Dosimetric comparison of pencil beam scanning proton therapy with or without multi-leaf collimator versus volumetric-modulated arc therapy for treatment of malignant glioma.

This study aimed to examine the dosimetric effect of intensity-modulated proton therapy (IMPT) with a multi-leaf collimator (MLC) in treating malignant glioma. We compared the dose distribution of IMPT with or without MLC (IMPTMLC+ or IMPTMLC-, respectively) using pencil beam scanning and volumetric-modulated arc therapy (VMAT) in simultaneous integrated boost (SIB) plans for 16 patients with malignant gliomas. High- and low-risk target volumes were assessed using D2%, V90%, V95%, homogeneity index (HI), and conformity index (CI). Organs at risk (OARs) were evaluated using the average dose (Dmean) and D2%. Furthermore, the dose to the normal brain was evaluated using from V5Gy to V40Gy at 5 Gy intervals. There were no significant differences among all techniques regarding V90%, V95%, and CI for the targets. HI and D2% for IMPTMLC+ and IMPTMLC- were significantly superior to those for VMAT (p < 0.01). The Dmean and D2% of all OARs for IMPTMLC+ were equivalent or superior to those of other techniques. Regarding the normal brain, there was no significant difference in V40Gy among all techniques whereas V5Gy to V35Gy in IMPTMLC+ were significantly smaller than those in IMPTMLC- (with differences ranging from 0.45% to 4.80%, p < 0.05) and VMAT (with differences ranging from 6.85% to 57.94%, p < 0.01). IMPTMLC+ could reduce the dose to OARs, while maintaining target coverage compared to IMPTMLC- and VMAT in treating malignant glioma.

Radiotherapy for ductal carcinoma of the prostate: an analysis based on the Japanese radiation oncology study group survey.

BACKGROUND: The clinical characteristics of prostate ductal carcinoma is still unclear, and treatment strategy has not yet been established due to its rarity. Therefore, we conducted a multicenter survey of radiation therapy for prostate ductal carcinoma in Japan. METHOD: Data of patients with ductal carcinoma of the prostate treated with radiation therapy between 1996 and 2018 were extracted from the database of each facility. RESULTS: Fifty-two treatment records of 41 patients were collected from nine institutions. The treatment purpose and situations were varied curative intent to palliation. Twenty-eight patients received curative treatments. The median follow-up period of these patients was 68 months. Androgen deprivation therapy was combined with radiation therapy in 26 cases (93%). X-ray and particle irradiation was used. Radiation dose range was 63-78 Gy; 5-year overall survival, progression-free survival and biochemical relapse-free survival were 87.0, 79.3 and 79.3%, respectively. One patient experienced Grade 3 radiation proctitis and one experienced Grade 3 radiation cystitis. There were no Grade 4 or worse adverse events. CONCLUSION: Most patient received similar treatment with adenocarcinoma of prostate, and the clinical results were compatible. For more reliable evidence, further studies are required.

A phase II study of concurrent chemoradiotherapy with 5-fluorouracil and mitomycin-C for squamous cell carcinoma of the anal canal (the JROSG 10-2 trial).

This study assessed the efficacy of chemoradiotherapy for squamous cell carcinoma of the anal canal (SCCAC). Patients with T1-4N0-3M0 SCCAC received chemoradiotherapy with 5-fluorouracil (5-FU, 800 mg/m2/day, 96-h infusion) and mitomycin-C (MMC, 10 mg/m2 bolus). Patients treated with 3-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) were administered 36.0 Gy in 20 fractions or 49.5 Gy in 33 fractions for elective nodal irradiation and 59.4 Gy in 33 fractions for primary tumor and metastatic nodal irradiation. The sample size was considered sufficient to estimate 95% confidence intervals (CIs) for the true 2-year disease-free survival (DFS) within a width of +15% when the expected true 2-year DFS was 70%. The primary endpoint was 2-year DFS. The secondary endpoints were 2-year overall survival (OS), locoregional control (LC), colostomy-free survival (CFS) and adverse events. Thirty-one patients were enrolled between January 2014 and July 2019. The median follow-up was 33.3 months (range, 16.2-65.8 months). Among the 31 patients, 13%, 32%, 16% and 39% had stage I, II, IIIA and IIIB disease, respectively. Thirty patients were treated with IMRT. Complete response (CR) was achieved in 27 patients. The 2-year DFS, OS, LC and CFS rates were 77.4% (95% CI, 58.4-88.5%), 93.5% (95% CI, 76.6-98.3%), 83.9% (95% CI, 65.5-92.9%) and 80.6% (95% CI, 61.9-90.8%), respectively. One patient experienced grade 3 late adverse events; however, no grade ≥ 4 late adverse events occurred. Good DFS with a low rate of late adverse events was observed. Chemoradiotherapy with 5-FU and MMC was effective for SCCAC.

Rapidly Growing Locally Advanced Non-Small Cell Lung Cancer Treated with Definitive Chemoradiotherapy Using Adaptive Volumetric Modulated Arc Therapy Followed by Durvalumab Maintenance: A Case Report.

BACKGROUND It is difficult to reduce lung toxicity in chemoradiotherapy for locally advanced lung cancer. Volume-modulated arc therapy (VMAT) is a useful lung dose-lowering radiation technique, but it is time-consuming because of its complexity. We present a case of a rapidly growing bulky lung cancer treated with VMAT and intensive adaptation to volume change. CASE REPORT A 43-year-old man with chest pain was diagnosed with non-small cell lung cancer, cT4N3M0 stage IIIC (UICC 8th edition). Concurrent chemoradiotherapy with a VMAT of 60 Gy in 30 fractions and carboplatin/paclitaxel was performed. Despite initiating chemoradiation, monitoring with cone-beam computed tomography (CT) revealed tumor progression. The peak tumor volume was 1.5 times larger than that on CT simulation. The VMAT plan was recreated to cover the increased tumor size. After the irradiation field was enlarged, the tumor, on the contrary, shrank rapidly. Therefore, VMAT planning was performed again to further shrink the irradiation field. CT at the end of the treatment showed a good volume reduction response. Durvalumab therapy was continued for 1 year. After that, the patient was alive and showed no sign of progression. Only asymptomatic radiation pneumonitis was observed as a sub-acute adverse event. CONCLUSIONS We present a case in which proper adaptive VMAT and durvalumab for dramatically progressive non-small cell lung cancer were effective, resulting in 1-year progression-free survival. Even when rapid progression of bulky lung cancer is suggested, the combination of VMAT and adaptive radiotherapy with improved target coverage and reduced lung dose can be a treatment option.

Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.

BACKGROUND: Stereotactic body radiation therapy (SBRT) has high efficacy for early-stage hepatocellular carcinoma (HCC) and is an accepted alternative to radiofrequency ablation (RFA). However, SBRT for HCC may cause subacute liver injury leading to negative clinical outcomes. In this study, we compared changes of liver function and prognosis after SBRT or RFA in patients with single, small HCC by using a propensity-score matching analysis. METHODS: We reviewed medical records of 140 patients with single ≤3 cm HCC treated with SBRT or RFA at Kurashiki Central Hospital between January 2014 and February 2019. Changes of albumin-bilirubin (ALBI) score, local recurrence, and overall survival were compared between the propensity-score matched groups (31 patients treated with SBRT and 62 treated with RFA). RESULTS: The ALBI score increased modestly but significantly after SBRT, while it was unchanged in the RFA group; the intergroup difference was statistically significant (P=0.004). No local recurrence was identified in the SBRT group, whereas the cumulative recurrence incidence was 9.7% in the RFA group (P=0.023). Overall survival was not significantly different between the two groups (hazard ratio: 1.32, 95% confidence interval: 0.60-2.89, P=0.401). CONCLUSIONS: SBRT had modestly negative impact on liver function but with appraisable local control of HCC. Our findings should contribute to the selection of this modality for treatment of single, small HCC.

Hypofractionated intensity-modulated radiotherapy with concurrent chemotherapy for elderly patients with locally advanced pancreatic carcinoma.

BACKGROUND: It is important to understand how elderly patients with locally advanced pancreatic carcinoma (LAPC) should be treated, since the number of elderly cancer patients will increase. However, the optimal treatment for elderly patients with LAPC remains unclear. The purpose of this study was to evaluate the efficacy and safety of hypofractionated intensity-modulated radiotherapy (IMRT) with concurrent gemcitabine for elderly patients with LAPC. METHODS: We retrospectively analysed the data from LAPC patients aged ≥ 75 years treated with hypofractionated IMRT (48 Gy in 15 fractions) with concurrent weekly gemcitabine at our institution from February 2013 to December 2018. Overall survival (OS), progression-free survival (PFS), locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), and the pattern of recurrence and toxicity were analysed. RESULTS: Fifteen patients received treatment during the study period. The median age was 78 years (range 75-86 years), and the Eastern Cooperative Oncology Group (ECOG) performance status (PS) of all patients was 0-1. The median survival time (MST) and median PFS were 20.4 [95% confidence interval (CI) 10.3-36.8] and 13.5 (95% CI 6.4-20.3) months, respectively, and the 1-year OS and PFS rates were 80.0% (95% CI 50-93.1%) and 66.7% (95% CI 37.5-84.6%), respectively. The median LRPFS and median DMFS were 15.6 (95% CI 6.4-36.8) and 14.9 (95% CI 7.0-20.5) months, respectively, and the 1-year LRPFS and DMFS rates were 73.3% (95% CI 43.6-89.1%) and 66.7% (95% CI 37.5-84.6%), respectively. Non-haematologic grade 3 toxicity was observed in three cases, of which only one was induced by radiotherapy, whereas grade 4-5 non-haematologic acute or late toxicities were not observed. CONCLUSIONS: The OS and PFS of elderly patients with LAPC treated using hypofractionated IMRT with concurrent gemcitabine were favourable and without the occurrence of severe toxicity. This treatment strategy is feasible and promising for elderly LAPC patients with good PS.

Application and limitation of radiomics approach to prognostic prediction for lung stereotactic body radiotherapy using breath-hold CT images with random survival forest: A multi-institutional study.

PURPOSE: To predict local recurrence (LR) and distant metastasis (DM) in early stage non-small cell lung cancer (NSCLC) patients after stereotactic body radiotherapy (SBRT) in multiple institutions using breath-hold computed tomography (CT)-based radiomic features with random survival forest. METHODS: A total of 573 primary early stage NSCLC patients who underwent SBRT between January 2006 and March 2016 and met the eligibility criteria were included in this study. Patients were divided into two datasets: training (464 patients in 10 institutions) and test (109 patients in one institution) datasets. A total of 944 radiomic features were extracted from manually segmented gross tumor volumes (GTVs). Feature selection was performed by analyzing inter-segmentation reproducibility, GTV correlation, and inter-feature redundancy. Nine clinical factors, including histology and GTV size, were also used. Three prognostic models (clinical, radiomic, and combined) for LR and DM were constructed using random survival forest (RSF) to deal with total death as a competing risk in the training dataset. Robust models with optimal hyper-parameters were determined using fivefold cross-validation. The patients were dichotomized into two groups based on the median value of the patient-specific risk scores (high- and low-risk score groups). Gray's test was used to evaluate the statistical significance between the two risk score groups. The prognostic power was evaluated by the concordance index with the 95% confidence intervals (CI) via bootstrapping (2000 iterations). RESULTS: The concordance indices at 3 yr of clinical, radiomic, and combined models for LR were 0.57 [CI: 0.39-0.75], 0.55 [CI: 0.38-0.73], and 0.61 [CI: 0.43-0.78], respectively, whereas those for DM were 0.59 [CI: 0.54-0.79], 0.67 [CI: 0.54-0.79], and 0.68 [CI: 0.55-0.81], respectively, in the test dataset. The combined DM model significantly discriminated its cumulative incidence between high- and low-risk score groups (P < 0.05). The variable importance of RSF in the combined model for DM indicated that two radiomic features were more important than other clinical factors. The feature maps generated on the basis of the most important radiomic feature had visual difference between high- and low-risk score groups. CONCLUSIONS: The radiomics approach with RSF for competing risks using breath-hold CT-based radiomic features might predict DM in early stage NSCLC patients who underwent SBRT although that may not have potential to predict LR.

Risk factors for severe gastrointestinal toxicity in patients receiving palliative radiotherapy for metastatic bone tumors: association with the use of molecular-targeted agents.

This study aimed to investigate whether the use of molecular-targeted agents could affect gastrointestinal (GI) toxicity in palliative radiotherapy (RT) for metastatic bone tumors in the abdominopelvic region. We collected data of patients who received palliative RT for bone metastases in the abdominopelvic region between 2013 and 2014 from six institutions. Data of 395 patients were collected and184 patients received molecularly targeted therapy, of whom 80 received vascular endothelial growth factor (VEGF)-targeted agents. For 556 lesions, 410 sessions of irradiation were undergone. GI toxicity of ≥G3 was observed in 3.8% of patients. The incidence rates of ≥G3 GI toxicity in patients without targeted agents use, in those using VEGF-targeted agents and in those using non-VEGF-targeted agents were 3.8, 7.5 and 1.0%, respectively. Regarding risk factors of the occurrence of ≥G3 GI toxicity, univariate analysis in all patients showed that a history of abdominopelvic surgery was a significant risk factor (P = 0.01), and the use of VEGF-targeted agents showed a trend of high incidence (P = 0.06). In patients using VEGF-targeted agents, both univariate and multivariate analysis showed that combined anticoagulant use (P = 0.03 and 0.01) and agent use between 1 week before and after RT (P = 0.046 and 0.03) were significant risk factors. In conclusion, the history of abdominopelvic surgery was associated with ≥G3 GI toxicity and the use of VEGF-targeted agents showed a trend for high incidence. When using VEGF-targeted agents, caution should be exercised in the combined use of anticoagulants and in the agent use between 1 week before and after RT.

Chemoradiotherapy for Unresectable INI1-negative Chordoma in a Child.

The characteristics of chordomas in children are distinct from those in adults. In particular, the prognosis of patients with INI1-negative chordoma is dismal. The standard treatment for localized chordoma, complete surgical resection with a wide margin, is seldom feasible for chordomas arising at the clivus in children, mainly due to associated complications. Therefore, other treatments for unresectable chordomas in children, including chemoradiotherapy, must be explored. Here, we report a 7-year-old girl with an INI1-negative chordoma of the clivus, who responded to conventional chemotherapy plus radiotherapy. Without surgical resection, she remains alive after 1 year and 7 months of the initial diagnosis.

Is Concurrent Chemotherapy With Radiotherapy for Esophageal Cancer Beneficial in Patients Aged 80 Years or Older?

BACKGROUND/AIM: To determine whether concurrent chemotherapy with radiotherapy should be performed in elderly patients with esophageal cancer. PATIENTS AND METHODS: A total of 185 patients aged 80 years or older who were treated with definitive radiotherapy alone or combined with chemoradiotherapy for esophageal cancer at seven institutions were enrolled. In order to compare survival rates of patients treated with chemoradiotherapy with those of patients treated with radiotherapy alone, propensity score matching was performed to homogenize the two populations. RESULTS: For the whole patient cohort, the 3-year overall survival (OS) rate was 52.6% and the median survival was 42.5 months. After propensity score matching, the 3-year OS rate for the chemoradiotherapy group was not significantly better than that for the group treated with radiotherapy alone (53.7% vs. 59.9%, p=0.876). CONCLUSION: Concurrent chemotherapy with radiotherapy for esophageal cancer in patients aged 80 years or older did not have significant OS benefit over radiotherapy alone.

Intensity-modulated radiotherapy for cervical esophageal squamous cell carcinoma without hypopharyngeal invasion: dose distribution and clinical outcome.

Hypopharyngeal invasion would be a key finding in determining the extent of the irradiation fields in patients with cervical esophageal squamous cell carcinoma (CESCC). This study aimed to investigate the clinical outcomes of chemoradiotherapy using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) omitting upper cervical lymph nodal irradiation in CESCC without hypopharyngeal invasion, and the dosimetric superiority of SIB-IMRT to 3D conformal radiotherapy (3DCRT). We retrospectively identified 21 CESCC patients without hypopharyngeal invasion [clinical Stage I/II/III/IV (M1LYM); 3/6/5/7] (UICC-TNM 7th edition) who underwent chemoradiotherapy using SIB-IMRT between 2009 and 2015. SIB-IMRT delivered 60 Gy to each primary tumor and the metastatic lymph nodes, and 48 Gy to elective lymph nodal regions, including Levels III and IV of the neck, supraclavicular, and upper mediastinal lymphatic regions, in 30 fractions. The overall survival rate, locoregional control rate, and initial recurrence site were evaluated. 3DCRT plans were created to perform dosimetric comparisons with SIB-IMRT. At a median follow-up of 64.5 months, the 5-year locoregional control and overall survival rates were 66.7% and 53.4%, respectively. Disease progressed in eight patients: all were locoregional progressions and no patients developed distant progression including upper cervical lymph nodal regions as initial recurrence sites. The planning study showed SIB-IMRT improved target coverage without compromising the dose to the organs at risk, compared with 3DCRT. In conclusion, omitting the elective nodal irradiation of the upper cervical lymph nodes was probably reasonable for CESCC patients without hypopharyngeal invasion. Locoregional progression remained the major progression site in this population.

Organ-preserving approach via radiotherapy for small cell carcinoma of the bladder: an analysis based on the Japanese Radiation Oncology Study Group (JROSG) survey.

Small cell carcinoma of the bladder is extremely rare, accounting for <1% of all malignant tumours in the urinary tract. Thus, no standard therapy modality for this malignancy has been established. This study aimed to retrospectively analyse the clinical outcomes associated with definitive radiotherapy for small cell carcinoma of the bladder. A questionnaire-based survey of patients with pathologically proven small cell carcinoma of the bladder treated with definitive radiation therapy between 1990 and 2010 was conducted by the Japanese Radiation Oncology Study Group. The clinical records of 12 eligible patients were collected from nine institutions. The median age of the patients was 70.5 years (range: 44-87 years), and the median follow-up period was 27.3 months (range: 3.3-117.8 months). The median prescribed dose was 60 Gy (range: 50.0-61.0 Gy), and a median of 2.0 Gy (range: 1.2-2.0 Gy) was administered per fraction. Systemic chemotherapy combined with radiotherapy was performed in eight cases (66.7%). The 3- and 5-year overall survival rates were 50.0% and 33.3%, respectively. And the 3- and 5-year local control rates were 66.7% and 55.6%, respectively. Chemotherapy significantly improved overall survival and relapse-free survival (P = 0.006 and 0.001, respectively). No serious adverse events occurred in the observation period. All patients who achieved local control maintained functional bladders. In conclusion, radiotherapy is a potential local treatment option and has an important role in maintaining quality of life. Systemic chemotherapy combined with local radiotherapy seems to be effective in improving survival.

Non-small cell lung cancer with pathological complete response: predictive factors and surgical outcomes.

OBJECTIVES: When induction therapy followed by surgery for locally advanced non-small cell lung cancer results in pathological complete response, the prognosis is excellent; however, relapses can occur. We analyzed the predictive factors for achieving pathological complete response and reviewed the clinicopathological features and surgical outcomes of locally advanced non-small cell lung cancer with pathological complete response. METHODS: Between March 2005 and January 2015, 145 resections after induction therapy for locally advanced non-small cell lung cancer were performed; 38 cases achieved pathological complete response. Predictive factors for achieving pathological complete response were analyzed, and the clinicopathological features and surgical outcomes of 38 cases with pathological complete response were retrospectively reviewed. RESULTS: Of 145 patients, 98 underwent induction chemoradiation and 47, induction chemotherapy. Squamous cell carcinoma occurred most frequently (n = 64), followed by adenocarcinoma (n = 53). Only squamous cell carcinoma was positively associated with achieving pathological complete response (p = 0.009). Of 38 patients with pathological complete response, 33 were men and the mean age was 67.0 ± 6.3 years; the clinical stages were IIA (n = 3), IIB (n = 2), IIIA (n = 26), and IIIB (n = 3). One patient died within 30 days post-surgery (2.6%). Eight recurrences occurred during the follow-up period; brain metastasis occurred most frequently. The 5-year overall and recurrence-free survival rates were 79.5% and 72.6%, respectively. CONCLUSIONS: Squamous cell carcinoma was identified as a positive predictive factor for achieving pathological complete response. Among patients undergoing lung cancer surgery after induction therapy with pathological complete response, brain metastasis occurred most frequently.

Evaluation of Dynamic Tumor-tracking Intensity-modulated Radiotherapy for Locally Advanced Pancreatic Cancer.

Intensity-modulated radiotherapy (IMRT) is now regarded as an important treatment option for patients with locally advanced pancreatic cancer (LAPC). To reduce the underlying tumor motions and dosimetric errors during IMRT as well as the burden of respiratory management for patients, we started to apply a new treatment platform of the dynamic tumor dynamic tumor-tracking intensity-modulated radiotherapy (DTT-IMRT) using the gimbaled linac, which can swing IMRT toward the real-time tumor position under patients' voluntary breathing. Between June 2013 and March 2015, ten patients were treated, and the tumor-tracking accuracy and the practical benefits were evaluated. The mean PTV size in DTT-IMRT was 18% smaller than a conventional ITV-based PTV. The root-mean-squared errors between the predicted and the detected tumor positions were 1.3, 1.2, and 1.5 mm in left-right, anterior-posterior, and cranio-caudal directions, respectively. The mean in-room time was 24.5 min. This high-accuracy of tumor-tracking with reasonable treatment time are promising and beneficial to patients with LAPC.

[Induction Chemoradiotherapy Followed by Surgery in Non-small-cell Lung Cancer;a Retrospective Study].

OBJECTIVE: The aim of this study is to investigate the outcomes of induction chemoradiotherapy (ICRT) followed by surgery in patients with non-small cell lung cancer( NSCLC). METHODS: We retrospectively analyzed consecutive patients with NSCLC who underwent ICRT followed by surgery at our hospital between January 2006 and December 2015. RESULTS: A total of 102 patients were eligible for evaluation (cStage/I B/II A/II B/III A/III B, 1/8/14/75/4). The median age was 66 years. Forty-one patients had adenocarcinoma, 42 patients had squamous cell carcinoma, and 19 patients had others. The regimen consisted of carboplatin and paclitaxel in 94 patients, and the others in 8 patients plus concurrent radiation at a dose of 28 Gy in 1 patient, 30 Gy in 28 patients, 40 Gy in 42 patients, 45 Gy in 3 patients, and 50 Gy in 28 patients. Major response was obtained in 84 patients. Grade 3/4 toxicity of ICRT reported in 57 patients. The 5-year relapse-free and overall survival rate was 51.4% and 62.7%, respectively. CONCLUSION: ICRT (carboplatin and paclitaxel plus concurrent standard radiation) followed by surgery in NSCLC can be safely performed and may contribute to satisfactory outcomes in locally advanced NSCLC. It is likely that 28~50 Gy radiation dose contributes to satisfactory outcomes in ICRT.

Surgical outcomes and complications of pneumonectomy after induction therapy for non-small cell lung cancer.

OBJECTIVES: Although surgical resection after induction therapy (IT) for locally advanced non-small cell lung cancer (NSCLC) is a possible treatment option, pneumonectomy may be avoided owing to high-surgical risks. However, reports exist that pneumonectomy after IT has acceptable safety and favorable outcomes. We reviewed pneumonectomies after IT in terms of surgical outcomes, perioperative management, and complications. METHODS: Between April 2004 and March 2015, 15 consecutive pneumonectomies were performed for locally advanced NSCLC after IT. Surgical outcomes, perioperative management, and complications were retrospectively reviewed. RESULTS: Thirteen patients were men, and 6 pneumonectomies were right-sided. One pneumonectomy was performed after induction chemotherapy and 14 followed induction chemoradiation. In all 15 cases the bronchial stumps were covered with autologous tissues. Pedunculated mediastinal fat pad and pedunculated intercostal muscles were used in 4 and 11 cases, respectively. Although postoperative complications were seen in 12 patients (80.0%), with major complications (Clavien-Dindo classification ≥ IIIa) in 5 patients (33.3%), there were no deaths within 30 days after pneumonectomy. Overall 3- and 5-year survivals were 80.0 and 57.1%, respectively. CONCLUSIONS: Owing to high-surgical risks and complication rates, careful surgical technique and postoperative management are essential for successful pneumonectomy after IT.

Clinical evaluation of intensity-modulated radiotherapy for locally advanced pancreatic cancer.

BACKGROUND: The purpose was to retrospectively evaluate the effect of intensity-modulated radiotherapy (IMRT) on gastrointestinal (GI) toxicities and outcomes compared to three-dimensional conformal radiotherapy (3DCRT) for locally advanced pancreatic cancer (LAPC). METHODS: We included 107 consecutive patients who underwent CRT for LAPC from September 2001 to March 2015; 80 patients underwent 3DCRT and 27 patients underwent IMRT. They were compared for GI toxicities, locoregional progression free survival (LRPFS), distant metastasis free survival (DMS), and overall survival (OS). RESULTS: Median radiation dose and fractions for 3DCRT and IMRT were 54 Gy/30 fr. and 48 Gy/15 fr. The regimens of CRT consisted of weekly gemcitabine 250 mg/m2 (for 3DCRT) or 1000 mg/m2 (for IMRT). Acute GI toxicity ≥grade 2 occurred in 32 patients (40%) treated with 3DCRT compared with five patients (19%) treated with IMRT. Late GI toxicity of grade 3 occurred in 10 patients (12%) treated with 3DCRT and one patient (4%) treated with IMRT. Patients who underwent IMRT had superior 1-year LRPFS (73.1% vs. 63.2%, p = 0.035) and 1-year OS (92.3% vs. 68.2%, p = 0.037) as compared with those treated with 3DCRT. Multivariate analysis showed that in IMRT patients, higher dose (≥45 Gy) was an independent factor for better LRPFS and OS. CONCLUSIONS: LAPC patients treated with hypofractionated full-dose gemcitabine IMRT had improved OS and LRPFS without increased GI toxicities when compared to those of patients treated with conventionally fractionated low dose gemcitabine 3DCRT. In IMRT patients, higher dose was an independent favorable prognostic factor for better LRPFS and OS, which suggests that dose escalation with IMRT for LAPC is a promising strategy.

Clinical results of dynamic tumor tracking intensity-modulated radiotherapy with real-time monitoring for pancreatic cancers using a gimbal mounted linac.

OBJECTIVES: We performed dynamic tumor-tracking IMRT (DTT-IMRT) in locally advanced pancreatic cancer (LAPC) patients using a gimbaled linac of Vero4DRT. The purpose of this study is to report the first clinical results. METHODS: From June 2013 to June 2015, eleven LAPC patients enrolled in this study and DTT-IMRT was successfully performed. The locoregional progression free survival (LRPFS), distant metastasis free survival (DMFS), overall survival (OS), hematologic and gastrointestinal (GI) toxicities were evaluated. Oncologic outcomes were estimated using Kaplan-Meier analysis, and toxicities using CTCAE v4.0. RESULTS: The median radiation dose was 48 Gy (range, 45-51) in 15 fractions. Concurrent chemoradiotherapy (CCRT) was performed using gemcitabine in 9 patients and S-1 in one, while one patient refused. With a median follow-up of 22.9 months, 1-year LRPFS, DMFS, and OS rates were 90.9%, 70.7%, and 100%, respectively. Median survival time was 23.6 months. Grade-3 leucopenia and neutropenia were observed in two (18%) and one patient (9%), respectively. Grade-2 acute GI toxicity occurred in 2 patients (18%) and late grade-3 in 1 patient (9%). CONCLUSIONS: Preliminarily application of DTT-IMRT using a gimbaled linac on CCRT in LAPC patients resulted in excellent locoregional control and OS without severe toxicity.

HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating expression and secretion of Sonic hedgehog.

Hypoxic and stroma-rich microenvironments, characteristic features of pancreatic cancers, are strongly associated with a poor prognosis. However, whether and how hypoxia increases stromal compartments remain largely unknown. Here, we investigated the potential importance of a master regulator of the cellular adaptive response to hypoxia, hypoxia-inducible factor-1 (HIF-1), in the formation of stroma-rich microenvironments of pancreatic tumors. We found that pancreatic cancer cells secreted more Sonic hedgehog protein (SHH) under hypoxia by upregulating its expression and efficiency of secretion in a HIF-1-dependent manner. Recombinant SHH, which was confirmed to activate the hedgehog signaling pathway, accelerated the growth of fibroblasts in a dose-dependent manner. The SHH protein secreted from pancreatic cancer cells under hypoxic conditions promoted the growth of fibroblasts by stimulating their Sonic hedgehog signaling pathway. These results suggest that the increased secretion of SHH by HIF-1 is potentially responsible for the formation of detrimental and stroma-rich microenvironments in pancreatic cancers, therefore providing a rational basis to target it in cancer therapy.

Long-term outcome of definitive radiotherapy for cervical esophageal squamous cell carcinoma.

BACKGROUND: The aim of this study was to identify the long-term clinical outcome of definitive radiotherapy using three-dimensional conformal radiotherapy (3DCRT) for cervical esophageal squamous cell carcinoma (CESCC). METHODS: We retrospectively reviewed the medical records of 30 patients with CESCC [clinical stage I/II/III/IV(M1LYM); 3/2/12/13] (TNM 7th edition) who underwent definitive radiotherapy using 3DCRT between 2000 and 2014 in our institution. The median prescribed dose for the gross tumor and metastatic lymph nodes was 60 Gy. Twenty-six patients underwent elective nodal irradiation for the neck node levels III, IV, and VI and for upper mediastinal lymph nodes with a median dose of 40 Gy. Twenty-six patients underwent concurrent chemotherapy. Initial disease progression sites, locoregional control (LRC) rate, overall survival (OS) rate, and toxicities were retrospectively evaluated. A univariate analysis was performed to identify prognostic factors. RESULTS: With a median follow-up of 110 months, the 5- and 10-year LRC rates were 43.7% and 37.4%, respectively. The 5- and 10-year OS rates were 48.3% and 40.2%, respectively. Locoregional, distant and both area accounted for 83%, 6% and 11% of the initial progression sites. Unresectable status and M1LYM were significantly associated with poor LRC (p < 0.05) and OS (p < 0.05). Grade 3 acute non-hematological toxicity occurred in 13.3% of patients. During the follow-up, patients without any disease progression did not need a permanent gastrostomy tube or tracheostomy. Late toxicity events, including hypothyroidism and cardiovascular disease, were observed; 5- and 10-year cumulative incidence rates of grade 2 hypothyroidism and ≥grade 3 cardiovascular disease were 31.6% and 62.5%, and 17.5% and 21.3%, respectively. CONCLUSIONS: Definitive radiotherapy yields a cure for patients with CESCC while preserving their laryngopharyngeal function. The poor LRC rate in the advanced stage needs to be overcome for a better prognosis. As the incidence of radiation-induced hypothyroidism and cardiovascular disease was not low, long-term survivors should be followed up for these symptoms.