Proton Beam Therapy for Intrahepatic Cholangiocarcinoma: A Multicenter Prospective Registry Study in Japan.

Introduction: Intrahepatic cholangiocarcinoma (ICC) can be treated with chemotherapy in unresectable cases, but outcomes are poor. Proton beam therapy (PBT) may provide an alternative treatment and has good dose concentration that may improve local control. Methods: Fifty-nine patients who received initial PBT for ICC from May 2016 to June 2018 at nine centers were included in the study. The treatment protocol was based on the policy of the Japanese Society for Radiation Oncology. Forty patients received 72.6-76 Gy (RBE) in 20-22 fr, 13 received 74.0-76.0 Gy (RBE) in 37-38 fr, and 6 received 60-70.2 Gy (RBE) in 20-30 fr. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results: The 59 patients (35 men, 24 women; median age: 71 years; range: 41-91 years) had PS of 0 (n = 47), 1 (n = 10), and 2 (n = 2). Nine patients had hepatitis and all 59 cases were considered inoperable. The Child-Pugh class was A (n = 46), B (n = 7), and unknown (n = 6); the median maximum tumor diameter was 5.0 cm (range 2.0-15.2 cm); and the clinical stage was I (n = 12), II (n = 19), III (n = 10), and IV (n = 18). At the last follow-up, 17 patients were alive (median follow-up: 36.7 months; range: 24.1-49.9 months) and 42 had died. The median OS was 21.7 months (95% CI: 14.8-34.4 months). At the last follow-up, 37 cases had recurrence, including 10 with local recurrence. The median PFS was 7.5 months (95% CI: 6.1-11.3 months). In multivariable analyses, Child-Pugh class was significantly associated with OS and PFS, and Child-Pugh class and hepatitis were significantly associated with local recurrence. Four patients (6.8%) had late adverse events of grade 3 or higher. Conclusion: PBT gives favorable treatment outcomes for unresectable ICC without distant metastasis and may be particularly effective in cases with large tumors.

Dose Evaluation in 2-Phase Method for Advanced Esophageal Cancer by Hybrid Irradiation Techniques.

Purpose: In concurrent chemoradiotherapy for advanced esophageal cancer, a 2-phase method consisting of initial irradiation of a wide elective nodal region and boost irradiation of the primary lesion is commonly employed. Although dose escalation to the primary lesion may be required to achieve higher local control rates, the radiation dose to critical organs must not exceed dose constraints. To achieve an optimum balance of dose prescription and dose reduction to surrounding organs, such as the lungs and heart, we compared hybrid dose distributions and investigated the best combination of the following recent irradiation techniques: volumetric modulation arc therapy (VMAT), proton broad-beam irradiation, and intensity-modulated proton beam therapy (IMPT). Materials and Methods: Forty-five patients with advanced esophageal cancer whose primary lesions were located in the middle- or lower-thoracic region were studied. Radiotherapy plans for the initial and boost irradiation in the 2-phase method were calculated using VMAT, proton broad-beam irradiation, and IMPT calculation codes, and the dose-volume histogram indices of the lungs and heart for the accumulated plans were compared. Results: In plans using boost proton irradiation with a prescribed dose of 60 Gy(RBE), all dose-volume histogram indices were significantly below the tolerance limits. Initial and boost irradiation with VMAT resulted in the median dose of V30 Gy(RBE)(heart) of 27.4% and an achievement rate below the tolerance limit of 57.8% (26 cases). In simulations of dose escalation up to 70 Gy(RBE), initial and boost IMPT resulted in the highest achievement rate, satisfying all dose constraints in 95.6% (43 cases). Conclusion: Applying VMAT to both initial and boost irradiation is not recommended because of the increased risk of the cardiac dose exceeding the tolerance limit. IMPT may allow dose escalation of up to 70 Gy(RBE) without radiation risks to the lungs and heart in the treatment of advanced esophageal cancer.

[Estimation of Uncertainty of the VMAT Absolute Dose Measurement Due to the Phantom Setup Error Using a Treatment Planning System].

PURPOSE: When performing single-point dose verification in VMAT, it is necessary to avoid the regions with steep dose gradient. We propose a method to obtain the estimated value ( Uplan) of uncertainty of the absolute dose measurement due to the phantom setup error by using dose gradient calculated from treatment planning system (TPS), for evaluating the appropriate measurement points. METHODS: The dose gradient was calculated from the planned dose values in the vicinity of the isocenter point using TPS. The phantom setup error was estimated. The Uplan was calculated using the proposed formula after estimating the phantom setup error. Then, the dose gradient was calculated from the measured dose values in the vicinity of the isocenter point specified by TPS using the Tough water phantom with ionization chamber (IC), and Umeas was calculated as in Uplan. RESULTS: The correlation coefficient between Uplan and Umeas was 0.984, which indicates a high correlation. The average of the difference between Umeas and Uplan was -0.24%. We considered that this result was caused by the influence of volume averaging effect of IC. CONCLUSION: The Uplan obtained from this proposed method reflects the uncertainty of the absolute dose measurement due to the phantom setup error and is useful for evaluating the appropriate measurement points for absolute dose measurement.

Proton Beam Therapy for Hepatocellular Carcinoma: Multicenter Prospective Registry Study in Japan.

PURPOSE: A prospective multicenter registry study was started May 2016 in Japan to evaluate the efficacy and safety of proton beam therapy (PBT) for hepatocellular carcinoma (HCC). METHODS AND MATERIALS: Patients who received PBT for HCC from May 2016 to June 2018 were registered in the database of the Particle Beam Therapy Committee and Subcommittee of the Japanese Society for Radiation Oncology. Overall survival (OS), progression-free survival (PFS), and local recurrence were evaluated. RESULTS: Of the 755 registered patients, 576 with initial PBT and no duplicate cancer were evaluated. At final follow-up, 322 patients were alive and 254 had died. The median follow-up period for survivors was 39 months (0-58 months). The median OS time of the 576 patients was 48.8 months (95% CI, 42.0-55.6 months) and the 1-, 2-, 3-, and 4-year OS rates were 83.8% (95% CI, 80.5%-86.6%), 68.5% (64.5%-72.2%), 58.2% (53.9%-62.2%), and 50.1% (44.9%-55.0%), respectively. Recurrence was observed in 332 patients, including local recurrence in 45 patients. The median PFS time was 14.7 months (95% CI, 12.4-17.0 months) and the 1-, 2-, 3-, and 4-year PFS rates were 55.2% (95% CI, 51.0%-59.2%), 37.5% (33.5%-41.5%), 30.2% (26.3%-34.2%), and 22.8% (18.5%-27.4%), respectively. The 1-, 2-, 3-, and 4-year OS rates were significantly higher for tumor size <5 versus 5 to 10 cm (P < .001) and <5 versus ≥10 cm (P < .001); Child-Pugh score A/B versus C (P < .001); and distance of the tumor from the gastrointestinal tract <1 versus 1 to 2 cm (P < .008) and <1 versus >2 cm (P < .001). At final follow-up, 27 patients (4.7%) had late adverse events of grade 3 or higher, with liver failure (n = 7), and dermatitis (n = 7) being most common. CONCLUSIONS: This multicenter prospective data registry indicated that PBT for HCC gives good therapeutic effects (3-year local control rate of 90%) with a low risk of severe late adverse events.

Longer Survival and Preserved Liver Function after Proton Beam Therapy for Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Proton beam therapy (PBT) has been recently reported to achieve excellent tumor control with minimal toxicity in patients with unresectable hepatocellular carcinoma (HCC). Radiofrequency ablation (RFA) combined with transcatheter arterial chemoembolization (TACE) was investigated for larger HCC. This study was designed to evaluate the therapeutic effect of PBT on unresectable HCC in comparison with TACE combined with RFA. METHODS: We retrospectively analyzed 70 patients with HCC which was difficult to control by surgical resection or RFA monotherapy, 24 patients treated with PBT and 46 patients with TACE plus RFA. The therapeutic effects were assessed as local progression-free survival (PFS) and overall survival (OS). RESULTS: The local PFS was more than 65% in 60 months for PBT and TACE plus RFA. The patients treated with PBT showed 82% OS at 60 months post-treatment. In contrast, those treated with TACE plus RFA showed 28% OS. When comparing the changes of ALBI scores in patients with different severities of chronic liver disease, the scores of PBT-treated patients were maintained at the baseline; however, those of TACE plus RFA-treated patients worsened after the treatments. CONCLUSIONS: The results indicated that PBT may show better benefits than TACE plus RFA therapy in terms of OS in patients with unresectable HCC by sparing the non-tumor liver tissues.

Analysis of particle therapy registries based on a unified treatment policy for esophageal cancer.

This study aimed to evaluate the efficacy and safety of particle therapy (proton beam therapy and carbon-ion radiotherapy) for esophageal cancer by analyzing prospective nationwide registry data from particle therapy facilities throughout Japan. Patients diagnosed with esophageal cancer who received particle therapy between May 2016 and June 2018 were recruited from the registries of 12 particle therapy centers in Japan. Eventually, we enrolled 174 patients who met the inclusion criteria. Of the 174 patients, 137 (78.7%) were male, with a median age of 69 years (range: 41-88 years). Clinical stages included I (n = 55; 31.6%), II (n = 31; 17.8%), III (n = 82; 47.1%), IV (n = 3; 1.7%) and unknown (n = 3; 1.7%) (Union for International Cancer Control, seventh edition), and the median follow-up period was 908 days (range: 76-1669 days) for all patients. The 3-year overall survival (OS) rate, the 3-year progression-free survival (PFS) rate and the 3-year local control (LC) rates were 60.5, 53.2 and 72.7%, respectively. For each clinical stage, the 3-year OS rates were I, 84.8%; II, 60.3% and III, 42.9%; the 3-year PFS rates were I, 71.9%; II, 58.3% and III, 37.0% and the 3-year LC were I, 78.4%; II, 79.8% and III, 65.2%, respectively. Notably, four patients (2.3%) with ≥Grade 3 cardiopulmonary toxicities were observed (Common Terminology Criteria for Adverse Events, version 5.0). Our study showed that particle therapy for esophageal cancer has lower rates of adverse cardiopulmonary events than X-ray radiotherapy.

Effectiveness of CT-image guidance in proton therapy for liver cancer and the importance of daily dose monitoring for tumors and organs at risk.

BACKGROUND: It is important to have precise image guidance throughout proton therapy in order to take advantage of the therapy's physical selectivity. PURPOSE: We evaluated the effectiveness of computed tomography (CT)-image guidance in proton therapy for patients with hepatocellular carcinoma (HCC) by assessing daily proton dose distributions. The importance of daily CT image-guided registration and daily proton dose monitoring for tumors and organs at risk (OARs) was investigated. METHODS: A retrospective analysis was conducted using 570 sets of daily CT (dCT) images throughout whole treatment fractions for 38 HCC patients who underwent passive scattering proton therapy with either a 66 cobalt gray equivalent (GyE)/10 fractions (n = 19) or 76 GyE/20 fractions (n = 19) protocol. The actual daily delivered dose distributions were estimated by forward calculation using the dCT sets, their corresponding treatment plans, and the recorded daily couch correction information. We then evaluated the daily changes of the dose indices D99% , V30GyE , and Dmax for the tumor volumes, non-tumorous liver, and other OARs, that is, stomach, esophagus, duodenum, colon, respectively. Contours were created for all dCT sets. We validated the efficacy of the dCT-based tumor registrations (hereafter, "tumor registration") by comparing them with the bone registration and diaphragm registration as a simulation of the treatment based on the positioning using the conventional kV X-ray imaging. The dose distributions and the indices of three registrations were obtained by simulation using the same dCT sets. RESULTS: In the 66 GyE/10 fractions, the daily D99% value in both the tumor and diaphragm registrations agreed with the planned value with 3%-6% (SD), and the V30GyE value for the liver agreed within ±3%; the indices in the bone registration showed greater deterioration. Nevertheless, tumor-dose deterioration occurred in all registration methods for two cases due to daily changes of body shape and respiratory condition. In the 76 GyE/20 fractions, in particular for such a treatment that the dose constraints for the OARs have to be cared in the original planning, the daily D99% in the tumor registration was superior to that in the other registration (p < 0.001), indicating the effectiveness of the tumor registration. The dose constraints, set in the plan as the maximum dose for OARs (i.e., duodenum, stomach, colon, and esophagus) were maintained for 16 patients including seven treated with re-planning. For three patients, the daily Dmax increased gradually or changed randomly, resulting in an inter-fractional averaged Dmax higher than the constraints. The dose distribution would have been improved if re-planning had been conducted. The results of these retrospective analyses indicate the importance of daily dose monitoring followed by adaptive re-planning when needed. CONCLUSIONS: The tumor registration in proton treatment for HCC was effective to maintain the daily dose to the tumor and the dose constraints of OARs, particularly in the treatment where the maintenance for the dose constraints needs to be considered throughout the treatment. Nevertheless daily proton dose monitoring with daily CT imaging is important for more reliable and safer treatment.

Evaluation of Exposure Doses of Elective Nodal Irradiation in Chemoradiotherapy for Advanced Esophageal Cancer.

We evaluated elective nodal irradiation (ENI) doses during radical chemoradiotherapy (CRT) for esophageal cancer (EC). A total of 79 patients (65 men and 14 women) aged 52-80 years with T1-3, N0-3, and M0 (including M1ly) who underwent CRT for EC during November 2012-September 2019 were eligible for this retrospective analysis. Patients were divided into two groups: the high-dose group (HG), including 38 patients who received ≥40 Gy as ENI; and the low-dose group (LG), including 41 patients who received <40 Gy. The median doses were 40.0 and 36.0 Gy in HG and LG, respectively. During the follow-up (median: 36.7 months), no lymph node recurrence was observed in the ENI field in all patients. Lymph node recurrence near the ENI field was observed in six patients. No significant differences were observed between the two groups in median overall survival, progression-free survival, and local control. Grade 3-4 acute and late adverse events were observed in five patients of HG and six patients of LG, respectively. No ulceration or stricture was observed in the ENI field on endoscopy examined with 58 Gy irradiation. In conclusion, an ENI dose of 36 Gy could be considered to control the elective nodes of EC.

Long-Term Results of Proton Therapy for Hepatocellular Carcinoma Using Four-Dimensional Computed Tomography Planning without Fiducial Markers.

We report here the long-term results of marker-less respiratory-gated proton therapy (PT), without fiducial markers for hepatocellular carcinoma (HCC), which was planned using a four-dimensional computed tomography technique. Local tumor control (LTC) and overall survival (OS) were estimated using the Kaplan-Meier method. Toxicity was graded per CTCAE v5.0. Patients (n = 105; median age 73 years, range 38-90 years) with 128 lesions were treated. The median radiation dose was 66 gray relative biological effectiveness (GyRBE) (range, 52.8-82.5 GyRBE) delivered in 2.0 to 6.6 GyRBE fractions, depending on lesion volume, the involved liver, and the patient's condition. The median follow-up of surviving patients was 63 months (range, 1-126 months), and the 5-year LTC and OS rates were 93.2% and 40.4%, respectively. Univariate and multivariate analyses identified tumors near the gastrointestinal tract as an independent risk factor for local recurrence and revealed that hepatic reserve, tumor stage, performance status, operability, sex, and portal vein thrombosis were independent risk factors for OS. Acute and late treatment-related grade 3 toxicities were experienced by eight patients (7.6%). Adverse events ≥ grade 4 were not evident. Marker-less respiratory-gated PT for HCC is a safe and effective treatment without severe complications.

Dosimetric advantages of daily adaptive strategy in IMPT for high-risk prostate cancer.

PURPOSE: To evaluate the dosimetric advantages of daily adaptive radiotherapy (DART) in intensity-modulated proton therapy (IMPT) for high-risk prostate cancer by comparing estimated doses of the conventional non-adaptive radiotherapy (NART) that irradiates according to an original treatment plan through the entire treatment and the DART that uses an adaptive treatment plan generated by using daily CT images acquired before each treatment. METHODS: Twenty-three patients with prostate cancer were included. A treatment plan with 63 Gy (relative biological effectiveness (RBE)) in 21 fractions was generated using treatment planning computed tomography (CT) images assuming that all patients had high-risk prostate cancer for which the clinical target volume (CTV) needs to include prostate and the seminal vesicle (SV) in our treatment protocol. Twenty-one adaptive treatment plans for each patient (total 483 data sets) were generated using daily CT images, and dose distributions were calculated. Using a 3 mm set-up uncertainty in the robust optimization, the doses to the CTV, prostate, SV, rectum, and bladder were compared. RESULTS: Estimated accumulated doses of NART and DART in the 23 patients were 60.81 ± 3.47 Gy (RBE) and 63.24 ± 1.04 Gy (RBE) for CTV D99 (p < 0.01), 62.99 ± 1.28 Gy (RBE) and 63.43 ± 1.33 Gy (RBE) for the prostate D99 (p = 0.2529), and 59.07 ± 5.19 Gy (RBE) and 63.17 ± 1.04 Gy (RBE) for SV D99 (p < 0.001). No significant differences were observed between NART and DART in the estimated accumulated dose for the rectum and bladder. CONCLUSION: Compared with the NART, DART was shown to be a useful approach that can maintain the dose coverage to the target without increasing the dose to the organs at risk (OAR) using the 3 mm set-up uncertainty in the robust optimization in patients with high-risk prostate cancer.

Stability of daily rectal movement and effectiveness of replanning protocols for sparing rectal doses based on the daily CT images during proton treatment for prostate cancer.

PURPOSE: To evaluate the optimal period of replanning to spare the rectal dose by investigating daily rectal movements during computed tomography (CT) image-guided proton therapy for prostate cancer. MATERIALS AND METHODS: To evaluate the optimum reference period for replanning, we analyzed 1483 sets of daily CT (dCT) images acquired from 40 prostate cancer patients and measured the daily rectal movement along the anterior-posterior direction based on the simulator CT (sCT) images and dCT images. We calculated daily dose distributions based on initial plans on the sCT images and replans on the dCT images for 13 representative patients, and evaluated daily dose volume histograms (DVHs) for the prostate, seminal vesicles, and rectum. RESULTS: The rectal anterior side on the dCT images around the seminal vesicles largely deviated toward the anterior side relative to the position on the reference sCT images, but the deviation decreased by referring to the dCT images and became nearly zero when we referred to the dCT images after 10-day treatment. The daily DVH values for the prostate showed good dose coverage. For six patients showing rectal movement toward the anterior side, the daily rectal DVH (V77% ) showed a 3.0 ± 1.7 cc excess from the initial plan and this excess was correlated with 9.9 ± 6.8 mm rectal movement. To identify the patients (37.5% in total) for whom the replanning on the 10th-day and 20th-day CT images reduced the V77% excess to 0.4 ± 1.5 cc and -0.2 ± 1.3 cc, respectively, we evaluated the accumulated mean doses with a 1.2 cc criterion. CONCLUSION: Our data demonstrate that the daily movement of the rectal anterior side tends to move toward the anterior side, which results in a rectal overdose, and the mean of the movement gradually decreases with the passage of days. In such cases, replanning with the reference CT after 10 days is effective to spare the rectal dose.

Proton beam therapy is a safe and effective treatment in elderly patients with esophageal squamous cell carcinoma.

BACKGROUND: There are many elderly patients with esophageal squamous cell carcinoma (ESCC). However, there are currently few articles regarding the clinical outcome following proton beam therapy in these patients. The purpose of this study was to evaluate the clinical results of proton beam therapy in elderly patients with ESCC. METHODS: Between January 2009 and December 2013, patients aged ≥75 years who underwent proton beam therapy were examined using multi-institutional data from Japan. RESULTS: There were 38 inoperable patients (70.4%) and 16 operable patients (29.6%). More than 40% of patients had stage III/IV ESCC. The five-year overall and cancer-specific survival rates were 56.2% and 71.7%, respectively. Performance status was the only factor that significantly influenced overall survival during the multivariate analysis. The five-year local control rate was 61.8%, and local recurrence occurred within 13 months in 82.4% of patients,. There was no grade 3 or higher toxicity, excluding three patients with grade 3 esophageal ulcers. CONCLUSIONS: In conclusion, proton beam therapy may become an alternative treatment with lower toxicity in elderly patients with ESCC, compared to surgery or conventional X-ray radiotherapy. This includes inoperable patients. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Proton beam therapy was a safe and effective treatment for elderly patients with esophageal squamous cell carcinoma (ESCC) including inoperable patients. WHAT THIS STUDY ADDS: Proton beam therapy may be a safer treatment choice for elderly patients with ESCC compared to conventional X-ray radiotherapy.

Proton Beam Therapy for Histologically or Clinically Diagnosed Stage I Non-Small Cell Lung Cancer (NSCLC): The First Nationwide Retrospective Study in Japan.

PURPOSE: To investigate the efficacy and safety of proton beam therapy (PBT) for the treatment of stage I non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Six hundred sixty-nine patients with 682 tumors histologically or clinically diagnosed stage I NSCLC according to the seventh edition of Union for International Cancer Control who received passive-scattering PBT from April 2004 and December 2013 in Japan were retrospectively reviewed to analyze survival, local control, and toxicities. RESULTS: Of 669 patients, 486 (72.6%) were men, with a median age of 76 years (range, 42-94 years). NSCLC was histologically confirmed in 440 patients (65.7%). Clinical T stages included T1a (n = 265; 38.9%), T1b (n = 216; 31.7%), and T2a (n = 201; 29.4%). The total irradiation doses of PBT ranged from 74.4 to 131.3 biological effective dose GyE (median, 109.6 biological effective dose GyE). The median follow-up period was 38.2 months (range, 0.6-154.5 months) for all patients. The 3-year overall survival and progression-free survival rates for all patients were 79.5% and 64.1%, respectively. For patients with stage IA tumors, the 3-year overall survival and progression-free survival rates were 82.8% and 70.6%, respectively, and the corresponding rates for patients with stage IB tumors were 70.8% and 47.3%, respectively. The 3-year local progression-free rates for all, stage IA, and stage IB patients were 89.8%, 93.5%, and 79.4%, respectively. The incidence of grade 2, 3, 4, and 5 pneumonitis was 9.8%, 1.0%, 0%, and 0.7%, respectively. The incidence of grade ≥3 dermatitis was 0.4%. No grade 4 or severe adverse events, other than pneumonitis, were observed. CONCLUSIONS: PBT appears to yield acceptable survival rates, with a low rate of toxicities.

Efficacy of Endoscopic Evaluation of Acute Radiation Esophagitis during Chemoradiotherapy with Proton Beam Therapy Boost for Esophageal Cancer.

BACKGROUND/AIM: To evaluate the utility of endoscopy for assessing radiation esophagitis during chemoradiotherapy (CRT) with proton beam therapy (PBT) boost for esophageal cancer. METHODS: Between December 2012 and December 2016, 38 patients with esophageal cancer were treated with CRT with PBT boost. To evaluate radiation esophagitis, endoscopy was performed after administration of CRT with standard PBT boost (total dose 50-60 Gy relative biological effectiveness [RBE]). Radiation esophagitis was evaluated and classified into 5 newly developed endoscopic grades (Fukui Acute Radiation Esophagitis [FARE] grade). The additional PBT boost was then adjusted and delivered (2-20 Gy [RBE]) to a maximum total dose of 74.4 Gy (RBE) based on the degree of radiation esophagitis, probability of residual tumor, and patient's general condition. To evaluate the utility of endoscopic examination, the incidences of adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0) were determined at the time of endoscopic examination after CRT with standard PBT boost (50-60 Gy [RBE]) and at the completion of treatment (60-74.4 Gy [RBE]), as well as during the 90 days from the beginning of treatment. RESULTS: There was a significant correlation between FARE grade and CTCAE esophagitis grade (ρ = 0.48; p = 0.03). Moreover, endoscopy detected severe esophagitis in an asymptomatic patient. Radiation dose escalation was achieved without severe acute adverse events. There was no significant difference between the incidence of acute toxicity at the time of the CRT with standard PBT boost (50-60 Gy [RBE]) and the higher dose at the completion of treatment (60-74.4 Gy [RBE]), which suggests this dose escalation strategy is safe. CONCLUSION: Endoscopic evaluation of radiation esophagitis using FARE grades was safely performed and useful for adjusting added radiation to ensure the safety of escalations in CRT with PBT boost for esophageal cancer.

Clinical Results of Proton Beam Therapy for Esophageal Cancer: Multicenter Retrospective Study in Japan.

There are few reports about the clinical results of proton beam therapy for esophageal cancer in a large population. The purpose of this study was to evaluate the clinical results of proton beam therapy for esophageal cancer in a large population using a multicentered database. Between January 2009 and December 2013, patients newly diagnosed with esophageal cancer and who had received proton beam therapy were retrospectively recruited from a database of four proton beam therapy centers in Japan. Two hundred and two patients (including 90 inoperable patients) fulfilled the inclusion criteria, and 100 patients (49.5%) had stage III/IV cancer (Union for International Cancer Control 8th). The 3-year and 5-year overall survival rate was 66.7% and 56.3%, respectively. The five-year local control rate was 64.4%. There were two patients with grade three pericardial effusion (1%) and a patient with grade three pneumonia (0.5%). No grade 4 or higher cardiopulmonary toxicities were observed (Common Terminology Criteria for Adverse Events version 4.0). This study suggests that proton beam therapy for esophageal cancer was not inferior in efficacy and had lower rates of toxicities in comparison to photon radiotherapy. Therefore, proton beam therapy can serve as an alternate treatment for patients with esophageal cancer.

Comparison Between Stereotactic Radiotherapy and Sublobar Resection for Non-Small Cell Lung Cancer.

BACKGROUND: The aim of this study was to compare outcomes of primary treatment with stereotactic body radiation therapy (SBRT) versus sublobar resection (SLR) for clinical stage I non-small cell lung cancer (NSCLC) in patients with medical comorbidities. METHODS: Consecutive patients who underwent SBRT (n = 106) or SLR (100 wedge resection, 41 segmentectomy) because of medical comorbidities associated with stage I NSCLC were enrolled. Lesions located in the outer third of the lung field on computed tomography were defined as external, and others were defined as internal. A propensity score-matched analysis was also performed that compared SBRT and SLR results. Charts were reviewed to determine local tumor recurrence, disease-specific survival (DSS), and overall survival (OS). RESULTS: A propensity score-matched analysis, recurrence-free survival (RFS) became significant in favor of surgery (p = 0.036). For large nodules of greater than 2.0 cm in diameter, RFS was significantly better in the surgery group (p = 0.042). No significant differences in OS, DSS, or RFS were observed with small nodules of less than 2.0 cm in diameter. In the external group, a higher recurrence rate was seen for SBRT group. For internal group, there was no statistical difference between each treatment. Local recurrence rate was higher in the SBRT group (p = 0.0082) in the external group. CONCLUSIONS: In a matched comparison of stage I NSCLC in patients with medical comorbidities, RFS was in favor of surgery comparing SBRT, but there were no significant differences in OS or DSS. The tumor size and tumor location should be considered before deciding whether to perform SBRT or surgery.

[Neoadjuvant Proton Beam Chemoradiotherapy for Locally Advanced Gall Bladder Cancer-A Case Report].

A 67-year-old man visited our hospital due to progressing appetite loss and fever. He presented with a fist-sized palpable mass in his right hypochondrium. Abdominal CT showed a 10 cm diameter tumor that originated from the gall bladder infiltrating the abdominal wall, liver, duodenum, and colon. Blood tests revealed leukocytosis, elevated C-reactive protein level, and severe malnutrition. FDG-PET showed markedly high uptake in the tumor and diffuse uptake in the spine. Owing to the inability of oral intake, he underwent laparoscopic gastrojejunostomy and intraoperative tumor biopsy, which demonstrated pathologically G-CSF-producing carcinoma in the gall bladder. For the rapidly progressive tumor, he underwent proton beam chemoradiotherapy as preoperative treatment. The tumor markedly shrunk with dramatic improvement of his inflammatory and nutritional status. Consequently, R0 resection could be performed by combination surgeries of right hemi-colectomy, pancreatoduodenectomy, and partial liver resection. He received adjuvant chemotherapy and was alive without recurrence 12 months after tumor resection. To our knowledge, this is the first report of the use of neoadjuvant proton beam chemoradiotherapy in biliary cancer.

Erratum: Shibata S.; et al. Proton Beam Therapy without Fiducial Markers Using Four-Dimensional CT Planning for Large Hepatocellular Carcinomas. Cancers 2018, 10, 71.

The authors wish to make the following corrections to this paper [...].

Segmental analysis of respiratory liver motion in patients with and without a history of abdominal surgery.

PURPOSE: The purpose of this study was to analyze the respiratory motion of each segment of the liver in patients with or without a history of abdominal surgery using four-dimensional computed tomography. MATERIALS AND METHODS: In total, 57 patients treated for abdominal tumors using proton beam therapy were enrolled. Eighteen patients had a history of abdominal surgery and 39 did not. The positions of clearly demarcated, high-density regions in the liver were measured as evaluation points with which to quantify the motion of each liver segment according to the Couinaud classification. RESULTS: In total, 218 evaluation points were analyzed. Comparison of differences in the motion of individual liver segments showed that among patients without a history of surgery, the maximum was 29.0 (7.2-42.1) mm in S6 and the minimum was 15.1 (10.6-19.3) mm in S4. Among patients with a history of surgery, the maximum was 28.0 (9.0-37.4) mm in S7 and the minimum was 6.3 (4.1-9.3) mm in S3. CONCLUSION: The distances and directions of respiratory motion differed for each liver segment, and a history of abdominal surgery reduced the respiratory motion of the liver. It is necessary to selectively use the internal margin setting.

Proton Beam Therapy without Fiducial Markers Using Four-Dimensional CT Planning for Large Hepatocellular Carcinomas.

We evaluated the effectiveness and toxicity of proton beam therapy (PBT) for hepatocellular carcinomas (HCC) >5 cm without fiducial markers using four-dimensional CT (4D-CT) planning. The subjects were 29 patients treated at our hospital between March 2011 and March 2015. The median total dose was 76 Cobalt Gray Equivalents (CGE) in 20 fractions (range; 66-80.5 CGE in 10-32 fractions). Therapy was delivered with end-expiratory phase gating. An internal target volume (ITV) margin was added through the analysis of respiratory movement with 4D-CT. Patient age ranged from 38 to 87 years (median, 71 years). Twenty-four patients were Child-Pugh class A and five patients were class B. Tumor size ranged from 5.0 to 13.9 cm (median, 6.9 cm). The follow-up period ranged from 2 to 72 months (median; 27 months). All patients completed PBT according to the treatment protocol without grade 4 (CTCAE v4.03 (draft v5.0)) or higher adverse effects. The two-year local tumor control (LTC), progression-free survival (PFS), and overall survival (OS) rates were 95%, 22%, and 61%, respectively. The LTC was not inferior to that of previous reports using fiducial markers. Respiratory-gated PBT with 4D-CT planning without fiducial markers is a less invasive and equally effective treatment for large HCCs as PBT with fiducial markers.