research Foundation; Beijing hope run fund.