Clinical course of longer than five years after definitive radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: This study aimed to reveal the long-term outcomes and late toxicities (> 5 years) after definitive intensity-modulated radiation therapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). METHODS: Data from 43 patients (median age, 55 years; range, 17-72 years) with NPC who underwent definitive IMRT between 2001 and 2018 were analyzed. All patients were alive and disease-free 5 years after IMRT. A total dose of 70 (range, 66-70) Gy was delivered in 35 (33-35) fractions with concurrent cisplatin chemotherapy. RESULTS: The median follow-up duration was 119 (range, 61.5-242.1) months. Three patients developed locoregional failure at 79, 92, and 149 months after IMRT, respectively. Of these, 2 patients died of disease progression at 136 and 153 months after IMRT. One patient died of aspiration pneumonia 141 months after IMRT, despite salvage of the recurrent tumor by re-irradiation. In addition, one patient died of aspiration pneumonia 62 months after the IMRT. Thus, the 10-year overall survival, progression-free survival, and locoregional control rates were 98%, 92%, and 94%, respectively. Grade ≥ 2 and ≥ 3 late toxicities were observed in 28 (65%) and 9 (21%) patients, respectively. Nine second primary cancers, including five tongue cancers and two external auditory canal carcinomas, were observed in seven (16%) patients. CONCLUSION: Late recurrences, severe late toxicities, and second primary cancers were observed > 5 years after IMRT. A long-term follow-up of > 5 years is needed in patients with NPC.

External beam radiotherapy combination is a risk factor for bladder cancer in patients with prostate cancer treated with brachytherapy.

PURPOSE: To investigate the risk of bladder cancer (BCa) in patients treated with brachytherapy for prostate cancer (PCa). METHODS: We retrospectively analyzed 583 patients with PCa who underwent brachytherapy with or without external beam radiotherapy (EBRT). We analyzed the disease-free survival (DFS) of BCa in patients with PCa who underwent brachytherapy with or without EBRT. We performed multivariate Cox regression analyses of DFS using age, EBRT, and Brinkman index (BI) score (number of cigarettes smoked per day × number of years smoking) ≥ 200 as variables for BCa after brachytherapy. RESULTS: Fourteen patients (2.4%) developed BCa after brachytherapy with or without EBRT. The percentage of high-grade urothelial carcinoma (UC) was 63.6%. A total of 85.7% of patients had non-muscle invasive BCa, and 14.3% of patients had muscle invasive BCa. DFS was longer in brachytherapy monotherapy than in combination therapy (brachytherapy + EBRT). Multivariate Cox regression analysis showed that a BI score ≥ 200 (Hazard Ratio (HR 8.61; 95% Confidence Interval (CI) 1.12-65.98) and EBRT combination (HR 3.29; 95% CI 1.03-10.52) were significantly associated with BCa development in patients with PCa treated with brachytherapy. Furthermore, patients with BI score ≥ 200 and EBRT combination had a significantly higher risk of BCa compared with patients with BI score < 200 (HR Log-rank test P = 0.010). CONCLUSION: Most cases of BCa after brachytherapy with or without EBRT are high grade and invasive. We hypothesized that the EBRT combination might be a risk factor for BCa in patients with PCa who underwent brachytherapy.

Impact of rectal gas on the planning target volume margin for pelvic bone and prostate matching in prostate cancer patients receiving volumetric-modulated arc therapy.

We performed daily cone-beam computed tomography (CBCT) to determine the impact of rectal gas on the movements of prostate and seminal vesicles (SVs). We aimed to determine the relationship between planning target volume (PTV) margins and rectal gas. In 30 treatments of 15 prostate cancer patients, excessive rectal gas was removed and CBCT images were analyzed. Image registration between planning CT and daily CBCT images before and after rectal gas removal was performed for pelvic bone and prostate matching. The couch movement distance between each matching was considered the prostate movement. In addition, we measured SV tip movement between each matching. The anterior-posterior movement of the prostate before rectal gas removal (3.1 ± 2.9 mm) was significantly greater than that after rectal gas removal (1.2 ± 1.2 mm; p < 0.01). The left-right and superior-inferior movements were similar regardless of the presence or absence of rectal gas. The SV movement distances before and after rectal gas removal were 11.0 ± 5.8 mm and 4.6 ± 3.8 mm, respectively (p < 0.01), in pelvic bone matching, and 8.0 ± 4.2 mm and 3.8 ± 3.2 mm, respectively (p < 0.01), in prostate matching. After rectal gas removal, the SV position did not differ significantly between each matching. In 26 of the 30 treatments, SV movement distance in the presence of rectal gas was >6 mm, which is the minimum PTV margin at our institution. In comparison, after rectal gas removal and prostate matching, only 6 treatments demonstrated an SV movement distance of >6 mm. In the presence of rectal gas, the SVs require greater PTV margins than the prostate. Rectal gas removal should be considered if the movement distance on prostate matching is greater than the minimum PTV margin at treating institution.

Visualization of tumor hypoxia and re-oxygenation after stereotactic body radiation therapy in early peripheral lung cancer: A prospective study.

BACKGROUND AND PURPOSE: In this study, fluoromisonidazole positron emission tomography (F-MISO PET/CT) was used to evaluate tumor hypoxia and re-oxygenation in patients with lung tumors treated with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: Patients with T1-2 N0 lung cancer were included in this study. The prescribed dose was 48-52 Gy in four fractions. F-MISO PET/CT was performed twice, before SBRT and 1-3 days after the first irradiation. The maximum standardized uptake value (SUVmax) and tumor/muscle ratio (TMR) were evaluated as indicators of hypoxia. The threshold for hypoxia was defined as a TMR of 1.30 or more. RESULTS: Between 2016 and 2021, 15 patients were included. Pre-treatment tumor hypoxia was observed in nine tumors (60 %). TMR in all six tumors without pre-treatment hypoxia rose after single high-dose irradiation. In contrast, TMR in six of nine tumors with pre-treatment hypoxia dropped after irradiation, suggesting re-oxygenation. Although no local recurrence was noted, regional and/or distant relapses were seen in four patients (27 %). Of these, three had tumors with abnormal F-MISO uptake. The remaining patient had a tumor without signs of hypoxia on pre-treatment PET/CT. The 2-year progression free survival of patients with tumors with and without pre-treatment hypoxia were 30 % and 63 %, respectively (p = 0.319). CONCLUSION: Tumor hypoxia reduced after single high-dose irradiation. Tumor with F-MISO uptake seems to be an unfavorable prognostic factor in lung SBRT.

Recurrence patterns and progression-free survival after chemoradiotherapy with or without consolidation durvalumab for stage III non-small cell lung cancer.

Chemoradiotherapy followed by consolidation durvalumab (CCRT+D) improves survival in patients with stage III non-small-cell lung cancer (NSCLC). We compared recurrence patterns and survival in the CCRT+D and CCRT cohorts. We conducted a multicenter, retrospective study in Japan. Patients who received CCRT for stage III NSCLC were included in this study. Of 178 eligible patients, 136 were in the CCRT+D and 42 were in the CCRT cohorts. Locoregional recurrence (LR), LR plus distant metastases (DM), and DM were observed in 20.6%, 8.8%, 27.9% of the CCRT+D, and 26.2%, 16.7% and 33.3% of the CCRT cohorts, respectively. In-field recurrence was the most common LR pattern in both cohorts. Squamous cell carcinoma and PD-L1 expression < 1%, and female sex and EGFR mutations were significantly associated with an increased risk of LR and DM. In patients with any risk factors for LR, the incidence of LR was similar in the CCRT+D and CCRT (39.5% vs 45.5%). The 24 month progression-free survival (PFS) and overall survival (OS) were 40.3% and 69.4% in the CCRT+D and 24.7% and 61.0% in the CCRT cohorts, respectively. Poor performance status and no consolidation durvalumab were significantly associated with shorter PFS. There was a significant difference in PFS between the CCRT+D and CCRT in the propensity score-matched cohort (HR = 0.51, P = 0.005). In conclusion, consolidation durvalumab decreased both LR and DM, and significantly improved PFS. However, in-field recurrence was still a major problem, as well as DM.

Difference in failure patterns after stereotactic body radiotherapy for lung cancer according to clinical T stage based on 4D computed tomography.

PURPOSE: Stereotactic body radiotherapy (SBRT) is a treatment option for early-stage lung cancer. We aimed to examine the differences in failure patterns after SBRT according to the clinical T stage. METHODS: A total of 120 patients with early-stage lung cancer (T1-3N0M0) who underwent SBRT were analysed. The clinical stage in patients whose tumours were in contact with the chest wall was confirmed using four-dimensional computed tomography (4D-CT). Local failure, regional node metastasis, and distant metastasis were confirmed from clinical charts. RESULTS: Median follow-up time was 27.5 months (range 7-122) after SBRT. Thirteen patients were restaged from clinical T2 with visceral pleural invasion to T3 with chest wall invasion using 4D-CT analysis. Thirty-seven patients developed recurrences. The median progression-free survival (PFS) and overall survival (OS) were 38.1 and 53.8 months, respectively. The 3­year PFS and OS rates were 50.7% and 60.3%, respectively. A significant difference was observed in PFS according to the clinical T stage (p = 0.001). No significant differences were observed in OS according to the clinical T stage (p = 0.213). The proportion of locoregional failures relative to distant metastasis decreased with progression from T1 to T3. The pleural dissemination rate was significantly higher in T3 tumours than in T1 and T2 tumours (p = 0.010). CONCLUSION: Clinical T stage is associated with PFS after SBRT for lung cancer. There were differences in the failure patterns according to T stage. 4D-CT might provide significant information for assessing chest wall invasion associated with unfavourable PFS.

Impact of Knowledge-based Plan Model Improvement on Plan Complexity and Deliverability in VMAT For Prostate Cancer: A Multi-institutional Study.

BACKGROUND/AIM: This study evaluated the impact of knowledge-based plan (KBP) model improvement on plan complexity and delivery accuracy in volumetric modulated arc therapy (VMAT) for prostate cancer at multiple institutions. MATERIALS AND METHODS: Five institutions created the first KBP model before April 2017 and subsequently devised a new model (second model) based on feedback from the first KBP and the efforts of planners after April 2019. The dose-volume histogram (DVH) parameters were validated for two prostate cancer cases between the first and second KBPs. Plan complexity metrics, of the modulation complexity score for VMAT (MCSv), closed leaf score (CLS), small aperture score (SAS), and leaf travel (LT), were compared. The delivery accuracy metrics of γ pass rate and point dose discrepancy (plan vs. measurement) at isocenter were also compared. RESULTS: There were no significant differences in DVH parameters between the KBPs. Conversely, V50% of the rectum and bladder was reduced in 6/10 and 8/10 patients, respectively, and these variations were also converged from the first KBP to the second KBP. The mean±1SDs of MCSv, CLS, SAS20mm, and LT (first KBP vs. second KBP) were 0.27±0.033 vs. 0.26±0.044, 0.062±0.032 vs. 0.14±0.091, 0.59±0.048 vs. 0.70±0.14, and 411.91±32.08 mm vs. 548.33±127.50 mm, respectively. The delivery accuracy did not differ, whereas MCSv was moderately correlated with the point dose discrepancy. CONCLUSION: Multi-leaf collimator motion could be more complex with KBP model improvement, which had the potential to deteriorate the delivery accuracy.

Multi-institution model (big model) versus single-institution model of knowledge-based volumetric modulated arc therapy (VMAT) planning for prostate cancer.

We established a multi-institution model (big model) of knowledge-based treatment planning with over 500 treatment plans from five institutions in volumetric modulated arc therapy (VMAT) for prostate cancer. This study aimed to clarify the efficacy of using a large number of registered treatment plans for sharing the big model. The big model was created with 561 clinically approved VMAT plans for prostate cancer from five institutions (A: 150, B: 153, C: 49, D: 60, and E: 149) with different planning strategies. The dosimetric parameters of planning target volume (PTV), rectum, and bladder for two validation VMAT plans generated with the big model were compared with those from each institutional model (single-institution model). The goodness-of-fit of regression lines (R2 and χ2 values) and ratios of the outliers of Cook's distance (CD) > 4.0, modified Z-score (mZ) > 3.5, studentized residual (SR) > 3.0, and areal difference of estimate (dA) > 3.0 for regression scatter plots in the big model and single-institution model were also evaluated. The mean ± standard deviation (SD) of dosimetric parameters were as follows (big model vs. single-institution model): 79.0 ± 1.6 vs. 78.7 ± 0.5 (D50) and 0.13 ± 0.06 vs. 0.13 ± 0.07 (Homogeneity Index) for the PTV; 6.6 ± 4.0 vs. 8.4 ± 3.6 (V90) and 32.4 ± 3.8 vs. 46.6 ± 15.4 (V50) for the rectum; and 13.8 ± 1.8 vs. 13.3 ± 4.3 (V90) and 39.9 ± 2.0 vs. 38.4 ± 5.2 (V50) for the bladder. The R2 values in the big model were 0.251 and 0.755 for rectum and bladder, respectively, which were comparable to those from each institution model. The respective χ2 values in the big model were 1.009 and 1.002, which were closer to 1.0 than those from each institution model. The ratios of the outliers in the big model were also comparable to those from each institution model. The big model could generate a comparable VMAT plan quality compared with each single-institution model and therefore could possibly be shared with other institutions.

Multi-institutional feasibility study of intensity-modulated radiotherapy with chemotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: This multi-institutional clinical trial evaluated the feasibility of intensity-modulated radiotherapy (IMRT) for patients with locally advanced non-small cell lung cancer (NSCLC). METHODS: The major inclusion criteria were clinical stage III NSCLC, age 20-74 years, and Eastern Cooperative Oncology Group performance status 0-1. Patients were treated with either cisplatin + S-1 (CS; four cycles every 4 weeks) or carboplatin + paclitaxel (CP; administered weekly with thoracic radiotherapy [RT], plus two consolidation cycles) concurrently with IMRT (60 Gy in 30 fractions). The primary endpoint was a treatment completion rate, defined as at least two cycles of CS or five cycles of CP during IMRT and completing 60 Gy IMRT within 56 days after the start of treatment, assumed its 90% confidence interval exceeds 60%. RT quality assurance was mandatory for all the patients. RESULTS: Twenty-two patients were registered. One patient withdrew due to pulmonary infection before starting treatment. RT plans were reviewed and none was judged as a protocol violation. Grade 2 and 3 pneumonitis occurred in four (19%) and one (5%) patients, respectively. Seventeen patients met the primary endpoint, with a treatment completion rate of 77.3% (90% confidence interval [CI] 58.0%-90.6%). Four patients failed to complete chemotherapy due to chemotherapy-related adverse events, but 20 patients completed IMRT. There were no treatment-related deaths. The 2-year progression-free and overall survival rates were 31.8% (95% CI 17.3%-58.7%) and 77.3% (95% CI 61.6%-96.9%), respectively. CONCLUSION: The treatment completion rate did not meet the primary endpoint, but 20 of 22 patients completed IMRT.

Escalated Maximum Dose in the Planning Target Volume Improves Local Control in Stereotactic Body Radiation Therapy for T1-2 Lung Cancer.

Stereotactic body radiotherapy (SBRT) is a treatment option for early-stage lung cancer. The purpose of this study was to investigate the optimal dose distribution and prognostic factors for local control (LC) after SBRT for lung cancer. A total of 104 lung tumors from 100 patients who underwent SBRT using various treatment regimens were analyzed. Dose distributions were corrected to the biologically effective dose (BED). Clinical and dosimetric factors were tested for association with LC after SBRT. The median follow-up time was 23.8 months (range, 3.4-109.8 months) after SBRT. The 1- and 3-year LC rates were 95.7% and 87.7%, respectively. In univariate and multivariate analyses, pathologically confirmed squamous cell carcinoma (SQ), T2 tumor stage, and a Dmax < 125 Gy (BED10) were associated with worse LC. The LC rate was significantly lower in SQ than in non-SQ among tumors that received a Dmax < 125 Gy (BED10) (p = 0.016). However, there were no significant differences in LC rate between SQ and non-SQ among tumors receiving a Dmax ≥ 125 Gy (BED10) (p = 0.198). To conclude, SQ, T2 stage, and a Dmax < 125 Gy (BED10) were associated with poorer LC. LC may be improved by a higher Dmax of the planning target volume.

Risk factors for radiation pneumonitis after rotating gantry intensity-modulated radiation therapy for lung cancer.

The risk factors for severe radiation pneumonitis (RP) in patients with lung cancer who undergo rotating gantry intensity-modulated radiation therapy (IMRT) using volumetric modulated arc therapy (VMAT) or helical tomotherapy (HT) are poorly understood. Fifty-two patients who received rotating gantry IMRT for locally advanced lung cancer were included in this retrospective study. In total, 31 and 21 patients received VMAT and HT, respectively. The median follow-up duration was 14 months (range, 5.2-33.6). Twenty (38%) and eight (15%) patients developed grade ≥ 2 and ≥ 3 RP, respectively. In multivariate analysis, lung V5 ≥ 40% was associated with grade ≥ 2 RP (P = 0.02), and past medical history of pneumonectomy and total lung volume ≤ 3260 cc were independently associated with grade ≥ 3 RP (P = 0.02 and P = 0.03, respectively). Rotating gantry IMRT was feasible and safe in patients with lung cancer undergoing definitive radiotherapy. Reducing lung V5 may decrease the risk of symptomatic RP, and care should be taken to avoid severe RP after radiotherapy in patients with a past medical history of pneumonectomy and small total lung volume.

Difference in VMAT dose distribution for prostate cancer with/without rectal gas removal and/or adaptive replanning.

We investigated differences in the volumetric-modulated arc therapy (VMAT) dose distribution in prostate cancer patients treated by rectal gas removal and/or adaptive replanning. Cone-beam computed tomography (CBCT) scans were performed daily for 22 treatments in eight prostate cancer patients with excessive rectal gas, and the CBCT images were analyzed. Rectal gas removal was performed, and irradiation was delivered after prostate matching. We compared dose-volume histograms for the daily CBCT images before and after rectal gas removal. Plan A was the original plan on CBCT images before rectal gas removal. Plan B was a single reoptimized plan on CBCT images before rectal gas removal. Plan C was the original plan on CBCT images after rectal gas removal. Plan D was a single reoptimized plan on CBCT images after rectal gas removal. D95 of the planning target volume (PTV) minus the rectum of Plan C (94.7% ± 6.6%) was significantly higher than that of Plan A (88.5% ± 10.4%). All dosimetric parameters of Plan C were improved by rectal gas removal compared with Plan A, regardless of the initial rectal gas volume. Dosimetric parameters of PTV minus the rectum of Plan B were significantly improved compared with Plan C. Additionally, the V78 of the rectal wall of Plan B (0.2% ± 0.5%) was significantly improved compared with Plan C (3.9% ± 6.3%, p = 0.003). The dosimetric parameters of Plan D were not significantly different from Plan B. The dose distribution of prostate VMAT was improved by rectal gas removal and/or adaptive replanning. An adaptive replanning on daily CBCT images might be a better method than rectal gas removal for prostate cancer patients with excessive rectal gas.

An updating approach for knowledge-based planning models to improve plan quality and variability in volumetric-modulated arc therapy for prostate cancer.

PURPOSE: The purpose of this study was to compare the dose-volume parameters and regression scatter plots of the iteratively improved RapidPlan (RP) models, specific knowledge-based planning (KBP) models, in volumetric-modulated arc therapy (VMAT) for prostate cancer over three periods. METHODS: A RP1 model was created from 47 clinical intensity-modulated radiation therapy (IMRT)/VMAT plans. A RP2 model was created to exceed dosimetric goals which set as the mean values +1SD of the dose-volume parameters of RP1 (50 consecutive new clinical VMAT plans). A RP3 model was created with more strict dose constraints for organs at risks (OARs) than RP1 and RP2 models (50 consecutive anew clinical VMAT plans). Each RP model was validated against 30 validation plans (RP1, RP2, and RP3) that were not used for model configuration, and the dose-volume parameters were compared. The Cook's distances of regression scatterplots of each model were also evaluated. RESULTS: Significant differences (p < 0.05) between RP1 and RP2 were found in Dmean (101.5% vs. 101.9%), homogeneity index (3.90 vs. 4.44), 95% isodose conformity index (1.22 vs. 1.20) for the target, V40Gy (47.3% vs. 45.7%), V60Gy (27.9% vs. 27.1%), V70Gy (16.4% vs. 15.2%), and V78Gy (0.4% vs. 0.2%) for the rectal wall, and V40Gy (43.8% vs. 41.8%) and V70Gy (21.3% vs. 20.5%) for the bladder wall, whereas only V70Gy (15.2% vs. 15.8%) of the rectal wall differed significantly between RP2 and RP3. The proportions of cases with a Cook's distance of <1.0 (RP1, RP2, and RP3 models) were 55%, 78%, and 84% for the rectal wall, and 77%, 68%, and 76% for the bladder wall, respectively. CONCLUSIONS: The iteratively improved RP models, reflecting the clear dosimetric goals based on the RP feedback (dose-volume parameters) and more strict dose constraints for the OARs, generated superior dose-volume parameters and the regression scatterplots in the model converged. This approach could be used to standardize the inverse planning strategies.

Dosimetric Evaluation of Simplified Knowledge-Based Plan with an Extensive Stepping Validation Approach in Volumetric-Modulated Arc Therapy-Stereotactic Body Radiotherapy for Lung Cancer.

PURPOSE: We investigated the performance of the simplified knowledge-based plans (KBPs) in stereotactic body radiotherapy (SBRT) with volumetric-modulated arc therapy (VMAT) for lung cancer. MATERIALS AND METHODS: For 50 cases who underwent SBRT, only three structures were registered into knowledge-based model: total lung, spinal cord, and planning target volume. We performed single auto-optimization on VMAT plans in two steps: 19 cases used for the model training (closed-loop validation) and 16 new cases outside of training set (open-loop validation) for TrueBeam (TB) and Halcyon (Hal) linacs. The dosimetric parameters were compared between clinical plans (CLPs) and KBPs: CLPclosed, KBPclosed-TB and KBPclosed-Hal in closed-loop validation, CLPopen, KBPopen-TB and KBPopen-Hal in open-loop validation. RESULTS: All organs at risk were comparable between CLPs and KBPs except for contralateral lung: V5 of KBPs was approximately 3%-7% higher than that of CLPs. V20 of total lung for KBPs showed comparable to CLPs; CLPclosed vs. KBPclosed-TB and CLPclosed vs. KBPclosed-Hal: 4.36% ± 2.87% vs. 3.54% ± 1.95% and 4.36 ± 2.87% vs. 3.54% ± 1.94% (P = 0.54 and 0.54); CLPopen vs. KBPopen-TB and CLPopen vs. KBPopen-Hal: 4.18% ± 1.57% vs. 3.55% ± 1.27% and 4.18% ± 1.57% vs. 3.67% ± 1.26% (P = 0.19 and 0.27). CI95 of KBPs with both linacs was superior to that of the CLP in closed-loop validation: CLPclosed vs. KBPclosed-TB vs. KBPclosed-Hal: 1.32% ± 0.12% vs. 1.18% ± 0.09% vs. 1.17% ± 0.06% (P < 0.01); and open-loop validation: CLPopen vs. KBPopen-TB vs. KBPopen-Hal: 1.22% ± 0.09% vs. 1.14% ± 0.04% vs. 1.16% ± 0.05% (P ≤ 0.01). CONCLUSIONS: The simplified KBPs with limited number of structures and without planner intervention were clinically acceptable in the dosimetric parameters for lung VMAT-SBRT planning.

Serum lactate dehydrogenase is a predictive biomarker in patients with oropharyngeal cancer undergoing radiotherapy: Retrospective study on predictive factors.

BACKGROUND: The present study aimed to evaluate the prognostic factors in human papillomavirus (HPV)-positive and HPV-negative oropharyngeal cancer (OPC) treated with definitive radiotherapy. METHODS: We retrospectively evaluated 101 patients with OPC who underwent definitive radiotherapy between 2008 and 2018. RESULTS: The median follow-up period of the surviving patients was 68 months (range, 8-164 months). The 5-year overall survival rate was 69.8%. Univariate analyses revealed that poor survival was associated with male sex, smoking ≥30 pack-years, Eastern Cooperative Oncology Group performance status ≥1, tumor-node-metastasis (TNM) stage III-IV (8th edition), HPV-negativity, serum lactate dehydrogenase (LDH) ≥202, C-reactive protein/albumin ratio ≥0.15, and lymphocyte-to-monocyte ratio <2.90. In multivariate analyses, poor survival was independently correlated with smoking ≥30 pack-years (p < 0.01) and LDH ≥202 (p = 0.02). CONCLUSIONS: The present study suggested that high LDH levels predicted poor survival after definitive radiotherapy for patients with both HPV-positive and HPV-negative OPC.

Phase II Study of Neoadjuvant Concurrent Chemo-immuno-radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage IIIA-B (Discrete N2) Non-small-cell Lung Cancer: SQUAT trial (WJOG 12119L).

INTRODUCTION: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069). PATIENTS AND METHODS: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%. CONCLUSION: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.

Incidence and Risk Factors of Symptomatic Radiation Pneumonitis in Non-Small-Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy and Consolidation Durvalumab.

INTRODUCTION: Data on the risk factors for symptomatic radiation pneumonitis (RP) in non-small-cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) and consolidation durvalumab are limited; we aimed to investigate these risk factors. MATERIALS AND METHODS: This multicenter retrospective study, conducted at 15 institutions in Japan, included patients who were ≥20 years of age; who started definitive CCRT for NSCLC between July 1, 2018, and July 31, 2019; and who then received durvalumab. The primary endpoint was grade 2 or worse (grade 2+) RP. RESULTS: In the 146 patients analyzed, the median follow-up period was 16 months. A majority of the patients had stage III disease (86%), received radiation doses of 60 to 66 Gy equivalent in 2-Gy fractions (93%) and carboplatin and paclitaxel/nab-paclitaxel (77%), and underwent elective nodal irradiation (71%) and 3-dimensional conformal radiotherapy (75%). RP grade 2 was observed in 44 patients (30%); grade 3, in four patients (3%); grade 4, in one patient (1%); and grade 5, in one patient (1%). In the multivariable analysis, lung V20 was a significant risk factor, whereas age, sex, smoking history, irradiation technique, and chemotherapy regimen were not. The 12-month grade 2+ RP incidence was 34.4% (95% confidence interval [CI], 26.7%-42.1%); the values were 50.0% (95% CI, 34.7%-63.5%) and 27.1% (95% CI, 18.8%-36.2%) in those with lung V20 ≥ 26% and < 26%, respectively (P = .007). CONCLUSION: The incidence of grade 2+ RP was relatively high in this multicenter real-world study, and its risk increased remarkably at elevated lung V20. Our findings can aid in RP risk prediction and the safe radiotherapy treatment planning.

[Impact of Aperture Shape Controller on Knowledge-based VMAT Planning of Prostate Cancer].

PURPOSE: Knowledge-based planning (KBP) has disadvantages of high monitor unit (MU) and complex multi-leaf collimator (MLC) motion. We investigated the optimal aperture shape controller (ASC) level for the KBP to reduce these factors in volumetric modulated arc therapy (VMAT) for prostate cancer. METHODS: The KBP model was created based on 51 clinical plans (CPs) of patients who underwent the VMAT for prostate cancer. Another 10 CPs were selected randomly, and the KBPs with/without ASC, changed stepwise from very low (KBP-VL) to very high (KBP-VH), were performed with a single auto-optimization. The parameters of dose-volume histograms (DVHs) and MLC performance metrics were evaluated. We obtained the modulation complexity score for VMAT (MCSv), closed leaf score (CLS), small aperture score (SAS), leaf travel (LT), and total MU. RESULTS: The ASC did not affect the DVH parameters negatively. The following comparisons of MLC performance were obtained (KBP vs. KBP-VL vs. KBP-VH, respectively): 0.25 vs. 0.27 vs. 0.30 (MCSv), 0.19 vs. 0.18 vs. 0.16 (CLS), 0.50 vs. 0.45 vs. 0.40 (SAS10 mm), 0.73 vs. 0.68 vs. 0.63 (SAS20 mm), 768.35 mm vs. 671.50 mm vs. 551.32 mm (LT), and 672.87 vs. 642.36 vs. 607.59 (MU). There were significant differences between KBP and KBP-VH for MCSv and LT (p<0.05). CONCLUSIONS: The KBP using an ASC set to the very high level could reduce the complexity of MLC motion significantly more without deterioration of the DVH parameters compared with the KBP in VMAT for prostate cancer.

Outcome of chemoradiotherapy using intensity-modulated radiation therapy for cervical esophageal cancer: a single institute experience.

BACKGROUND: The role of intensity-modulated radiation therapy in the treatment of cervical esophageal cancer remains unclear. The outcome of concurrent chemoradiotherapy for cervical esophageal squamous cell carcinoma using intensity-modulated radiation therapy was retrospectively evaluated. METHODS: Between 2004 and 2017, 36 patients with cervical esophageal cancer treated with intensity-modulated radiation therapy were included. Among these patients, one had stage II disease, three stage III, 19 stage IVA, and 13 stage IVB. All patients received radiotherapy at a dose of 60 Gy and concurrent platinum-based doublet chemotherapy. RESULTS: The median follow-up period for surviving patients was 36 months. Three-year locoregional control, progression-free survival, and overall survival rates were 54, 40, and 46%, respectively. Disease progression was noted in 20 out of 36 patients (56%). Grade 3 late toxicities were observed in four patients (three esophageal stenoses and one carotid artery stenosis). There were no grade 4-5 toxicities. Univariate analysis identified the duration of radiotherapy as a prognostic factor for overall survival. CONCLUSIONS: Chemoradiotherapy using intensity-modulated radiation therapy for locally advanced cervical esophageal carcinoma achieved satisfactory locoregional control and survival with acceptable toxicities.

Dosimetric evaluation with knowledge-based planning created at different periods in volumetric-modulated arc therapy for prostate cancer: a multi-institution study.

Dosimetric evaluation and variation assessment were performed with two knowledge-based planning (KBP) models created at different periods for volumetric-modulated arc therapy (VMAT) for prostate cancer at five institutes. The first and second models (F- and S-models) for KBP were created before April 2017 and April 2019, respectively. The S-model was created using feedback plans from the F-model. Dose evaluation was compared between the two models using the same two computed tomography (CT) datasets and structures. The evaluation metrics were the dose received by 95.0% and 2.0% of the planning target volume (PTV); dose-volume parameters to the rectum and bladder as V90, V80, and V50; and monitor unit (MU). Dosimetric variation was compared by exporting estimated dose-volume histograms for each model to the Model Analytics website and assessing the organ at risk volume. There were no dosimetric differences between the two models for PTV. The V50 of the rectum in the S-model had improved compared to that of the F-model (case I: 49.3 ± 15.6 and 43.5 ± 15.2 [p = 0.08]; case II: 42.5 ± 16.9 and 36.0 ± 15.6 [p = 0.138]). The differences in other parameters were within ± 1.8% between the rectum and the bladder. The MU was slightly higher in the S-model than in the F-model, and dosimetric variation was reduced to the rectum and bladder among all the institutes. The polished S-model for KBP could be used for standardization of the plan quality and sharing of KBP models in VMAT for prostate cancer.