Regional Failure-free Survival Research Articles

The Role of Elective Nodal Irradiation in Treating Clinically Node-Negative Sinonasal Squamous Cell Carcinoma

PurposeThis study aims to examine the role of elective nodal irradiation (ENI) in clinically node-negative (cN0) sinonasal squamous cell carcinoma (SNSCC) and to define the optimal radiation fields for ENI. Methods and MaterialsWe retrospectively reviewed 368 cN0 SNSCC patients treated between 2009 and 2021. The study evaluated the impact of ENI on overall survival (OS), progression-free survival (PFS), regional-failure-free survival (RFS), and distant metastasis-free survival (DMFS), along with the coverage areas of ENI. ResultsThe majority of patients underwent surgery (n=316, 85.9%), with 75% (n=276) having tumors in the maxillary sinus or nasal cavity and 67.7% (n=249) presenting with T4 disease. Additionally, 32.3% (n=119) of the tumors were poorly differentiated. The 5-year OS, PFS, RFS, and DMFS rates were 59.3%, 54.0%, 57.6%, and 58.8%, respectively. ENI was performed in 217 patients (59%), with sixteen experiencing neck relapse during follow-up. While ENI did not enhance survival rates, it significantly reduced the overall regional-failure rate (7.9% vs. 1.8%, χ2 =7.98, p<0.01) and the cumulative incidence of regional failure (p=0.045). Additionally, the subgroups with maxillary sinus origin (2.33% vs. 13.51%, p=0.025), T4 stage (1.80% vs. 8.54%, p=0.028), and poor differentiation (2.44% vs. 13.51%, p=0.029) had higher cumulative incidences of regional failure in patients without ENI. No significant difference was observed in survival and regional failure rates between patients treated with ENI to levels Ib and II with or without level III, as well as between cN0 patients with non-midline crossing lesions receiving unilateral or bilateral ENI. ConclusionsDespite no survival benefit, ENI significantly decreases the regional failure rate in cN0 SNSCC patients. For primary lesions not crossing the midline, ipsilateral ENI targeting levels Ib and II proves to be an effective strategy.

Omission of radiotherapy to lymph node level III in patients with cN0 adenoid cystic carcinoma of the major salivary gland: a single center experience.

Due to the rarity of adenoid cystic carcinoma (ACC) of the major salivary gland, there is no consensus on the extent of prophylactic neck irradiation (PNI) for patients with clinically negative lymph nodes (cN0) disease. We conducted a retrospective analysis of all patients with ACC of the major salivary gland who received treatment at our center between January 2010 and April 2020. The primary endpoint was regional failure-free survival(RRFS). Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), local recurrence-free survival (LRFS), and acute toxicity. A total of 139 patients were included in the analysis. For cN0 patients, the 5-year RRFS, OS, DMFS, and LRFS were 93.2%, 90.2%, 75.7%, and 91.4%, respectively. Multivariate analysis revealed that PORT was an independent prognostic factor for RRFS and LRFS. No statistically significant differences were observed between the Level III sparing PNI group and the Standard PNI group in terms of RRFS, OS, DMFS, and LRFS. The doses delivered to the larynx and thyroid in the Level III sparing PNI group were significantly lower than those in the Standard PNI group. In patients with cN0 ACC of the major salivary gland, PNI improves regional control, and the level III nodal region sparing radiotherapy does not increase the risk of level III recurrence, while potentially reducing toxicity.

Patterns of lymph node metastasis in 441 patients with sinonasal squamous cell carcinoma.

Due to the rarity of sinonasal squamous cell carcinoma (SNSCC), the distribution patterns of lymph node metastasis (LNM), the relationship between LNM and prognosis, and the optimal treatment of LNM lack sufficient evidence-based support. To investigate the patterns of LNM in SNSCC and evaluate the impact of LNM on prognosis. This was a retrospective cohort study. The medical records of 441 patients with SNSCC between 2009 and 2022 in one institution were retrospectively reviewed. We assessed the incidence, the distribution of LNM, and the relationship between LNM and long-term survival. Seventy-three out of 441 patients (16.6%) presented LNM initially. Among the 73 patients, 34 patients (46.6%) had LNM in the region of ipsilateral level II; 22 patients (30.1%) had positive retropharyngeal lymph nodes; 20 patients (27.4%) had LNM in the region of ipsilateral level Ib; and nine patients (12.3%) had evidence of parotid LNM. Poor differentiation (p = 0.001), nasal cavity (p = 0.018), skin involvement (p = 0.036), and nasopharynx involvement (p = 0.009) were the risk factors for LNM. In the univariate and multivariate analyses, the overall survival (p = 0.25), progression-free survival (p = 0.22), regional failure-free survival (p = 0.20), and distant metastasis-free survival (p = 0.14) rates were not significantly decreased by the LNM. After the propensity score matching, LNM was still not correlated with poor long-term survival. The incidence of retropharyngeal and parotid LNM was higher than in previous studies. At initial diagnosis, the risk factors for LNM were identified, and LNM was not associated with poor survival outcomes.

Vision Transformer-Based Multilabel Survival Prediction for Oropharynx Cancer After Radiation Therapy

A reliable and comprehensive cancer prognosis model for oropharyngeal cancer (OPC) could better assist in personalizing treatment. In this work, we developed a vision transformer-based (ViT-based) multilabel model with multimodal input to learn complementary information from available pretreatment data and predict multiple associated endpoints for radiation therapy for patients with OPC. A publicly available data set of 512 patients with OPC was used for both model training and evaluation. Planning computed tomography images, primary gross tumor volume masks, and 16 clinical variables representing patient demographics, diagnosis, and treatment were used as inputs. To extract deep image features with global attention, we used a ViT module. Clinical variables were concatenated with the learned image features and fed into fully connected layers to incorporate cross-modality features. To learn the mapping between the features and correlated survival outcomes, including overall survival, local failure-free survival, regional failure-free survival, and distant failure-free survival, we employed 4 multitask logistic regression layers. The proposed model was optimized by combining the multitask logistic regression negative-log likelihood losses of different prediction targets. We employed the C-index and area under the curve metrics to assess the performance of our model for time-to-event prediction and time-specific binary prediction, respectively. Our proposed model outperformed corresponding single-modality and single-label models on all prediction labels, achieving C-indices of 0.773, 0.765, 0.776, and 0.773 for overall survival, local failure-free survival, regional failure-free survival, and distant failure-free survival, respectively. The area under the curve values ranged between 0.799 and 0.844 for different tasks at different time points. Using the medians of predicted risks as the thresholds to identify high-risk and low-risk patient groups, we performed the log-rank test, the results of which showed significantly larger separations in different event-free survivals. We developed the first model capable of predicting multiple labels for OPC simultaneously. Our model demonstrated better prognostic ability for all the prediction targets compared with corresponding single-modality models and single-label models.

Survival analyses of different treatment modalities and clinical stage for hypopharyngeal carcinoma.

We investigated the effects of different treatment modalities and clinical stage for hypopharyngeal carcinoma (HPC) patients. Between February 2004 and December 2012, 167 HPC patients were reviewed. We calculated overall survival (OS), progression-free survival (PFS), local failure-free survival (LFFS), regional failure-free survival (RFFS), and distant metastasis failure-free survival (DMFFS) using the Kaplan-Meier method and compared various survival outcomes between definitive chemoradiotherapy (CRT) and surgery-based therapy (SBT). There were no significant differences in baseline characteristics between SBT (n = 102) and definitive CRT (n = 65) groups. The 5-year rates of OS (59.7% vs. 24.0%, p < 0.0001) and PFS (49.9% vs. 22.6%, p = 0.0002) were significantly better in patients who received SBT than in those who received definitive CRT. The SBT group also obtained better LFFS (p < 0.0001), RFFS (p = 0.0479), and DMFFS (p = 0.0110). We did similar analyses by different T-classification (T1-2, T3, and T4) and found that SBT had better OS (p < 0.0001 and p = 0.0020), PFS (p < 0.0001 and p = 0.0513), LFFS (p = 0.0002 and p = 0.0075), RFFS (p = 0.1949 and p = 0.0826), and DMFFS (p = 0.0248 and p = 0.0436) in the T4 and T1-2 subgroups but similar OS (p = 0.9598), PFS (p = 0.5052), RFFS (p = 0.9648), and DMFFS (p = 0.8239) in T3 patients. Analyses by different overall stages revealed no differences between definitive CRT and SBT for stage III patients but significantly better results for stage IV patients who received SBT. SBT can obtain significant survival benefits when compared with definitive CRT for the whole cohort of patients. Definitive CRT has similar survival outcomes compared with SBT only for T3 tumors or overall stage III disease.

Relationship of PI3K-Akt/mTOR/AMPK signaling pathway genetic mutation with efficacy and prognosis in nasopharyngeal carcinoma.

Genetic mutation is one of the important causes for tumor genesis and development, but genetic mutation in nasopharyngeal carcinoma (NPC) has rarely been reported. This study explored the role of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR), and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway in the efficacy and prognosis in patients with NPC. A total of 31 patients with advanced NPC, who came from the Affiliated Cancer Hospital of Xiangya School of Medicine of Central South University/Hunan Provincial Cancer Hospital, were enrolled. All of the exons of 288 genes, introns of 38 genes and promoters or fusion breakpoint regions from the nasopharyngeal biopsy tissues before treatment were detected by the gene sequencing platform Illumina NextSeq CN500. The coding regions of 728 genes were carried out a high-depth sequencing of target region capture, and the 4 variant types of tumor genes (including point mutations, insertion deletions of small fragments, copy number variations, and currently known fusion genes) were detected. All of 31 patients received platinum-based induction chemotherapy combined with concurrent chemoradiotherapy and were followed up for a long time. The 3-year regional failure-free survival (RFFS) and disease-free survival (DFS) in patients with PI3K-Akt pathway mutation were significantly lower than those in unmutated patients (χ2=6.647, P<0.05). The 3-year RFFS and DFS in patients with mTOR pathway mutations were significantly lower than those in unmutated patients, and there was significant difference (χ2=5.570, P<0.05). The rate of complete response (CR) in patients with unmutated AMPK pathway was significantly higher than that in patients with mutation at 3 months after treatment (P<0.05), and the 3-year RFFS and DFS in patients with AMPK pathway mutation were significantly lower than those in unmutated patients (χ2=4.553, P<0.05). PI3K-Akt/mTOR/AMPK signaling pathway mutations and pre-treatment EB virus DNA copy numbers were independent prognostic factors for 3-year RFFS and DFS in patients with NPC (both P<0.05). The NPC patients with PI3K-Akt/mTOR/AMPK signaling pathway mutation have poor prognosis, and the detection of PI3K-Akt, mTOR, AMPK driver genes and signaling pathways by next-generation sequencing is expected to provide new idea for basic research and targeted therapy of NPC.

Tumor Control and Survival Outcomes Based on Maximum Standardized Uptake Value on FDG-PET/CT in T1-2 NSCLC Treated With SBRT

<h3>Purpose/Objective(s)</h3> Stereotactic body radiotherapy (SBRT) is standard of care in medically inoperable early-stage non-small cell lung cancer (NSCLC). Assessment of maximum standardized uptake value (SUVmax) on FDG-PET/CT before and after SBRT may stratify tumor control and survival outcomes. <h3>Materials/Methods</h3> Retrospective chart review identified patients with T1-2N0M0 NSCLC who were only treated with SBRT between 2012 and 2019. Pretreatment SUVmax and percent change in SUVmax at 3 and 6 months following SBRT were assessed as independent predictors of local control (LC), regional failure-free survival (RFFS), distant failure-free survival (DFFS), progression-free survival (PFS), and overall survival (OS). Receiver operator characteristic (ROC) analysis yielded optimal cut points for comparison. Survival analyses were performed with Kaplan-Meier estimates with log rank testing, and Cox proportional hazards models including age, sex, T stage, histology, and performance status. <h3>Results</h3> 71 (43.6%) out of 163 patients underwent repeat PET/CT within 6 months of SBRT completion. Median follow-up was 19 months (range 1 – 94 months). For the whole cohort, 1-year and 2-year LC, PFS, and OS were 95.0% and 80.3%, 75.9% and 47.7%, and 87.1% and 67.0%, respectively. For DFFS, pretreatment SUVmax greater than 4 had an aHR of 3.33 (95% CI 1.42 – 7.84, <i>P</i> = 0.006). Pre-SBRT SUVmax over 12.3 had an aHR of 2.80 (95% CI 1.3 – 6.2, <i>P</i> = 0.011) for PFS, and a cut point of 12.6 had an aHR of 3.00 (95% CI 1.6 – 5.8, <i>P</i> = 0.003) for OS. Pretreatment SUVmax did not significantly predict LC or RFFS. At 3 months following SBRT, an SUVmax decrease of at least 45% was associated with improved LC (aHR = 0.15, 95% CI 0.02 – 0.91, <i>P</i> = 0.018). A 6-month SUVmax decrease of more than 53% was associated with better LC (<i>P</i> = 0.038), and a decrease over 11% was associated with improved RFFS (aHR = 0.12, 95% CI 0.02 – 0.96, <i>P</i> = 0.046). Change in SUVmax was not significantly associated with DFFS, PFS, or OS at either time point. No factors other than performance status for PFS and OS were significant. <h3>Conclusion</h3> At 3 and 6 months following SBRT, cut points for percentage change in SUVmax can stratify risk of local recurrence and possibly regional recurrence. Pretreatment SUVmax cutoffs can predict distant failure, progression-free survival, and overall survival in early-stage NSCLC.

Prognostic implication of PD-L1 polymorphisms in non-small cell lung cancer treated with radiotherapy.

BackgroundTo investigate the impact of programmed death‐ligand 1 (PD‐L1) polymorphisms on the prognosis of non‐small cell lung cancer (NSCLC) patients treated with curative radiotherapy.MethodsFour single nucleotide polymorphisms (SNPs) (rs822336G>C, rs822337T>A, rs822338C>T, and rs2297136A>G) in the PD‐L1 gene were evaluated in 124 NSCLC patients. Clinical stage was I in 28, II in 17, and III in 79 patients. Fifty‐seven patients received radiotherapy alone, including 28 patients who received stereotactic body radiotherapy. Sixty‐seven patients received sequential or concurrent chemoradiotherapy. Risk factors for survival outcomes were analyzed with the log‐rank test and multivariate Cox proportional hazards models.ResultsThe rs822336GC+CC genotype was associated with better overall survival (OS) (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.37–0.97, p = 0.036) and regional failure‐free survival (RFFS) (HR = 0.32, 95% CI = 0.14–0.76, p = 0.009), compared with rs822336GG genotype. The rs822337TA+AA genotype was associated with better OS (HR =0.54, 95% CI = 0.34–0.88, p = 0.014), progression‐free survival (PFS) (HR = 0.64, 95% CI = 0.41–0.99, p = 0.046), and RFFS (HR = 0.38, 95% CI = 0.17–0.81, p = 0.013), compared with rs822337TT genotype. Three SNPs (rs822336, rs822337, and rs822338) were in linkage disequilibrium. Combined GTC and GTT (GT*) haplotype was associated with significantly worse OS (p = 0.018), PFS (p = 0.044), and RFFS (p = 0.038), compared with those with other combined haplotypes. Patients with diplotypes of two GT* haplotypes showed significantly worse OS (p = 0.023) and RFFS (p = 0.014) than those with other diplotypes.ConclusionsThese findings suggest that PD‐L1 polymorphisms could be predictive markers for NSCLC patients receiving radiotherapy.

Mid-treatment Fluorodeoxyglucose Positron Emission Tomography in Human Papillomavirus-related Oropharyngeal Squamous Cell Carcinoma Treated with Primary Radiotherapy: Nodal Metabolic Response Rate can Predict Treatment Outcomes

AimsTo evaluate whether biomarkers derived from fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) performed prior to (prePET) and during the third week (interim PET; iPET) of radiotherapy can predict treatment outcomes in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPC). Materials and methodsThis retrospective analysis included 46 patients with newly diagnosed OPC treated with definitive (chemo)radiation and all patients had confirmed positive HPV status (HPV+OPC) based on p16 immunohistochemistry. The maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) of primary, index node (node with the highest TLG) and total lymph nodes and their median percentage (≥50%) reductions in iPET were analysed, and correlated with 5-year Kaplan–Meier and multivariable analyses (smoking, T4, N2b-3 and AJCC stage IV), including local failure-free survival, regional failure-free survival, locoregional failure-free survival (LRFFS), distant metastatic failure-free survival (DMFFS), disease-free survival (DFS) and overall survival. ResultsThere was no association of outcomes with prePET parameters observed on multivariate analysis. A complete metabolic response of primary tumour was seen in 13 patients; the negative predictive value for local failure was 100%. More than a 50% reduction in total nodal MTV provided the best predictor of outcomes, including LRFFS (88% versus 47.1%, P = 0.006, hazard ratio = 0.153) and DFS (78.2% versus 41.2%, P = 0.01, hazard ratio = 0.234). More than a 50% reduction in index node TLG was inversely related to DMFFS: a better nodal response was associated with a higher incidence of distant metastatic failure (66.7% versus 100%, P = 0.009, hazard ratio = 3.0). ConclusionThe reduction (≥50%) of volumetric nodal metabolic burden can potentially identify a subgroup of HPV+OPC patients at low risk of locoregional failure but inversely at higher risk of distant metastatic failure and may have a role in individualised adaptive radiotherapy and systemic therapy.

Evaluation of Genetic Variants in Signaling Pathway Genes as Prognostic Biomarkers for Nasopharyngeal Carcinoma

We hypothesized that genetic variants in signaling pathways identified by next generation sequencing (NGS) are novel prognostic biomarkers for nasopharyngeal carcinoma. The purpose of this study was to evaluate gene variants in Adherens junction, PI3K-Akt, AMPK, Wnt and mTOR signaling pathway genes in patients with nasopharyngeal carcinoma (NPC) to predict treatment response and survival. A total of 32 NPC patients were enrolled from February 2018 to November 2018. Eligible patients were aged 33-66 years with histologically proven WHO Ⅱ-Ⅲ, stage Ⅱ-ⅣB (AJCC 7th) NPC. All patients received induction chemotherapy followed by concurrent chemoradiotherapy. Paraffin-embedded endoscopically NPC samples by endoscopic biopsy were available for all patients. The custom next generation sequencing assay was used to detect exons of 288 genes, introns, promoters or fusion in the dot region of 38 genes and partial exons of 728 genes related to NPC. Alterations of genes encoding the components of Adherens junction, PI3K-Akt, AMPK, Wnt and mTOR signaling pathway were detected. The association between genetic variants in these signaling pathway genes and treatment response and survival of NPC patients were analyzed. Patients with genetic variants in PI3K-Akt (HR = 0.32, P = 0.023), AMPK (HR = 0.26, P = 0.033), and mTOR (HR = 0.21, P = 0.016) signaling pathway genes had significantly inferior complete response rates as compared to patients without such genetic variants. Presence of gene variants in PI3K-Akt (P = 0.045), AMPK (P = 0.005) and mTOR signaling pathway (P = 0.001) were associated with significantly inferior 1-year regional failure-free survival (RFFS) and disease-free survival (DFS). No significant differences were observed in local failure-free survival (LFFS), distant metastasis-free survival (DMFS), and overall survival (OS) in patients with or without genetic variants in all of these signaling pathways. Gene variants in PI3K-Akt, AMPK and mTOR signaling pathway were associated with significantly inferior treatment response and disease-free survival in NPC patients. Gene variants in these signaling pathways identified by NGS profiling are potential novel prognostic markers for NPC.

The declining role of post-treatment neck dissection in human papillomavirus-associated oropharyngeal cancer

Background and purposeHuman papillomavirus-associated oropharyngeal cancer (HPV+ OPC) with regional lymph node metastases has a good prognosis following (chemo)radiation therapy (C/RT) but lymph nodes may remain detectable for several months. Delayed [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (PET) can identify patients who may avoid post-treatment neck dissection (PTND). We investigated the rate of PTND in HPV+ OPC treated with C/RT and delayed PET-directed management of the neck. Materials and methodsThis is a retrospective cohort study from a prospectively updated institutional database. Eligible patients were treated between January 2005 and July 2017 with a minimum of 18 months follow up, had node-positive, non-distant metastatic HPV+ OPC and were treated with RT (70 Gy/35#/5 per week) with concurrent Cisplatin or Cetuximab, or accelerated RT alone (68 Gy/34#/6 per week). The primary endpoint was rate of PTND. Secondary endpoints were locoregional failure free survival (LRFFS), regional failure free survival (RFFS), distant metastatic failure free survival (DMFFS), overall survival (OS) and oropharyngeal cancer-specific survival (CSS). Results418 patients were eligible. Nineteen patients (4.5%) received a PTND. None of the tested variables were associated with an increased risk of PTND. Five-year probabilities for LRFFS, RFFS, DMFS, OS and CSS were, 91.2% (95% CI 88.3–94.2), 93.4% (95% CI 90.8–96.0), 91.2% (95% CI 88.3–94.2), 86.4% (95% CI 83.0–90.1) and 90.2% (95% CI 87.1–93.4), respectively. ConclusionIn a large cohort with good median follow up and protocolized C/RT, delayed PET-directed management of the neck affords a lower rate of PTND than reported in historical series without compromising disease control and survival.

Adding Concurrent Chemotherapy to Intensity-Modulated Radiotherapy Does Not Improve Treatment Outcomes for Stage II Nasopharyngeal Carcinoma: A Phase 2 Multicenter Clinical Trial.

Purpose: To explore the efficacy of concomitant chemotherapy in intensity-modulated radiotherapy (IMRT) to treat stage II nasopharyngeal carcinoma (NPC).Methods and Materials: In this randomized phase 2 study [registered with ClinicalTrials.gov (NCT01187238)], eligible patients with stage II (2010 UICC/AJCC) NPC were randomly assigned to either IMRT alone (RT group) or IMRT combined with concurrent cisplatin (40 mg/m2, weekly) (CCRT group). The primary endpoint was overall survival (OS). The second endpoints included local failure-free survival (LFFS), regional failure-free survival (RFFS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and acute toxicities.Results: Between May 2010 to July 2012, 84 patients who met the criteria were randomized to the RT group (n = 43) or the CCRT group (n = 41). The median follow-up time was 75 months. The OS, LFFS, RFFS, DFS, and DMFS for the RT group and CCRT group were 100% vs. 94.0% (p = 0.25), 93.0% vs. 89.3% (p = 0.79), 97.7% vs. 95.1% (p = 0.54), 90.4% vs. 86.6% (p = 0.72), and 95.2% vs. 94.5% (p = 0.77), respectively. A total of 14 patients experienced disease failure, 7 patients in each group. The incidence of grade 2 to 4 leukopenia was higher in the CCRT group (p = 0.022). No significant differences in liver, renal, skin, or mucosal toxicity was observed between the two groups.Conclusion: For patients with stage II NPC, concomitant chemotherapy with IMRT did not improve survival or disease control but had a detrimental effect on bone marrow function.

Observational approach on regional lymph node in cutaneous melanomas of extremities.

PurposeWe evaluated failure pattern and treatment outcomes of observational approach on regional lymph node (LN) in cutaneous melanoma of extremities and sought to find clinico-pathologic factors related to LN metastases.Material and MethodsWe retrospectively reviewed 73 patients with cutaneous melanoma of extremities between 2005 and 2016. If preoperative 18-F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) findings were non-specific for regional LNs, surgical resection of primary tumors with adequate margins was performed without sentinel lymph node biopsy (SLNB) and/or complete lymph node dissection (CLND), irrespective of tumor thickness or size. In patients with suspicious or positive findings on PET/CT or CT, SLNB followed by CLND or CLND was performed at the discretion of the surgeon. We defined LN dissection (LND) as SLNB and/or CLND.ResultsWith a median follow-up of 38 months (range, 6 to 138 months), the dominant pattern of failure was regional failure (17 of total 23 events, 74%) in the observation group (n = 56). Pathologic LN metastases were significant factor for poor regional failure-free survival (hazard ration [HR] = 3.21; 95% confidence interval [CI], 1.03–10.33; p = 0.044) and overall survival (HR = 3.62; 95% CI, 1.02–12.94; p = 0.047) in multivariate analysis. In subgroup analysis for cN0 patients according to the preoperative PET/CT findings, LND group showed the better trend of LRFFS (log rank test, p = 0.192) and RFFS (p = 0.310), although which is not statistically significant.ConclusionObservational approach on regional LNs on the basis of the PET/CT in patients with cutaneous melanoma of extremities showed the dominant regional failure pattern compared to upfront LND approach. To reveal regional lymph node status, SLND for cN0 patients may of importance in managing cutaneous melanoma patients.

The limited role of elective neck dissection in patients with cN0 salivary gland carcinoma

PurposeTo evaluate whether elective neck dissection (END) was beneficial for cN0 patients with salivary gland carcinoma. Materials and methodsThe rates of regional failure-free survival and disease-free survival were calculated using Kaplan–Meier methods and Cox models. The risk factors for occult lymph node metastasis (OLNM) in cN0 patients undergoing END was analyzed using logistic regression. A nomogram was formulated to calculate the estimated probability of OLNM. ResultsNeck dissection was performed in 84 patients (43.3%). OLNM was detected in eight of the patients who underwent END. During the follow-up period, regional recurrences involving cervical lymph nodes were found in 10 patients. Cox model analysis revealed that neck dissection was not related to regional failure-free survival and disease-free survival. Logistic regression analysis revealed that older age, neural symptoms, and positive adjacent lymph nodes were associated with OLNM. A nomogram comprising age, neural symptoms, and adjacent lymph nodes was developed to predict the risk of OLNM. ConclusionThe incidence of OLNM was low in cN0 patients after detailed preoperative evaluations. There was no strong evidence supporting END as a conventional therapy in cN0 patients with salivary cancers. Our nomogram is a simple and practical instrument for strengthening the prediction of OLNM.

Prognostic value of TIGAR and LC3B protein expression in nasopharyngeal carcinoma

PurposeAutophagy, the process responsible for degrading cytoplasmic organelles to sustain cellular metabolism, has been associated with cancer initiation and progression. As TP53-induced glycolysis and apoptosis regulator (TIGAR) is among the important genes that can regulate autophagy, we aimed to investigate the correlation between the expression levels of TIGAR and the autophagy-related protein microtubule-associated protein 1 light chain 3 (LC3B), as well as their association with clinical outcomes, in nasopharyngeal carcinoma (NPC) patients.MethodsWe detected the expressions of TIGAR and LC3B in 182 NPC tissue samples via immunohistochemical staining.ResultsA significant correlation between TIGAR and LC3B expressions was identified (P=0.045). Moreover, survival analysis showed that TIGAR− or LC3B+ expression was associated with improved overall survival, local regional failure-free survival, distant failure-free survival, and failure-free survival rates, compared with TIGAR+ or LC3B− expression, respectively. Meanwhile, when combining TIGAR with LC3B expression in terms of prognostic value, patients with TIGAR+/LC3B− expression were significantly disadvantaged with regard to overall survival, local regional failure-free survival, distant failure-free survival, and failure-free survival compared with other groups based on the log-rank test and Cox regression analyses (all P<0.05).ConclusionTIGAR and LC3B may be novel biomarkers for predicting the prognosis of NPC patients and could be utilized as potential targets for future therapeutics aimed at treating NPC patients.

The role of endobronchial ultrasound-guided transbronchial needle aspiration in stereotactic body radiation therapy for non-small cell lung cancer

ObjectiveTo evaluate the diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in stereotactic body radiation therapy (SBRT) candidates and compare with computed tomography (CT) and positron emission tomography (PET). MethodsInclusion criteria for this single institutional retrospective study were 1) biopsy-proven or suspicious NSCLC with diameter <6 cm; 2) no distant metastasis; 3) EBUS-TBNA staging between April 2008 and November 2014; 4) SBRT eligible. CT and PET positive nodes were defined as short axis ≧1 cm and standardized uptake value ≧2.5, respectively. Node positive by clinical-pathologic confirmation (NPCP) was defined as confirmed malignancy by EBUS-TBNA or recurrence in hilar or mediastinal lymph nodes within one year after SBRT. The survival after SBRT was compared between radiologically node-positive, but EBUS-TBNA negative, patients (Case) and a matched cohort (tumor size; radiation dose; operability) who underwent SBRT without EBUS-TBNA staging (Control). ResultsThere were 35 eligible patients (mean age 77 ± 8.2; mean diameter 2.5 ± 1.0 cm). Thirty were medically inoperable. Twenty out of 24 patients with radiologically positive node(s) were negative by EBUS-TBNA. All eleven radiologically negative patients were N0 following EBUS-TBNA. Thirty-one patients underwent SBRT. Per-person based sensitivity/specificity of CT, PET and EBUS-TBNA for NPCP were 42.9/64.3%, 100/64.3% and 57.1/100%, respectively. A 1:4 match was obtained. Regional failure-free survival (p = 0.71; HR = 0.88 95%CI 0.45–1.74) and disease-free survival (p = 0.77; HR = 1.10 95%CI 0.58–2.11) of the Case were not significantly different from the Control. ConclusionPatients with radiographically positive lymph nodes can be considered for EBUS-TBNA and may remain candidates for SBRT.

Treatment outcomes of nasopharyngeal carcinoma in modern era after intensity modulated radiotherapy (IMRT) in Hong Kong: A report of 3328 patients (HKNPCSG 1301 study)

PurposeTo evaluate treatment outcomes, failure patterns and late toxicities in patients with nasopharyngeal carcinoma (NPC) treated by intensity modulated radiotherapy (IMRT) in 6 public hospitals in Hong Kong over a 10-year period from 2001 to 2010. Material and methodsEligible patients were identified through the Hong Kong Cancer Registry data base. Clinical information was retrieved and verified by oncologists working in the individual centers. Treatment details, survival outcomes and late toxicities were analyzed. ResultsA total of 3328 patients were recruited. The median follow-up time was 80.2 months. The 8-year actuarial overall survival (OS), local failure-free survival (LFFS), regional failure-free survival (RFFS), distant failure free survival (DFFS), progression-free survival (PFS) for the whole group was 68.5%, 85.8%, 91.5%, 81.5% and 62.6% respectively. Male gender, older age, advanced T and N stage were adverse prognostic factors for OS, DFFS and PFS, whereas use of chemotherapy in form of concurrent chemo-irradiation (CRT), neoadjuvant + CRT, or CRT + adjuvant chemotherapy were favorable prognostic factors for OS and PFS. The local control was adversely affected by advanced T stage. N stage remained as the single adverse prognostic factor for regional control. Distant metastasis was the commonest site of failure. ConclusionIMRT is an effective treatment for NPC with excellent overall loco-regional control. Distant metastasis is the major site of failure. Concurrent chemotherapy with cisplatin has an established role in NPC patients treated by IMRT.

Cytomembranic PD-L1 expression in locoregionally advanced nasopharyngeal carcinoma

Background and objectiveThe aim of this study was to evaluate the expression of cytomembranic programmed death-ligand 1 (PD-L1) and its clinical significance in locoregionally advanced nasopharyngeal carcinoma (NPC).Patients and methodsFormalin-fixed, paraffin-embedded tissue biopsies from 85 patients with histological diagnosis of locoregionally advanced NPC treated with radical intensity-modulated radiotherapy and concurrent cisplatin-based chemotherapy were studied. By using immunohistochemistry staining, expressions of cytomembranic PD-L1 on tumor cells were detected.ResultsAfter a median follow-up duration of 65.8 months, 7 (8.2%), 5 (5.9%), and 5 (5.9%) patients suffered from local failure, regional failure, and distant metastases, respectively. The 5-year local failure-free survival, regional failure-free survival, distant failure-free survival, and overall survival (OS) rates were 90.9%, 94.8%, 94.0%, and 92.2%, respectively. Our results revealed that a high expression of cytomembranic PD-L1 was correlated with shorter OS (5y-OS: 82.5% vs 97.6%, P=0.022). In the multivariate analysis, only the cytomembranic PD-L1 was an independent prognostic factor for OS (hazard ratio: 6.176, 95% confidence interval, 1.166–32.710, P=0.032).ConclusionCytomembranic PD-L1 expression levels correlated with OS in locoregionally advanced NPC. Agreement between different methods is needed for further application of PD-L1 biomarker assays in NPC.

Cosmetic Outcomes and Toxicity in Patients Treated With Proton Therapy After Breast Conserving Surgery

There has been reluctance to treat post-lumpectomy patients with proton therapy due to potential skin toxicity and setup uncertainty. Here we report skin toxicity, cosmesis, and treatment efficacy/reproducibility in a cohort of breast cancer patients treated with lumpectomy followed by postoperative proton radiation therapy to the intact breast. 26 patients treated with lumpectomy followed by proton therapy with at least 6 months of follow up were analyzed. Six (23.1%) had stage III disease, 13 (50%) stage II, 5 (19.2%) stage I and 2 (7.7%) DCIS. Fifteen patients (57.7%) were treated to the breast and regional nodes (with internal mammary node coverage in 93.3%) and 42.3% were treated to the breast alone. Seven (26.9%) had an axillary dissection. Proton therapy was delivered with uniform scanning beams using 2-4 en face fields per day with a daily feathered match. The median dose to the initial volume was 48.6 Gy (RBE) (range 45 – 52), and the lumpectomy cavity was boosted to a median of 60.6 Gy (RBE) (48.7 – 65). Patients were seen and photographed weekly while on treatment, 1 month after RT completion and, in general, every 6 months thereafter. Toxicity was assessed using CTCAE v4.0. Cosmesis was retrospectively assessed via photographs and validated among 3 blinded practitioners using the Harvard 4-point breast cosmesis scale. Based on clinical assessment of edema during treatment, and verification CT scans as needed, no patients required adaptive re-planning. With a median follow up of 15 months, the 2-year local failure free survival is 95.8%, regional failure free survival 89.4%, and distant failure free survival 96.2%. Locoregional failures included a Stage II patient that experienced a combined breast and axillary recurrence 9 months after therapy, and a stage III patient with known supraclavicular lymph node involvement who progressed in the SCV 14 months after completion of RT to the breast and nodes. There were no Grade 3 adverse early or late events. The incidence of acute Grade 2 dermatitis was 46.2% (n=12). Six (23.1%) developed moist desquamation. The rate of late Grade 1 hyperpigmentation, telangiectasia, and fibrosis was 46.2% (n=12), 3.8% (n=1), and 11.5% (n=3) respectively. One patient (3.8%) developed Grade 2 fibrosis. There have been no cases of pneumonitis, cardiac toxicity, or rib fractures. 88.4% of patients had an excellent or good cosmetic outcome and 11.5% experienced a fair cosmetic outcome. There were no cases of poor cosmesis. Locoregional control with postoperative proton therapy after lumpectomy was excellent and does not seem compromised due to reproducibility/setup issues. Due to the higher skin dose with uniform scanning protons, the rate of moist desquamation was slightly higher than historical series of photons; however, late skin toxicity and fibrosis was minimal and 88% of patients had excellent/good cosmesis. Further follow up is planned to assess for long-term outcomes and toxicity.

Long-term Patterns of Regional Failure for Nasopharyngeal Carcinoma following Intensity-Modulated Radiation Therapy.

Purpose: To analyze the long-term patterns of regional failure following intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC).Methods: From January 2005 to December 2010, 275 non-metastatic NPC patients treated with IMRT were retrospectively enrolled. Patients staged as II (lymph nodes measuring 4 or more cm in diameter), III or IV also received chemotherapy. Failures were assessed as in-field or out-field relative to the pretreatment planning computed tomography data sets. Univariate and multivariate analyses were performed with Cox proportional hazards model to analyze the effect of various prognostic factors on regional failure-free survival (RFFS) and overall survival (OS).Results: During a median follow-up of 71 months, the RFFS and OS rates were 94.3% and 83.9%, respectively. Seventeen patients developed regional failures, of which 16 were in-field; one patient showed an out-field failure in the parotid gland, and no recurrences were seen for level Ib. Failures in level II and in the retropharyngeal area accounted for 70.6% (12/17) and 52.9% (9/17) of all failures, respectively. The 5-year RFFS rates for patients with classifications of N0-1 and N2-3 were 98.5% and 90.2%, respectively (p = 0.001). Multivariate analysis showed that N stage was the only independent prognostic predictor of RFFS (HR 7.363, 95% CI 1.516-35.756, p = 0.013).Conclusions: The regional failure of NPC after treatment with IMRT is uncommon but is significantly higher in N2-3 patients than in N0-1 patients. In-field failures represent the main pattern of regional recurrence and are most often detected in level II and in the retropharyngeal area, while out-field failure is rare. Close attention should be directed to NPC patients with advanced N stages.