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.

BACKGROUND AND PURPOSE:Magnetic resonance-guided adaptive radiotherapy (MRgART) may improve the efficacy of large brain metastases (BMs)(≥2 cm), whereas the workflow requires optimized. This study develops a two-stage, personalized deep learning auto-segmentation (DLAS) model to assist online delineation of large BMs. MATERIALS AND METHODS:Multi-sequences images from 177 BMs were trained to develop the basic DLAS model. Then, 741 daily online MR images of 20 large BMs from a prospective trial were collected for developing a personalized model. The dice similarity coefficient (DSC) was evaluated across three methods: basic model, rigid registration and personalized model, at intervals of every five fractions. The accuracy and efficiency were compared between manual delineation (MD) and DLAS assistant delineation (DLAS-AD) in 8 patients who underwent contrast T1 re-scan during MRgART. RESULTS:The personalized DLAS model demonstrated significantly better performance compared to the basic model and rigid registration during the last fraction of MRgART (when the tumor volume achieved a significant reduction). The mean DSC for basic model vs. rigid registration vs. personalized model were 0.86 (p = 0.01) vs. 0.88 (p = 0.05) vs. 0.90, respectively. The DLAS-AD significantly improved contouring accuracy compared to MD, with a mean DSC of 0.89 vs. 0.85 (p = 0.001), and reduced contouring time by an average of 53.5 % (193 s vs. 424 s, p < 0.001). CONCLUSION:Personalized DLAS model may increase the accuracy and efficiency of MD to optimize the workflow of MRgART for large BMs.

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.

GTV contouring variability was seen between T1c, T2f and T2 sequences. The coincidence of T1+c and T2f was better than T1+c and T2 in BMs. Since reductions in volume and changes of lesion center was observed during HFRT, the use of MR-guided radiation therapy (RT) and treatment adaptation is needed. The optimal timing for treatment plan modification might be when the course of treatment reaches 2/3 for most large BMs. Further research to find out patients who may benefit form MR-guided adaptive RT is ongoing.

PURPOSETo develop and validate a nomogram integrating lymph node ratio (LNR) to predict cancer-specific survival (CSS) and assist decision making for postoperative management in nonmetastatic oral cavity squamous cell carcinoma (OCSCC).MATERIALS AND METHODSWe retrospectively retrieved 6,760 patients with OCSCC primarily treated with surgery from surveillance, epidemiology, and end results database between 2010 and 2015. They were randomly divided into training and validation cohorts. Performance of the nomogram was evaluated by calibration curve, consistency index, area under the curve, and decision curve analysis and was compared with that of the LNR, positive lymph nodes (PLN) and tumor node metastasis (TNM) staging. According to the individualized nomogram score, patients were classified into three risk cohorts. The therapeutic efficacy of postoperative radiotherapy and chemotherapy was evaluated in each cohort.RESULTSThe nomogram incorporated six independent variables, including race, tumor site, grade, T stage, PLN, and LNR. Calibration plots demonstrated a good match between the predicted and observed CSS. C-indices for training and validation cohorts were 0.746 (95% CI, 0.740 to 0.752) and 0.726 (95% CI, 0.713 to 0.739), compared with 0.687, 0.695, and 0.669 for LNR, PLN, and TNM staging, respectively ( P < .001). Decision curve analyses confirmed that nomogram showed the best performance in clinical utility. Postoperative radiotherapy presented survival benefit in medium-and high-risk groups but showed a negative effect in the low-risk group. Chemotherapy was only beneficial in the high-risk group.CONCLUSIONThe LN status-incorporated nomogram demonstrated good discrimination and predictive accuracy of CSS for patients with OCSCC and could identify those most likely to benefit from adjuvant therapy.

Abstract Background The main challenge in follow-up duration of patients with brain metastases after stereotactic radiotherapy is to distinguish between pseudo-progression and tumor recurrence. The objective of this study is to retrospectively analyze the predictive factors. Methods The study included 123 patients with enlarged brain metastases after hypo-fractionated radiotherapy in our center from March 2009 to October 2019, and the baseline clinical features, radiotherapy planning parameters, and enhanced magnetic resonance imaging before and after radiation therapy were analyzed. Logistic regression was performed to compare the differences between groups. Independent risk factors with P < 0.05 and associated with recurrence were used to establish a nomogram prediction model and validated by Bootstrap repeated sampling, which was validated in an internal cohort (n = 23) from October 2019 to December 2021. Results The median follow-up time was 68.4 months (range, 8.9–146.2 months). A total of 76 (61.8%) patients were evaluated as pseudo-progression, 47 patients (38.2%) were evaluated as tumor recurrence. The median time to pseudo-progression and tumor recurrence were 18.3 months (quartile range, 9.4–27.8 months) and 12.9 months (quartile range, 8.7–19.6 months) respectively. Variables associated with tumor recurrence included: gross tumor volume ≥ 6 cc, biological effective dose < 60 Gy, target coverage < 96% and no targeted therapy. The area under curve values were 0.730 and 0.967 in the training and validation cohorts, respectively. Thirty-one patients received salvage therapy in the tumor recurrence group. The survival time in pseudo-progression and tumor recurrence groups were 66.3 months (95% CI 56.8–75.9 months) and 39.6 months (95% CI 29.2–50.0 months, respectively; P = 0.001). Conclusions Clinical and dosimetry features of hypo-fractionated radiation therapy based on enhanced brain magnetic resonance can help distinguish pseudo-progression from tumor recurrence after hypo-fractionated radiotherapy for brain metastases. Gross tumor volume, biological effective dose, target coverage, and having received targeted therapy or not were factors associated with the occurrence of tumor recurrence, and the individual risk could be estimated by the nomogram effectively.

Abstract Purpose: Multiple brain metastases (BMs) remain a therapeutic challenge. Helical tomotherapy (HT) is a novel equipment which has shown favorable dosimetric properties in previous studies. The aim of this single institutional phase II trial was to investigate the feasibility and toxicity of hypofractionated radiotherapy (HFRT) with or without simultaneous whole brain radiotherapy (WBRT) by HT in treating patients with multiple BMs. Methods:Patients with at least 3 BMs were enrolled. All the patients were treated with HT. The prescribed dose was 40 Gy in 20 fractions for WBRT and 60 Gy in 20 fractions for BMs simultaneously. For patients who had prior WBRT or refusing WBRT, focal HFRT for the lesions with optimized doses based on tumor volumes and locations were given. The primary endpoint was 1y-intracranial progression free survival (IPFS). Results: Between September 2014 and June 2017, 69 patients were enrolled and finally been analyzed. The median follow-up time was 40.1 months. The 1-year IPFS rate was 80.5%. The median survival time was 18.1 months (95% CI, 15.5- 20.7). The 1-year local control, overall survival and brain metastasis-specific survival rates were 96.4%, 71.0% and 94.6%, respectively. The 2-year rates were 87.6%, 51.1% and 39.1%, respectively. Only 1 patient (1.4%) had Grade 3 hematological toxicity and the radiation necrosis rate was 2.9%. Conclusion: Helical tomotherapy was well tolerated and could significantly extend IPFS compared with historical controls in multiple BMs.

ObjectiveTo analyze the failure patterns in patients with different histological subtypes of sinonasal malignancies (SNMs).Study DesignRetrospectively gathered data.SettingAcademic university hospital.MethodsPatients with SNMs treated at a tertiary referral center between January 1999 and January 2019 were included. We assessed the failure patterns within different histological subtypes.ResultsThe study included 897 patients. The median follow-up time was 100 months. Adenoid cystic carcinoma (ACC) had a moderate risk of developing local recurrence (LR) and distant metastasis (DM). Compared with ACC, squamous cell carcinoma (SCC), adenocarcinoma (AC), soft tissue sarcoma (STS), and mucosal melanoma (MM) were classified as a high LR risk group. For DM, neuroendocrine carcinoma (NEC), STS, and MM were in the high-risk group.ConclusionsACC had intermediate local and distant failure risks, while SCC, AC, STS, and MM were at high LR risks. NEC, STS, and MM were at high DM risk.

Purpose To provide a direct evidence for the current practice of prescribing antiemetic with aprepitant, dexamethasone and ondansetron in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) receiving concurrent chemoradiotherapy (CCRT). Methods Treatment-naïve LA-HNSCC patients received intensity-modulated radiotherapy with concomitant cisplatin 100 mg/m² every 3 weeks for two cycles. All patients were given orally aprepitant 125 mg once on d1, then 80mg once on d2-5; ondansetron 8 mg once on d1; and dexamethasone 12 mg once on d1, then 8mg on d2-5. The primary endpoint was complete response (CR). Pursuant to δ=0.2 and α=0.05, the expected CR rate was 80%. Results A total of 43 patients with LA-HNSCC were enrolled. The median age was 53 years old, and 86.0% were male. All patients received radiotherapy and 86.0% of patients completed both cycles as planned. The overall CR rate was 86.0% (95% CI: 72.1-94.7). The CR rates for cycles 1 and 2 were 88.4% (95% CI: 74.9-96.1) and 89.2% (95% CI: 74.6-97.0). The complete protection rate in the overall phase was 72.1% (95% CI: 56.3-84.7). The emesis-free response and nausea-free response in overall phase were 88.4% (95% CI: 74.9-96.1) and 60.5% (95% CI: 44.4-75.0), respectively. The adverse events related to antiemetics were constipation (65.1%) and hiccups (16.3%), but both were grade 1-2. There was no grade 4 or 5 treatment-related adverse event with antiemetic usage. Conclusion The addition of aprepitant into ondansetron and dexamethasone provided effective protection from nausea and emesis in patients with LA-HNSCC receiving CCRT. Trial registration ID: NCT03572829.

The necessity of level III irradiation in patients with node‐negative advanced sinonasal squamous cell carcinoma (SNSCC) is unclear.

Abstract Background To investigate the clinical characteristics of metachronous second primary malignancies (Met‐SPMs) and its impact on prognosis in hypopharyngeal carcinoma (HPC). Methods We reviewed 593 newly diagnosed HPC patients without invasive synchronous SPMs (Syn‐SPMs) who were treated in our cancer center between 2009 and 2019. According to the status during follow‐up, patients were classified into three groups: (a) without SPMs (No‐SPMs, n = 440), (b) with tumors in situ in the esophagus or stomach (Tis, n = 80), or (c) with Met‐SPMs (n = 73). Results The median follow‐up time for entire cohort (n = 593) was 66.7 months. Met‐SPMs were present in 12.3% of the cohort (73/593). The predominant site of SPMs was esophagus, followed by lung, oral cavity, thyroid, stomach, and oropharynx. In Met‐SPMs group, both index tumor and SPMs were the main causes of death. Tis group exhibited comparable 5‐year overall survival (OS) and disease‐specific survival (DSS) with that of No‐SPMs group. The Met‐SPMs group had similar 5‐year OS rate and better 5‐year DSS rate of 47.3% versus 43.6% (odds ratio [OR], 0.931; 95% confidence interval [CI], 0.681–1.274, p = 0.657) and 66.3% vs. 46.2% (OR, 0.600; 95% CI, 0.402–0.896, p = 0.012), respectively, compared with the No‐SPMs group. Conclusion The overall incidence of Met‐SPMs in HPC was 12.3%. The occurrence of Met‐SPMs does not jeopardize the survival outcome of HPC. Routine surveillance of Met‐SPMs was requisite for patients with HPC.

Abstract Purpose This study implemented a piecewise volumetric modulated arc therapy (P-VMAT) for realizing whole-brain radiation therapy (WBRT) with simultaneous integrated boost (SIB) for multiple brain metastases (> 40 metastases) with a conventional C-arm linear accelerator. Materials and methods This study retrospectively analyzed 10 patients with multiple brain metastases (40–120 metastases, median 76), who underwent WBRT and SIB using helical tomotherapy (HT). The prescribed doses were 40 Gy/20 f and 60 Gy/20 f for WBRT and SIB, respectively. Corresponding new HT plans were designed with P-VMAT using 7 arcs. For each arc, the collimator was rotated to 45°, and the field width was limited to 2.5 cm with 0.5 cm overlap with adjacent arcs. Thus, each arc covered only one section of the brain target volume. A conventional dual arc VMAT (DA-VMAT) plan was also designed. HT, P-VMAT, and DA-VMAT plans were compared using dose distribution reviews and dosimetric parameters. ArcCHECK phantom measurements were performed for verification of P-VMAT plans. Results No significant differences in the mean coverage of the whole-brain target and metastases were observed between HT and P-VMAT (p > 0.05). The conformity index for the whole-brain target improved with P-VMAT compared with HT (p < 0.05). Furthermore, the volume of 44 Gy V44 (110% of prescribed dose for WBRT) received for whole-brain significantly reduced with P-VMAT from 38.2 ± 12.9% to 23.3 ± 9.4% (p < 0.05), and the maximum dose for organs at risks such as the hippocampus, optical nerve, optical chiasm, and spinal cord declined with P-VMAT (p < 0.05). Unlike HT and P-VMAT, DA-VMAT was clinically unacceptable because V44 in the whole-brain was too high (54.7 ± 8.2%). The mean absolute dose gamma passing rate for P-VMAT plans was 97.6 ± 1.1% (3%/3 mm criterion, 10%). Conclusions P-VMAT is favorable for WBRT and SIB for multiple brain metastases. It provides comparable coverage of whole-brain target and SIB, with better conformity, lower V44, and better dose sparing of organs at risk compared with HT. Furthermore, results show that DA-VMAT fails clinical practice even for a relatively large number of brain metastases with a high degree of plan complexity. The patient specific verification demonstrates the feasibility of P-VMAT for clinical application.

Objective:To evaluate the prognostic value of pretreatment systemic immune-inflammation index (SII) and lactate dehydrogenase (LDH) in non-metastatic nasopharyngeal carcinoma (NPC).Methods:We retrospectively collected the data of 839 patients with non-metastatic NPC from National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Sun Yat-sen University Cancer Center between January 2007 and October 2015. All patients received intensity modulated radiation based treatment. Optimal cutoff value of SII and LDH were determined by X-title software. The association between SII, LDH and clinical prognosis of non-metastatic NPC patients were analyzed. Kaplan-Meier method was used for survival analysis, and Log rank test was used for comparison of survival rates between groups. Propensity score matching (PSM) analysis was carried out to minimize the effects of confounding factors. The risk stratification model of prognosis by combining N stage, SII and LDH was constructed to compare the prognosis of patients in high risk group, middle risk group and low risk group, and the receiver operating characteristic (ROC) curve analysis was used to evaluate its prognostic value.Results:The optimal cutoff value of SII is 447.2×10 9/L for predicting the 5-year overall survival (OS) of NPC patients, and the best cutoff value of LDH is 198.9 U/L. The proportion of patients with stage T3-4 and stage III-IVB in high SII group was higher than that in low SII group ( P<0.001). Multivariate Cox regression analysis showed that N stage, SII and LDH were independent factors of OS, progression-free survival (PFS) and distant metastasis-free survival (DMFS) of NPC patients (N stage, HR=1.705, 95% CI: 1.247-2.332; HR=1.755, 95% CI: 1.342-2.295; HR=2.161, 95% CI: 1.515-3.082. SII, HR=1.525, 95% CI: 1.097-2.119; HR=1.518, 95% CI: 1.150-2.004; HR=1.837, 95% CI: 1.272-2.653. LDH, HR=2.041, 95% CI: 1.403-2.968; HR=1.725, 95% CI: 1.233-2.414; HR=2.492, 95% CI: 1.690-3.672, respectively). After PSM, SII was still an independent prognostic factor of OS, PFS and DMFS in NPC patients ( HR=1.52, 95% CI: 1.09-2.12; HR=1.52, 95% CI: 1.15-2.00; HR=1.82, 95% CI: 1.26-2.63, respectively). Combined with N 2-3 stage, SII (>447.2×10 9/L), and LDH (>198.9 U/L), patients were divided into high-(3 risk factors), intermediate- (2 risk factors) and low-risk (0-1 risk factors) groups. The 5-year OS rates of patients in low-, intermediate- and high-risk groups were 86.1%, 79.8% and 41.2% respectively, the 5-year PFS rates were 80.7%, 70.2% and 33.9% respectively, and the 5-year DMFS rates were 88.9%, 79.2% and 47.5% respectively. There were significant differences in OS, PFS and DMFS among these three groups ( P<0.001). Distant metastasis was the main failure pattern in low-, intermediate- and high-risk groups, and the highest rate of distant metastasis was 83.3% (15/31) in high-risk group. ROC curve of the risk stratification model for predicting 5-year OS of NPC patients is 0.610, which is higher than TNM stage (0.609), SII (0.574) and LDH (0.558). Conclusions:Pretreatment SII and LDH are significantly correlated with the prognosis of patients with non-metastatic NPC. The combination of SII, LDH and N stage can stratify the prognostic risk of NPC patients. The risk stratification model can enhance the accuracy of prognosis.

Purpose Concurrent chemoradiotherapy (CCRT) is a standard treatment choice for locally advanced hypopharyngeal carcinoma. The aim of this study was to investigate whether induction chemotherapy (IC) followed by CCRT is superior to CCRT alone to treat locally advanced hypopharyngeal carcinoma. Methods and materials Patients ( n = 142) were randomized to receive two cycles of paclitaxel/cisplatin/5-fluorouracil (TPF) IC followed by CCRT or CCRT alone. The primary end point was overall survival (OS). The secondary end points included the larynx-preservation rate, progression-free survival (PFS), distant metastasis-free survival (DMFS), and toxicities. Results Ultimately, 113 of the 142 patients were analyzed. With a median follow-up of 45.6 months (interquartile range 26.8–57.8 months), the 3-year OS was 53.1% in the IC + CCRT group compared with 54.8% in the CCRT group (hazard ratio, 1.004; 95% confidence interval, 0.573–1.761; P = 0.988). There were no statistically significant differences in PFS, DMFS, and the larynx-preservation rate between the two groups. The incidence of grade 3–4 hematological toxicity was much higher in the IC+ CCRT group than in the CCRT group (54.7% vs. 10%, P < 0.001). Conclusions Adding induction TPF to CCRT did not improve survival and the larynx-preservation rate in locally advanced hypopharyngeal cancer, but caused a higher incidence of acute hematological toxicities. Trial registration ClinicalTrials.gov , number NCT03558035. Date of first registration, 15/06/2018.

OBJECTIVES:To explore the prevalence of hypopharyngeal carcinoma (HPC) with synchronous second primary malignancies (Syn-SPMs), their impact on clinical outcomes, and associated risk factors in the image-enhanced endoscopy era.MATERIALS AND METHODS:We retrospectively analyzed 673 patients newly diagnosed with HPC at our cancer center between 2009 and 2019. The patients were divided into three groups: (a) no second primary malignancies (N-SPMs, n = 533); (b) synchronous carcinoma in situ (Syn-Tis, n = 60); (c) synchronous invasive tumors (Syn-invasive, n = 80). Propensity score matching was conducted to balance the N-SPMs and Syn-invasive groups at a 3:1 ratio.RESULTS:Most (96.1%) underwent pretreatment esophagogastroduodenoscopy evaluation with image-enhanced endoscopy. The incidence rates were: Syn-SPMs, 20.8%; Syn-Tis, 8.9%; Syn-invasive, 11.9%. At a median follow-up of 66.7 months, the Syn-Tis and N-SPMs groups had a similar 5-year overall survival (OS; 45.6% vs. 44.5%; hazard ratio [HR], 0.956; 95% confidence interval [CI], 0.660-1.385; p = 0.806). Compared to the N-SPMs group, the Syn-invasive group had poorer 5-year OS (27.0% vs. 52.9%; HR, 2.059; 95% CI, 1.494-2.839; p < 0.001). Alcohol consumption was significantly associated with Syn-SPMs occurrence (odds ratio, 2.055, 2.414, and 3.807 for light, intermediate, and heavy drinkers, respectively).CONCLUSION:The prevalence of Syn-SPMs among patients with HPC was high. Syn-invasive SPMs decreased the survival of patients with HPC. Routine screening with image-enhanced endoscopy should be recommended to detect early-stage SPMs, especially for heavy alcohol drinkers.LEVEL OF EVIDENCE:3 Laryngoscope, 133:1906-1913, 2023.

Objective: To explore the effects of elective neck irradiation (ENI) in clinically node-negative (cN0) sinonasal adenoid cystic carcinoma (SNACC). Materials and methods: Between January 2000 and December 2016, 60 patients with cN0 sinonasal adenoid cystic carcinoma receiving surgery combined with radiotherapy were analyzed retrospectively, there were 39 received ENI (ENI group) and 21 with no ENI (non-ENI group). Propensity score matching (PSM) was performed to balance clinical factors and match patients. Kaplan-Meier method and Cox proportional hazard model were used to evaluate the impact of ENI on regional relapse risk and survival outcomes. Results: The median follow-up time for our cohort was 82.0 months (12.4-190.7 months). Four patients (6.7%) developed neck nodal relapses, with a median time to progression of 38.8 months. Among them, two patients in ENI group but failed out-field. After PSM, 21 patients were matched in each group. The 7-year regional relapsefree survival (RRFS), distant metastasis free survival (DMFS), progression-free survival (PFS), and overall survival (OS) between ENI group and non-ENI group were 85.4% vs 73.3% (p = 0.845), 65.2% vs 65.6% (p = 0.548), 68.3% vs 66.2% (p = 0.425), and 87.3% vs 84.0% (p = 0.953). Multivariate Cox analysis showed ENI was not an independent prognostic factor associated with RRFS, DMFS, PFS and OS. Conclusion: Our findings firstly demonstrated the omission of elective neck irradiation in the management of cN0 sinonasal adenoid cystic carcinoma might be safe without compromising disease control and should be further investigated.

IMPORTANCE Laryngeal preservation strategies for resectable locally advanced hypopharyngeal carcinoma (LAHPC) have been explored. However, the optimal strategy remains unclear. OBJECTIVE To evaluate a response-adapted strategy based on an early response to radiotherapy (RT) in patients with resectable LAHPC. DESIGN, SETTING, AND PARTICIPANTS This cohort study was conducted from May 2009 to October 2019 with a median (IQR) follow-up period of 66.5 (44.7-97.0) months. The study was conducted at a tertiary academic medical center and included 423 patients pathologically confirmed stage III and IVB LAHPC. A total of 250 patients with previous cancer history, synchronous primary cancer, stage I or II, or with unresectable hypopharyngeal carcinoma were excluded. EXPOSURES Patients who reached 80% or greater tumor regression when evaluated endoscopically and by imagingmethods at 50 Gy received definitive RT or concurrent chemoradiotherapy, and those with less than 80% regression underwent surgery 4 to 6 weeks after RT. MAIN OUTCOMES AND MEASURES Five-year overall survival and survival with a functional larynx. RESULTS Overall, 423 patients were included in the study (median [IQR] age, 55 [50-63] years; 408 [96.5%] men and 15 [3.5%] women). The response-adapted and primary surgery groups had significantly better survival than the primary RT group (52.7% and 54.4% vs 27.7%, respectively; P <.001). The response-adapted and primary surgery groups had similar 5-year overall survival of 52.7% vs 54.4%, respectively (hazard ratio [HR], 1.02; 95% CI, 0.75 to 1.39; P =.89). The responseadapted group had better 5-year survival with functional larynx than the primary surgery group (40.6% vs 33.9%; HR, 0.64; 95% CI, 0.49 to 0.84, P =.001). Surgery complications did not significantly differ between the 2 groups. Among patients in the response-adapted group who required total laryngectomy (n = 186) as indicated by pretreatment evaluation, the 5-year cumulative Kaplan-Meier survival with functional larynx was 39.8%. CONCLUSIONS AND RELEVANCE In this cohort study, the response-adapted strategy based on an early RT response facilitated better treatment tailoring, maximum tumor control, and higher laryngeal preservation compared with primary surgery and primary RT strategies. This approach could provide a feasible laryngeal preservation strategy in patients with LAHPC.

IntroductionLeptomeningeal metastasis (LM) commonly occurs in non-small cell lung cancer (NSCLC) patients and has a poor prognosis. Due to limited access to leptomeningeal lesions, the genetic characteristics of LM have not been explored to date. Cerebrospinal fluid (CSF) may be the most representative liquid biopsy medium to obtain genomic information from LM in NSCLC.MethodsCSF biopsies and matched peripheral blood biopsies were collected from 33 NSCLC patients with LM. We profiled genetic alterations from LM by comparing CSF cell-free DNA (cfDNA) with plasma cfDNA. Somatic mutations were examined using targeted sequencing. Genomic instability was analyzed by low-coverage whole-genome sequencing (WGS).ResultsDriver mutations were detected in 100% of CSF cfDNA with much higher variant allele frequency than that in matched plasma cfDNA (57.5%). Furthermore, we found that the proportions of CSF cfDNA fragments below 150 bp were significantly higher than those in plasma cfDNA. These findings indicate enrichment of circulating tumor DNA (ctDNA) in CSF and explain the high sensitivity of mutation detection in the CSF. The absence of some mutations in CSF cfDNA—especially the first-/second-generation mutation T790M, which confers resistance to epidermal growth factor receptor (EGFR)-Tyrosine kinase inhibitors (TKIs)—that were present in plasma cfDNA samples indicates different mechanisms of cancer evolution between LM and extracranial lesions. In addition, 86.6% of CSF ctDNA samples revealed high levels of genomic instability compared with 2.5% in plasma cfDNA samples. A higher number of large-scale state transitions (LSTs) in CSF cfDNA were associated with a shorter overall survival (OS).ConclusionOur results suggest that LM and extracranial lesions develop independently. Both CSF cfDNA genetic profiling and plasma cfDNA genetic profiling are necessary for clinical decision-making for NSCLC patients with LM. Through CSF-based low-coverage WGS, a high level of LSTs was identified as a potential biomarker of poor prognosis.

Abstract PURPOSE The main challenge in follow-up duration of patients with brain metastases after stereotactic radiotherapy is to distinguish between pseudo-progression and tumor recurrence. The objective of this study is to retrospectively analyze the predictive factors. METHODS The study included 123 patients with enlarged brain metastases after hyper-fractionated radiotherapy in our center from 2009 to 2019, and the baseline clinical features, radiotherapy planning parameters, and enhanced magnetic resonance imaging before and after radiation therapy were analyzed. Logistic regression was performed to compare the differences between groups. independent risk factors with P < 0.05 and associated with recurrence was used to establish a predicting nomogram and validated by Bootstrap in internal cohort. RESULTS The median volume of lesions was 8.4 cc. The median follow-up time was 68.4 months (interquartile range [IQR], 30.4 – 63.2 months). A total of 76 (61.8%) patients were evaluated as pseudo-progression, 47 patients (38.2%) were evaluated as tumor recurrence. The median time to tumor recurrence and pseudo-progression were 12.9 months (IQR, 8.7 – 19.6 months) and 18.3 months (IQR, 9.4 – 27.8 months) respectively. Variables associated with tumor recurrence included: gross tumor volume ≥ 6 cc, biological effective dose < 60 Gy, target coverage < 96% and no targeted therapy. The area under curve value was 0.730 and mean absolute error in calibration curve was 0.041. Sixty-one patients received salvage therapy, including re-irradiation (n = 32, 26.0%), surgical resection (n = 22, 17.9%) or systemic therapy (n = 22, 17.9%). The survival time in pseudo-progression and tumor recurrence groups were 66.3 months (95% CI, 56.8 – 75.9 months) and 39.6 months (95% CI, 29.2 – 50.0 months, respectively; P = 0.001). CONCLUSIONS Clinical and dosimetry features of hyper-fractionated radiation therapy based on enhanced brain magnetic resonance can help distinguish pseudo-progression from tumor recurrence after hyper-fractionated radiotherapy for brain metastases. And the individual risk could be estimated by the nomogram effectively.