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Purpose In the treatment of concurrent chemoradiotherapy (CCRT) in limited-stage small cell lung cancer, the optimal once-daily radiotherapy (RT) dose/fractionation remain unclear although it is the most frequently used. Therefore, this study aimed to compare the treatment outcomes and toxicities of modest dose RT (≤ 54 Gy) with those of standard dose RT (> 54 Gy) and investigate the benefit of the high dose based on patient factors.Materials and Methods Since 2004, our institution has gradually increased the thoracic RT dose. Among the 225 patients who underwent CCRT, 84 patients (37.3%) received > 54 Gy. Because the patients treated with RT > 54 Gy were not randomly assigned, propensity score matching (PSM) was performed.Results The proportion of patients treated with > 54 Gy increased over time (p=0.014). Multivariate analysis revealed that the overall tumor stage and dose > 54 Gy (hazard ratio, 0.65; p=0.029) were independent prognostic factors for overall survival (OS). PSM confirmed that thoracic RT doses of > 54 Gy showed significantly improved progression-free survival (3-year, 42.7% vs. 24.0%; p < 0.001) and OS (3-year, 56.2% vs. 38.5%; p=0.003). Sensitivity analysis also showed that 60 Gy resulted in better survival than 54 Gy. However, in patients with underlying lung disease, OS benefit from > 54 Gy was not observed but considerable rates of severe pulmonary toxicities were observed (p=0.001).Conclusion Our analysis supports that the 60 Gy RT dose should be considered in the once-daily regimen of CCRT for limited-stage small cell lung cancer without underlying lung disease, but RT dose > 54 Gy did not seem to benefit for patients with chronic obstructive pulmonary disease or interstitial lung disease. Further study is needed to validate these results.

We evaluated the efficacy and safety of postoperative radiotherapy (PORT) for differentiated thyroid cancer (DTC) with high risk features.This retrospective study analyzed 187 patients treated for DTC from 1985 to 2019. DTC referred to nonanaplastic thyroid cancer originating from follicular cells. PORT was defined as the administration of external beam radiation to the thyroid and regional lymph nodes following surgery for initially diagnosed DTC. The patients were included in the analysis if they received PORT or exhibited any of the following features: (a) pT4 or pN1b according to the 8th American Joint Committee on Cancer, (b) poorly differentiated thyroid cancer (PDTC), or (c) unfavourable variants such as anaplastic foci and etc. After 1:1 propensity matching, a total of 108 patients were analyzed according to PORT receipt. The median follow-up duration of the matched group was 10.4 years.After matching, most of the variables became balanced, but the PORT group still had more PDTC and DTC with anaplastic foci. Radioactive iodine (RAI) was less frequently administered in the PORT group. PORT yielded a significantly higher 5-year locoregional recurrence free survival (LRFS) than the No PORT group (5-year LRFS 86.1% vs. 72.7%, p = 0.022), but the 10-year cancer specific survival (CSS) was similar between them (97.8% vs. 85.9%, p = 0.122). The multivariable analysis indicated that PORT was a favourable prognostic factor (Hazard ratio 0.3, 95% Confidence interval 0.1-0.8, p = 0.02) for LRFS, but not for CSS. Among 133 patients without PORT for initial disease, 39 of them received salvage surgery followed by salvage PORT. No severe toxicity after PORT was reported.PORT reduced locoregional recurrence in DTC patients without severe toxicity. PORT can be an effective and safe treatment to improve locoregional control in DTC with high risk features. However, further study is warranted to identify those who can benefit from PORT.

Purpose: The purpose of this study was to evaluate the treatment outcomes and toxicity profile of patients with early glottic cancer who underwent hypofractionated radiation therapy (RT) with 3.5 Gy per fraction.Materials and Methods: A retrospective review was performed of the medical records of 35 patients with early stage (T1-2N0M0) glottic cancer who underwent definitive RT. The dose fractionation scheme was 59.5 Gy in 17 fractions. Posterior commissure was excluded from the clinical target volume (CTV) for 26 patients (74.3%) without glottic lesions close to this region. Results: With a median follow-up of 16.23 months (range, 6.82 to 67.15 months), no local, regional, or distant recurrence was reported. Acute hoarseness (65.7%), mucositis (68.6%), radiation dermatitis (60.0%) was frequent. One patient (2.9%) reported grade 3 acute toxicity (mucositis) and there was no grade 4–5 acute toxicity. There was no grade ≥3 late toxicities; however, grade 1 late intermittent hoarseness was frequent (45.7%). The receiver operative characteristic analysis revealed that mean hypopharyngeal dose was predictive for acute grade ≥2 mucositis (area under the curve=0.9314; 95% confidence interval, 0.8524–1). The optimal threshold of mean hypopharyngeal dose for occurrence of acute grade ≥2 mucositis was 26.31 Gy, with a specificity and sensitivity of 83.3% and 88.2%, respectively.Conclusion: Hypofractionated RT with fraction size of 3.5 Gy for early glottic cancer is effective. The hypopharyngeal mean dose could predict the occurrence of grade ≥2 acute mucositis. The posterior commissure can be safely excluded from the CTV.

Supplementary Figures S1-S2.

Histone deacetylase inhibitors (HDI) are emerging as potentially useful components of the anticancer armamentarium and as useful tools to dissect mechanistic pathways. HDIs that globally inhibit histone deacetylases (HDAC) have radiosensitizing effects, but the relative contribution of specific HDAC classes remains unclear. Newly characterized HDIs are now available that preferentially inhibit specific HDAC classes, including SK7041 (inhibits class I HDACs) and splitomicin (inhibits class III HDACs). We investigated in human cancer cells the relative radiosensitizations that result from blocking specific HDAC classes. We found that trichostatin A (TSA; inhibitor of both class I and II HDACs) was the most effective radiosensitizer, followed by the class I inhibitor SK7041, whereas splitomicin (inhibitor of class III) had least effect. Interestingly, radiosensitization by TSA in cell lines expressing p53 was more pronounced than in isogenic lines lacking p53. Radiosensitization of cells expressing p53 by TSA was reduced by pifithrin-α, a small-molecule inhibitor of p53. In contrast, the radiosensitization by TSA of cells expressing low levels of p53 was enhanced by transfection of wild-type p53–expressing vector or pretreatment with leptomycin B, an inhibitor of nuclear export that increased intracellular levels of p53. These effects on radiosensitization were respectively muted or not seen in cells treated with SK7041 or splitomicin. To our knowledge, this may be among the first systematic investigations of the comparative anticancer effects of inhibiting specific classes of HDACs, with results suggesting differences in the degrees of radiosensitization, which in some cell lines may be influenced by p53 expression.

Supplementary Figures 1-2 from Histone Deacetylase Inhibitor–Mediated Radiosensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53

To evaluate the efficacy and safety of reducing target volume in definitive radiotherapy for HPV-associated tonsil cancer.A single-institution cohort of 90 patients with human papillomavirus (HPV)-associated tonsil cancer who received definitive radiotherapy with a 5-mm expansion from the gross tumor volume to clinical target volume between 2008 and 2019 were included. The overlapping volume of initial planning target volume and the recurrent tumor was calculated and categorized as one of three failure types: in-field: ≥95%; marginal-field: 50%-94%; and out-field:50%.With a median follow-up of 59.4 months, the 3-year and 5-year local control rates were 94.4% and 92.8%, respectively. A total of seven local failures were identified, of which 4 (4.4%) were in-field, 2 (2.2%) were marginal-field, and 1 (1.1%) was out-field. Grade 3 acute and late toxicities developed in 30 (33.3%) and 5 (5.6%) patients, respectively.Reducing target volume could be an alternative option for selected patients with HPV-associated tonsil cancer.

Purpose: To investigate the efficacy and safety of intensity-modulated radiotherapy (IMRT)-based re-irradiation (reRT) for recurrent or second primary head and neck cancer (HNC).Materials and Methods: Patients who underwent IMRT-based reRT for recurrent or second primary HNC between 2007 and 2019 at two institutions were included. Medical records and dosimetric data were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), severe late toxicities, and clinicopathological prognostic factors were analyzed.Results: A total of 42 patients were analyzed. With a median follow-up of 15.1 months (range, 3.7 to 85.8 months), the median OS was 28.9 months with a 2-year OS rate of 54.6%. The median PFS and 2-year PFS rates were 10.0 months and 30.9%, respectively. Multivariate analysis showed that good performance (Eastern Cooperative Oncology Group [ECOG] 0 or 1), a longer time interval (≥24 months) between radiotherapy courses, and higher reRT dose (>60 Gy) were significantly favorable factors for OS (all p < 0.05). Higher reRT dose and salvage surgery were significantly associated with improved PFS (all p < 0.05). Regarding the Multi‐Institution Reirradiation (MIRI) Collaborative RPA classification, the 2-year OS rates of each class were 87.5% in class I, 51.8% in class II, and 0% in class III (p = 0.008). Grade ≥3 late toxicity was reported in 10 (23.8%) patients. There was no significant factor associated with increased late toxicities.Conclusion: IMRT-based reRT should be considered as a treatment option for patients with recurrent or second primary HNC. Further trials are needed to establish a subset of patients who may benefit from reRT without severe late toxicity.

Exogenous epidermal growth factor (EGF) causes apoptosis in EGF receptor (EGFR)-overexpressing cell lines. The apoptosis-inducing factors could be a therapeutic target. We aimed to determine the mechanism of EGF-induced apoptosis using a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR)-based knockout screen.Two-vector system of the human genome-scale CRISPR knockout library v2 was used to target 19,050 genes using 123,411 single guide RNAs (sgRNAs). Recombinant human EGF (100 nM) or distilled water four times was administered to the experimental and control groups, respectively. The read counts of each sgRNA obtained from next-generation sequencing were analyzed using the edgeR algorithm. We used another EGFR-overexpressing cell line (A549) and short hairpin RNAs (shRNAs) targeting five EGF-resistance genes for validation. DUSP1 expression in A431, A549, and HEK293FT cells was calculated using reverse transcription-quantitative polymerase chain reaction.We found 77 enriched and 189 depleted genes in the experimental group using the CRISPR-based knockout screen and identified the top five EGF-resistance genes: DDX20, LHFP, REPS1, DUSP1, and KRTAP10-12. Transfecting shRNAs targeting these genes into A549 cells significantly increased the surviving fractions after EGF treatment, compared with those observed in the control shRNA-transfected cells. The expression ratio of DUSP1 (inhibits ERK signaling) increased in A431 and A549 cells after EGF treatment. However, DUSP1 expression remained unchanged in HEK293FT cells after EGF treatment.The CRISPR-based knockout screen revealed 266 genes possibly responsible for EGF-induced apoptosis. DUSP1 might be a critical component of EGF-induced apoptosis and a novel target for EGFR-overexpressing cancers.

Purpose In radiotherapy for head and neck cancer, it is crucial to define the appropriate treatment volume to determine treatment outcome and toxicity. We examined the feasibility of omitting elective high retropharyngeal lymph node (RPLN) irradiation in patients with oropharyngeal cancer. Materials and Methods We performed a retrospective review of 189 patients with oropharyngeal squamous cell carcinoma who were treated with definitive or postoperative radiation therapy between 2009 and 2016. Of them, 144 (76.2%) underwent ipsilateral RPLN irradiation up to the superior border of the C1 vertebral body, while the other 45 (23.8%) were irradiated up to the transverse process of the C1 vertebra. High RPLN-treated and spared group were propensity matched based on key clinical variables. Results During the follow-up period, only three patients (one in the high RPLN-treated group and two in the high RPLN-spared group) developed RPLN recurrence. There were no significant between-group differences in 5-year locoregional failure-free survival (82.8% vs. 90.6%; p = 0.14), distant metastasis-free survival (93.1% vs. 93.3%; p = 0.98) and RPLN failure-free survival (99.3% vs. 95.0%; p = 0.09). In the matched groups, high RPLN-spared patients received a lower mean ipsilateral parotid gland dose (mean, 20.8 Gy vs. 29.9 Gy; p < 0.001) and had a lower incidence of chronic xerostomia (grade 0, 43.5% vs. 13.0%; p = 0.023) at 1 year after radiotherapy compared with high RPLN-treated patients. Conclusion Omission of ipsilateral high RPLN irradiation seems safe, and reduces the incidence of chronic xerostomia in patients with oropharyngeal squamous cell carcinoma.

Charged-particle therapy (CPT) such as proton beam therapy (PBT) and carbon-ion radiotherapy (CIRT) exhibit substantial physical and biological advantages compared to conventional photon radiotherapy. As it can reduce the amount of radiation irradiated in the normal organ, CPT has been mainly applied to pediatric cancer and radioresistent tumors in the eloquent area. Although there is a possibility that more patients can benefit from it, high set-up cost and dearth of high level of clinical evidence hinders wide spread of CPT. This review aims to present recent clinical results of PBT and CIRT in selected diseases focusing on possible indications of CPT. We also discussed how clinical studies are conducted to increase the number of patients who can benefit from CPT considering the high cost of it.

Introduction We investigated the correlation between optical surface imaging using a three‐dimensional (3D) scanner and magnetic resonance imaging (MRI) for suggesting feasibility in the clinical process of tracking volume changes in head and neck patients during radiation treatment. Methods Ten patients were divided into two groups depending on the location of their tumor (i.e., right or left side). With weekly imaging data, the change in volume based on MRI was evaluated during the treatment course. Four volumes of interest (VOIs) were calculated on the 3D surface image of the facial and cervical areas using an optical 3D scanner, and the correlation between volumetric parameters were analyzed. Results The target volume changed significantly overall for both groups. The changes parotid volume reduced by up to 3.8% and 28.0% for groups A (right side) and B (left side), respectively. In Group A, VOI 1 on the facial area and VOI 3 on the cervical area decreased gradually during the treatment course by up to 3.3% and 10.7%, respectively. In Group B, only VOI 4 decreased gradually during the treatment course and reduced by up to 9.2%. In group A, the change in target volume correlated strongly with right‐side parotid, VOI 1, and VOI 3, respectively. The parotid also showed strong correlations with VOIs (P 0.05). In group B (left side), the change in target volume correlated strongly with each volumetric parameter, including weight loss. For individual patient, PTV showed more correlation with VOIs on the cervical area than VOIs on the facial area. Conclusions An optical 3D scanner can be applied to track changes in volume without radiation exposure during treatment and the optical surface image correlated with MRI.

Background/Aims: Adenoid cystic carcinoma (ACC) is a rare salivary gland tumor characterized by indolence, with a high rate of local recurrence and distant me tastasis. This study aimed to investigate the effect of concurrent chemoradiation (CCRT) on locally advanced unresectable ACC. Methods: We retrospectively analyzed clinical data from 10 patients with patho logically confirmed ACC of the head and neck who received CCRT with cisplatin in Seoul National University Hospital between 2013 and 2018. Results: Ten patients with unresectable disease at the time of diagnosis or with positive margins after surgical resection received CCRT with weekly cisplatin. Eight patients (80%) achieved complete remission, of which three later developed distant metastases without local relapse; one patient developed distant metastasis and local relapse. Two patient achieved partial remission without progression. Patients experienced several toxicities, including dry mouth, radiation dermatitis, nausea, and salivary gland inflammation of mostly grade 1 to 2. Only one patient showed grade 3 oral mucositis. Median relapse-free survival was 34.5 months (95% confidence interval, 22.8 months to not reached). Conclusions: CCRT with cisplatin is effective for local control of ACC with man ageable toxicity and may be an effective treatment option for locally advanced un resectable ACC.

Neural stem cells (NSCs) harboring cancer-driving mutations in the subventricular zone (SVZ) have recently been reported as the cells of origin for human GBM. However, the pathological role of residual tumor-initiating NSCs (tNSCs) in the SVZ is undetermined for recurrent tumors after surgical removal of the primary tumor. After the primary resection of GBM, most recurrences still appear as local tumors around the resection cavity (RC). Accordingly, after surgical removal, we hypothesized that the tNSCs in SVZ might be the source for tumor construction at RC as local recurrence. Here, we examined the role of tNSCs in developing local tumors around RC using a mouse model and human tissues. First, cancer-driving mutations, including Trp53, Pten, and Egfr mutations, were introduced to NSCs in SVZ through in vivo electroporation, and the RC was generated in the remote cortex through surgical resection. We found that the NSCs harboring driver mutations migrated specifically to the RC through the aberrant growth of oligodendrocyte-precursor cells (OPCs). Furthermore, the SVZ-originated cells constituted the GBM around the RC at four weeks post-resection in 64% of mouse models. Second, the CXCR4/CXCL12 axis was upregulated through migration from the SVZ and tumor formation at the RC compared with primary tumors without the RC. Blockage of the CXCR4/CXCL12 axis decreased the number of immigrating OPC lineage and switched the differentiation of tNSC to astrocyte lineage. Furthermore, it improved survival rates in vivo. Third, we validated the independent clonal evolution of recurrent tumor from SVZ and the upregulation of CXCR4 axis in the recurrent tumor in a human patient. Taken together, our results reveal that the residual tNCSs harboring cancer-driving mutations in the SVZ can re-construct tumors after surgical resection of GBM. Blocking CXCL12/CXCR4 might be a potential treatment strategy for preventing recurrences after resection.

The objective of this study was to fabricate an anthropomorphic multimodality pelvic phantom to evaluate a deep-learning-based synthetic computed tomography (CT) algorithm for magnetic resonance (MR)-only radiotherapy.Polyurethane-based and silicone-based materials with various silicone oil concentrations were scanned using 0.35 T MR and CT scanner to determine the tissue surrogate. Five tissue surrogates were determined by comparing the organ intensity with patient CT and MR images. Patient-specific organ modeling for three-dimensional printing was performed by manually delineating the structures of interest. The phantom was finally fabricated by casting materials for each structure. For the quantitative evaluation, the mean and standard deviations were measured within the regions of interest on the MR, simulation CT (CTFor the prostate site, the mean MR intensities for the patient and phantom were 78.1 ± 13.8 and 86.5 ± 19.3, respectively. The mean intensity of the synthetic image was 30.9 Hounsfield unit (HU), which was comparable to that of the real CT phantom image. The original and synthetic CT intensities of the fat tissue in the phantom were -105.8 ± 4.9 HU and -107.8 ± 7.8 HU, respectively. For the target volume, the difference in DThis work demonstrated that the anthropomorphic phantom was physiologically and geometrically similar to the patient organs and was employed to quantitatively evaluate the deep-learning-based synthetic CT algorithm.

Introduction We evaluated the incidence of cardiac events after chemoradiotherapy in patients with stage III non-small cell lung cancer (NSCLC) based on baseline cardiovascular risk and the heart substructures’ radiation dose. Methods From 2008 to 2018, the cardiac events of 258 patients with stage III NSCLC who received definitive chemoradiotherapy were reviewed. The 10-year cardiovascular risk was calculated using the Atherosclerotic Cardiovascular Disease (ASCVD) scoring system. Dose-volume histograms were estimated for each cardiac chamber. A multivariate competing-risk regression analysis was conducted to assess each cardiac event’s subhazard function (SHR). Results The median follow-up was 27.5 months overall and 38.9 months for survivors. Among the 179 deaths, none was definitely related to cardiac conditions. Altogether, 32 cardiovascular events affected 27 patients (10.5%) after chemoradiotherapy. Ten were major cardiac adverse events, including heart failure (N = 6) and acute coronary syndrome (ACS, N = 4). Most cardiovascular events were related to well-known risk factors. However, the volume percentage of the left ventricle (LV) receiving 60 Gy (LV V60) > 0 was significantly associated with ACS (SHR = 9.49, 95% CI = 1.28–70.53, P = 0.028). In patients with high cardiovascular risk (ASCVD score > 7.5%), LV V60 > 0% remained a negative ACS prognostic factor (P = 0.003). Meanwhile, in patients with low cardiovascular risk, the LV radiation dose was not associated with ACS events (P = 0.242). Conclusions A high LV radiation dose could increase ACS events in patients with stage III NSCLC and high cardiovascular risk. Pre-treatment cardiac risk evaluation and individualized surveillance may help prevent cardiac events after chemoradiotherapy.

Most patients with head and neck cancer experience salivary gland dysfunction after chemo- and radiotherapies. There is currently no available treatment for this condition. Intervention with stem cell therapy has emerged as a promising approach. Although some progress has been made with systemic delivery of stem cells, it remains challenging to deliver a sufficient number of stem cells to the damaged tissue. Furthermore, local delivery of stem cells involves frequent cell loss. Herein, we evaluated the ability of adipose-derived stem cells (ASCs) with or without hydrogel to prevent salivary gland damage. Salivary gland cells were isolated from irradiated mouse submandibular glands. These cells exhibited higher expression levels of amylase, mucin, and aquaporin-5 when co-cultured with ASCs. Local delivery of ASCs into the salivary gland, using in situ-forming hyaluronic acid-based hydrogel (HA gel) as a carrier, revealed that ASCs remained at the injection site for a longer duration, compared with ASCs that were injected without HA gel. The salivary gland exhibited better function and morphology when ASCs were injected using an HA gel. In conclusion, retention of locally delivered ASCs by HA gels can enhance the paracrine effect of ASCs, thereby preventing irradiation-induced damage to the salivary gland and subsequent dysfunction.

Purpose This study was aim to evaluate the patterns of failure according to radiotherapy (RT) target volume for cervical lymph nodes in metastases of unknown primary origin in head and neck region (HNMUO). Materials and Methods Sixty-two patients with HNMUO between 1998 and 2016 were retrospectively reviewed. We analyzed the clinical outcomes and primary site failure depending on the radiation target volume. The target volume was classified according to whether the potential head and neck mucosal sites were included and whether the neck node was treated involved side only or bilaterally. Results Potential mucosal site RT (mucosal RT) was done to 23 patients and 39 patients did not receive mucosal RT. Mucosal RT showed no significant effect on overall survival (OS) and locoregional recurrence (LRR). The location of primary site failure encountered during follow-up period was found to be unpredictable and 75% of patients with recurrence received successful salvage therapies. No significant differences in OS and LRR were found between patients treated to unilateral (n = 35) and bilateral neck irradiation (n = 21). Treatment of both necks resulted in significantly higher mucositis. conclusions We found no advantages in OS and LRR of patients with HNMUO when mucosal sites and bilateral neck node were included in the radiation target volume.

The performance of a visual guidance patient-controlled (VG-PC) respiratory gating system for magnetic-resonance (MR) image-guided radiation therapy (MR-IGRT) was evaluated through a clinical trial of patients with either lung or liver cancer. Patients can voluntarily control their respiration utilizing the VG-PC respiratory gating system. The system enables patients to view near-real-time cine planar MR images projected inside the bore of MR-IGRT systems or an external screen. Twenty patients who had received stereotactic ablative radiotherapy (SABR) for lung or liver cancer were prospectively selected for this study. Before the first treatment, comprehensive instruction on the VG-PC respiratory gating system was provided to the patients. Respiratory-gated MR-IGRT was performed for each patient with it in the first fraction and then without it in the second fraction. For both the fractions, the total treatment time, beam-off time owing to the respiratory gating, and number of beam-off events were analyzed. The average total treatment time, beam-off time, and number of beam-off events with the system were 1507.3 s, 679.5 s, and 185, respectively, and those without the system were 2023.7 s (p 0.001), 1195.0 s (p 0.001), and 380 times (p 0.001), respectively. The VG-PC respiratory gating system improved treatment efficiency through a reduction in the beam-off time, the number of beam-off events, and consequently the total treatment time when performing respiratory-gated MR-IGRT for lung and liver SABR.

Background The purpose of this study was to compare the treatment efficacy and safety of re-irradiation (re-RT) using stereotactic ablative radiotherapy (SABR) and initial SABR for primary, recurrent lung cancer or metastatic lung tumor. Methods A retrospective review of the medical records of 336 patients who underwent lung SABR was performed. Re-RT was defined as the overlap of the 70% isodose line of second-course SABR with that of the initial radiotherapy, and 20 patients were classified as the re-RT group. The median dose of re-RT using SABR was 54 Gy (range 48–60 Gy), and the median fraction number was 4 (range 4–6). One-to-three case-matched analysis with propensity score matching was used, and 60 patients were included in the initial SABR group of the matched cohort. Results The 1- and 2-year local control rates for the re-RT group were 73.9% and 63.3% and those for the initial SABR group in the matched cohort were 92.9% and 87.7%, respectively (P = 0.013). There was no difference in distant metastasis-free, progression-free, and overall survival rates. The crude grade ≥ 2 toxicity rates were 40.0% for the re-RT group and 25.0% for the initial SABR group (P = 0.318). Re-RT group had higher acute grade ≥ 2 toxicity rates (25.0% vs 5.0%, P = 0.031). One incident of grade 3 toxicity (pulmonary) was reported in the re-RT group; there was no grade 4‒5 toxicity. Conclusions The local control rate of the in-field re-RT SABR was lower than that of the initial SABR without compromising the survival rates. The toxicity of re-RT using SABR was acceptable.

Background Long-term side effects after radiotherapy for organ preservation ‘could deteriorate’ the laryngeal function. This study intended to identify the incidence of severe late dysphagia following the multimodal treatment for stage III/IV laryngeal and hypopharyngeal cancer ‘to evaluate the function of larynx’. Methods The medical records of patients successfully treated for laryngeal and hypopharyngeal cancer with a multimodal approach, including radiotherapy, were retrospectively analyzed. ‘Functional larynx was defined as tolerable oral diet without severe late dysphagia or tracheostoma’. Results The study included 99 patients with a median follow-up period of 72 months. ‘Tracheostomy during the follow-up period was required in only one patient due to aspiration pneumonia, and dysphagia is the main determinant for functional larynx’. The probability of maintaining functional larynx was 63% for 10 years, when the treatment was started with radiotherapy or concurrent chemoradiotherapy. In upfront surgery (operation first and adjuvant radiotherapy/concurrent chemoradiotherapy) group, 37% of patients required total laryngectomy as primary treatment and 43% of patients could maintain laryngeal function for 10 years. And severe late dysphagia in the latter group developed mainly after laryngeal preservation surgery. The patients aged ≥65 years showed significantly higher incidence of dysphagia. Severe late dysphagia was very rare in laryngeal cancer successfully cured with radiotherapy/concurrent chemoradiotherapy (1/25, 4%); however, it gradually increased over time in hypopharyngeal cancer patients showing a statistically significant difference from laryngeal cancer patients (P = 0.040). Conclusion Severe late dysphagia occurred in 19.2% of patients treated for laryngeal and hypopharyngeal cancers, regardless of whether treatment started with radiotherapy/concurrent chemoradiotherapy or surgery.

Background/Aims: Since patients with human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) have favorable outcomes after treatment, treatment de-escalation for these patients is being actively investigat ed. However, not all HPV-positive HNSCCs are curable, and some patients have a poor prognosis. The purpose of this study was to identify poor prognostic factors in patients with HPV-positive HNSCC. Methods: Patients who received a diagnosis of HNSCC and tested positive for HPV from 2000 to 2015 at a single hospital site (n = 152) were included in this ret rospective analysis. HPV typing was conducted using the HPV DNA chip assay or liquid bead microarray system. Expression of p16 in the tumors was assessed by immunohistochemistry. To determine candidate factors associated with overall survival (OS), univariate and multivariable Cox regression analyses were per formed. Results: A total of 152 patients with HPV-positive HNSCC were included in this study; 82.2% were male, 43.4% were current or former smokers, and 84.2% had oropharyngeal cancer. By univariate analysis, old age, performance status ≥ 1, non-oropharyngeal location, advanced T classification (T3-4), and HPV genotype 18 were significantly associated with poor OS. By multivariable analysis, perfor mance status ≥ 1 and non-oropharyngeal location were independently associated with shorter OS (hazard ratio [HR], 4.36, p = 0.015; HR, 11.83, p = 0.002, respective ly). Furthermore, HPV genotype 18 positivity was also an independent poor prog nostic factor of OS (HR, 10.87, p < 0.001). Conclusions: Non-oropharyngeal cancer, poor performance status, and HPV gen otype 18 were independent poor prognostic factors in patients with HPV-positive HNSCC. Patients with these risk factors might not be candidates for de-escalation treatment.

Purpose We first analyzed the prognostic power of albumin-to-alkaline phosphatase ratio (AAPR) before radical radiotherapy (RT) in non-metastatic nasopharyngeal carcinoma (NPC) patients. Materials and methods The records of 170 patients with biopsy-proven, non-metastatic NPC treated by radical RT between 1998 and 2016 at our institution were retrospectively reviewed. Median follow-up duration was 50.6 months. All patients received intensity-modulated RT and cisplatin based chemotherapy before, during, or after RT. The major treatment of patients was based on concurrent chemoradiotherapy (92.4%). The AAPR was calculated by the last value of both albumin and alkaline phosphatase within 1 month immediately preceding RT. The optimal cut-off level of AAPR was determined by using Cutoff Finder, a web-based system. Propensity score matching (PSM) analysis was performed. Results The optimal cut-off level of AAPR was 0.4876. After PSM analysis of whole cohort, an AAPR was not related to survival outcomes. In PSM analysis for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC), an AAPR ≥ 0.4876 was related to better overall survival (OS), progression-free survival (PFS), and locoregional relapse-free survival (LRRFS) (OS: hazard ratio [HR], 0.341; 95% confidence interval [CI], 0.144 to 0.805; p=0.014; PFS: HR, 0.416; 95% CI, 0.189 to 0.914; p=0.029; and LRRFS: HR, 0.243; 95% CI, 0.077 to 0.769; p=0.016, respectively). Conclusion The AAPR, inexpensive and readily derived from a routine blood test, could be an independent prognostic factor for patients with LA-NPC. And it might help physicians determine treatment plans by identifying the patient's current status. Future prospective clinical trials to validate its prognostic value are needed.

Purpose The early results of a phase 1 study of stereotactic ablative radiation therapy for early-stage glottis cancer were previously reported. However, additional late adverse events occurred in the second arm during the follow-up period. In this study, the dose-limiting toxicities and premature closure of the clinical trial are reported. Methods and Materials Thirteen patients with cT1-2N0M0 squamous cell carcinoma of the glottis were enrolled between May 2015 and July 2018. Seven patients in the first arm received 59.5 Gy to the gross tumor volume and 47.6 Gy to the remaining larynx, delivered in 17 fractions. The second arm dose was 55 Gy and 40.7 Gy in 11 fractions to the gross tumor volume and the remaining larynx, respectively. Patients were treated according to the simultaneous integrated boost approach with volumetric modulated arc therapy. Results The median follow-up was 37 months (range, 6-41.4) for the first arm and 14.5 months (range, 4.8-21.5) for the second arm. Maximum acute toxicity was grade 2 laryngeal mucositis for each arm. Maximum chronic toxicity was grade 3 laryngeal inflammation, occurring in 2 patients (33.3%) in the second arm. One patient underwent a laryngomicrosurgical biopsy for a vocal cord ulcer, and another patient underwent supraglottic laryngectomy because of arytenoid cartilage necrosis. In the first arm, chronic toxicity was not observed, except for grade 1 laryngeal edema in 1 patient. Conclusions The phase 1 dose escalation study was terminated early because of the unexpected dose-limiting toxicities occurring in patients in the second arm. It was concluded that stereotactic ablative radiation therapy is not feasible for early-stage glottic cancer owing to treatment-related toxicity.

Background The aim of this study was to compare the plan quality of magnetic-resonance image-based intensity modulated radiation therapy (MRI-based-IMRT) with the MRIdian Linac system to that of volumetric modulated arc therapy (VMAT) with the TrueBeam STx system for lung stereotactic ablative radiotherapy (SABR). Methods A total of 22 patients with tumors located in the lower lobe were retrospectively selected for the study. For each patient, both the MRI-based-IMRT and VMAT plans were generated using an identical CT image set and identical structures with the exception of the planning target volume (PTV). The PTVs of the MRI-based-IMRT were generated by adding an isotropic margin of 3 mm from the gross tumor volume, whereas those of VMAT were generated by adding an isotropic margin of 5 mm from the internal target volume. For both the MRI-based-IMRT and VMAT, the prescription doses to the PTVs were 60 Gy in four fractions. Results The average PTV volume of the MRI-based-IMRT was approximately 4-times smaller than that of VMAT (p