Hypoxia predicts favorable response to carbon ion radiotherapy in non-small cell lung cancer (NSCLC) defined by 18F-FMISO positron emission tomography/computed tomography (PET/CT) imaging.

Background: Hypoxia is the bottleneck that affects the response of conventional photon radiotherapy, but it does not seem to have much effect on carbon ion radiotherapy (CIRT). This study aimed to evaluate the changes of hypoxia before and after CIRT in patients with non-small cell lung cancer (NSCLC) and whether 18F-fluoromisonidazole (18F-FMISO) positron emission tomography/computed tomography (PET/CT) imaging could predict the response to CIRT in NSCLC patients. Methods: A total of 29 patients with NSCLC who received CIRT were retrospectively included. 18F-FMISO PET/CT imaging was performed before and after treatment, and chest CT was performed after radiotherapy. Radiation response within 1 week after radiotherapy and at the initial follow-up were defined as the immediate response (IR) and early response (ER), respectively. The tumor-to-muscle ratio (TMR), hypoxia volume (HV), and the ΔTMR and ΔHV values of 18F-FMISO uptake were collected. Fisher's exact test, Mann-Whitney U test, Wilcoxon signed-rank test, and binary logistic regression were used to analyze data. Results: (I) Baseline TMR could predict the IR to CIRT with a baseline TMR cut-off value of 2.35, an area under the curve (AUC) of 0.85 [95% confidence interval (CI): 0.62-1.00], a sensitivity of 80.0%, a specificity of 87.5%, and an accuracy of 85.7%. Taking the baseline TMR =2.35 as the cut-off value of high-hypoxia and low-hypoxia group, the IR rate of the high-hypoxia group [66.7% (4/6)] and the low-hypoxia group [6.7% (1/15)] was statistically different (P=0.01). (II) ΔTMR could predict early treatment response after CIRT at initial follow-up, with a cut-off value of ΔTMR =36.6%, AUC of 0.80 (95% CI: 0.61-1.00), sensitivity of 72.7%, specificity of 90.0% and accuracy of 71.4%. Conclusions: A higher degree of tumor hypoxia may be associated with a better IR to CIRT. ΔTMR could predict early treatment response after CIRT.

18F-FAPI PET/CT performs better in evaluating mediastinal and hilar lymph nodes in patients with lung cancer: comparison with 18F-FDG PET/CT.

BACKGROUND: The aim of this study was to evaluate the efficacy of fluorine 18 (18F) labeled fibroblast activation protein inhibitor (FAPI) in identifying mediastinal and hilar lymph node metastases and to develop a model to quantitatively and repeatedly identify lymph node status. METHODS: Twenty-seven patients with 137 lymph nodes were identified by two PET/CT images. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of lymph node status were analyzed, and the optimal cut-off value was identified by ROC analysis. RESULTS: The SUVmax of metastatic lymph nodes on 18F-FAPI was higher than that on 18F-FDG PET/CT (10.87 ± 7.29 vs 6.08 ± 5.37, p < 0.001). 18F-FAPI presented much greater lymph node detection sensitivity, specificity, accuracy, PPV and NPV than 18F-FDG PET/CT (84% vs. 71%; 92% vs. 67%; 90% vs. 69%, 84% vs. 52%, and 92% vs. 83%, respectively). Additionally, the diagnostic effectiveness of 18F-FAPI in small lymph nodes was greater than that of 18F-FDG PET/CT (specificity: 96% vs. 72%; accuracy: 93% vs. 73%; PPV: 77% vs. 33%, respectively). Notably, the optimal cut-off value for specificity and PPV of 18F-FAPI SUVmax was 5.3; the optimal cut-off value for sensitivity and NPV was 2.5. CONCLUSION: 18F-FAPI showed promising diagnostic efficacy in metastatic mediastinal and hilar lymph nodes from lung cancer patients, with a higher SUVmax, especially in small metastatic nodes, compared with 18F-FDG. In addition, this exploratory work recommended optimal SUVmax cutoff values to distinguish between nonmetastatic and metastatic lymph nodes, thereby advancing the development of image-guided radiation. Trial registration ClinicalTrials.gov identifier: ChiCTR2000036091.

Intensity-modulated proton and carbon-ion radiotherapy using a fixed-beam system for locally advanced lung cancer: dosimetric comparison with x-ray radiotherapy and normal tissue complication probability (NTCP) evaluation.

Objective. To assess the dosimetric consequences and the normal tissue complication probability (NTCP) for the organs at risk (OARs) in intensity-modulated particle radiotherapy of proton (IMPT) and carbon-ion (IMCT) using a fixed-beam delivery system when compared with intensity-modulated photon radiotherapy (IMRT) for locally advanced small-cell lung cancer.Approach. The plans were all designed under the same total relative biological effectiveness (RBE)-weighted prescription dose, in which the planning target volume (PTV) of the internal gross target volume(IGTV) and the PTV of the clinical target volume was irradiated with 69.3 Gy (RBE) and 63 Gy (RBE), respectively, using a simultaneously integrated boosting (SIB) technique. NTCPs were estimated for heart, lung, esophagus and spinal cord by Lyman-Kutcher-Burman (LKB) and logistic models. Dose escalation was simulated under the desired NTCP values (0.05, 0.10 and 0.50) of the three radiation techniques.Main results. Under the similar target coverage, almost all OARs were significantly better spared (p< 0.05) when using the particle radiotherapy except for D1cc (the dose to 1 cm3of the volume) of the proximal bronchial tree (p> 0.05). At least 57.6% of mean heart dose, 28.8% of mean lung dose and 19.1% of mean esophageal dose were reduced compared with IMRT. The mean NTCP of radiation-induced pneumonitis (RP) in the ipsilateral lung was 0.39 ± 0.33 (0.39 ± 0.31) in IMPT plans and 0.36 ± 0.32 (0.35 ± 0.30) in IMCT plans compared with 0.66 ± 0.30 (0.64 ± 0.28) in IMRT plans by LKB (logistic) models. The target dose could be escalated to 78.3/76.9 Gy (RBE) in IMPT/IMCT plans compared with 61.7 Gy (RBE) in IMRT plans when 0.50 of NTCP in terms of RP in the ipsilateral lung was applied.Significance. This study presents the potential of better control of the side effects and improvement of local control originating from the dosimetric advantage with the application of IMPT and IMCT with the SIB technique for locally advanced lung cancer, even with limited beam directions.

Dosimetric rationale and preliminary experience in proton plus carbon-ion radiotherapy for esophageal carcinoma: a retrospective analysis.

BACKGROUND: Concurrent chemoradiotherapy has been standard of care for unresectable esophageal carcinoma. There were no reports on proton radiotherapy (PRT) plus carbon-ion radiotherapy (CIRT) with pencil beam scanning (PBS) for esophageal carcinoma. This study evaluated the tolerability and efficiency of proton and sequential carbon-ion boost radiotherapy for esophageal carcinoma. METHODS: From April 2017 to July 2020, 20 patients with primary esophageal carcinoma at stages II-IV were treated with PRT plus sequential CIRT with PBS. A median relative biological effectiveness-weighted PRT dose of 50 Gy in 25 fractions, and a sequential CIRT dose of 21 Gy in 7 fractions were delivered. Respiratory motion management was used if the tumor moved > 5 mm during the breathing cycle. A dosimetric comparison of photon intensity-modulated radiotherapy (IMRT), PRT, and CIRT was performed. The median times and rates of survivals were estimated using the Kaplan-Meier method. Comparison of the dose-volume parameters of the organs at risk employed the Wilcoxon matched-pairs test. RESULTS: Twenty patients (15 men and 5 women, median age 70 years) were included in the analysis. With a median follow-up period of 25.0 months, the 2-year overall survival and progression-free survival rates were 69.2% and 57.4%, respectively. The patients tolerated radiotherapy and chemotherapy well. Grades 1, 2, 3, and 4 acute hematological toxicities were detected in 25%, 30%, 10%, and 30% of patients, respectively. Grades 3-5 acute non-hematological toxicities were not observed. Late toxicity events included grades 1, 2, and 3 in 50%, 20%, and 10% (pulmonary and esophageal toxicity in each) of patients. Grades 4-5 late toxicities were not noted. PRT or CIRT produced lower doses to organs at risk than did photon IMRT, especially the maximum dose delivered to the spinal cord and the mean doses delivered to the lungs and heart. CONCLUSIONS: PRT plus CIRT with PBS appears to be a safe and effective treatment for esophageal carcinoma. PRT and CIRT delivered lower doses to organs at risk than did photon IMRT. Further investigation is warranted.

Selection of breathing phase number in 4D scanned proton treatment planning optimization for lung tumors.

The standard four-dimensional (4D) treatment planning includes all breathing states in the optimization process, which is time-consuming. This work was aimed to optimize the number of intermediate phases needed for 4D proton treatment planning optimization to reduce the computational cost. Five 4D optimization strategies adopting different numbers of intermediate states and one three-dimensional (3D) optimization plan were studied for fifteen lung cancer patients treated with scanned protons, optimizing on all ten phases (4D_10), two extreme phases (4D_2), six phases during the exhalation stage (4D_6EX), six phases during the inhalation stage (4D_6IN), two extreme phases plus an intermediate state (4D_3) and average computed tomography image (3D), respectively. The 4D dose evaluation was conducted on all the ten phases, considering the interplay effect. The resulting doses accumulated on the reference phase were computed and compared. Compared to the 4D optimization plans, the 3D optimization plan performed inferiorly in target coverage, but superiorly in organ at risks (OARs) sparing. For the 4D optimization, all the five 4D plans showed similar performance in OARs protection. However, the 4D_6EX and 4D_6IN strategies out-performed the 4D_2 and 4D_3 plans in dose homogeneity. The computing times of the 4D_2, 4D_3, 4D_6EX and 4D_6IN approaches decreased to 32%, 41%, 66% and 67% of the 4D_10 method, respectively. Thus, our study suggested that the use of all phases during inhalation or exhalation stage might be a feasible approach substituting for the full phase strategy to reduce the calculation load while guaranteeing the plan quality for scanned proton therapy.

METTL3-mediated m6A mRNA contributes to the resistance of carbon-ion radiotherapy in non-small-cell lung cancer.

Lung cancer is one of the leading causes of death among cancer patients worldwide. Carbon-ion radiotherapy is a radical nonsurgical treatment with high local control rates and no serious adverse events. N6-methyladenosine (m6A) modification is one of the most common chemical modifications in eukaryotic messenger RNA (mRNA) and has important effects on the stability, splicing, and translation of mRNAs. Recently, the regulatory role of m6A in tumorigenesis has been recognized more and more. However, the dysregulation of m6A and its role in carbon-ion radiotherapy of non-small-cell lung cancer (NSCLC) remains unclear. In this study, we found that the level of methyltransferase-like 3 (METTL3) and its mediated m6A modification were elevated in NSCLC cells with carbon-ion radiotherapy. Knockdown of METTL3 in NSCLC cells impaired proliferation, migration, and invasion in vitro and in vivo. Moreover, we found that METTL3-mediated m6A modification of mRNA inhibited the decay of H2A histone family member X (H2AX) mRNA and enhanced its expression, which led to enhanced DNA damage repair and cell survival.

Proton and Carbon Ion Radiation Therapy Decreased Severe Lymphopenia by Reducing Thoracic Vertebra and Aortic Doses in Non-Small Cell Lung Cancer Versus Intensity Modulated Radiation Therapy.

PURPOSE: Lymphopenia is a common adverse effect of radiation therapy (RT). Little is known about the difference in lymphopenia between intensity modulated (photon) radiation therapy (IMRT) and proton and carbon ion radiation therapy (PCIRT). This study aimed to investigate lymphopenia differences between IMRT and PCIRT in non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Clinical and dosimetric parameters were collected from 343 patients who received definitive IMRT or PCIRT for NSCLC. Severe lymphopenia (SRL) was defined as an absolute lymphocyte count (ALC) ≤0.5 × 103 cells/µL. Overall survival (OS) was analyzed using the Kaplan-Meier method. Propensity score matching was performed between the IMRT and PCIRT groups. Least absolute shrinkage and selection operator analysis was used to select appropriate dosimetric parameters. Univariate and multivariate logistic regression analyses were conducted to identify the predictors of SRL. RESULTS: Compared with the IMRT group, the PCIRT group was less likely to develop SRL (P < .001). Compared with the non-SRL group, the SRL group showed significant association with poorer OS, with a median survival time of 29.2 versus 15.0 months (P = .046). IMRT was an independent risk factor of SRL (P = .004). A lower ALC before RT (P = .030) and larger planning target volume (PTV) (P = .002) were also significant independent risk factors for SRL. Moreover, the majority of dosimetric parameters of organs at risk in PCIRT were lower than those in IMRT (P < .001). Thoracic vertebra V5 (P = .002) and aorta V5 (P = .026) were identified as independent risk predictors of SRL after adding dosimetric parameters to the regression model. CONCLUSIONS: Compared with IMRT, PCIRT could reduce SRL incidence, possibly by limiting thoracic vertebra and aortic doses, and SRL was associated with poor outcomes in patients with NSCLC.

Deep learning-based internal gross target volume definition in 4D CT images of lung cancer patients.

BACKGROUND: Contouring of internal gross target volume (iGTV) is an essential part of treatment planning in radiotherapy to mitigate the impact of intra-fractional target motion. However, it is usually time-consuming and easily subjected to intra-observer and inter-observer variability. So far, few studies have been explored to directly predict iGTV by deep learning technique, because the iGTV contains not only the gross target volume (GTV) but also the motion information of the GTV. PURPOSE: This work was an exploratory study to present a deep learning-based framework to segment iGTV rapidly and accurately in 4D CT images for lung cancers. METHODS: Five models, including 3D UNet, mmUNet with point-wise add merging approach (mmUNet-add), mmUNet with concatenate fusion strategy (mmUNet-cat), gruUNet with point-wise add fusion approach (gruUNet-add), and gruUNet with concatenate method (gruUNet-cat), were adopted for iGTV segmentation. All the models originated from the 3D UNet network, with multi-channel multi-path and convolutional gated recurrent unit (GRU) added in the mmUNet and gruUNet networks, respectively. Seventy patients with lung cancers were collected and 55 cases were randomly selected as the training set, and 15 cases as the testing set. In addition, the segmentation results of the five models were compared with the ground truths qualitatively and quantitatively. RESULTS: In terms of Dice Similarity Coefficient (DSC), the proposed four networks (mmUNet-add, mmUNet-cat, gruUNet-add, and gruUNet-cat) increased the DSC score of 3D UNet from 0.6945 to 0.7342, 0.7253, 0.7405, and 0.7365, respectively. However, the differences were not statistically significant (p > 0.05). After a simple post-processing to remove the small isolated connected regions, the mean 95th percentile Hausdorff distances (HD_95s) of the 3D UNet, mmUNet-add, mmUNet-cat, gruUNet-add, and gruUNet-cat networks were 19.70, 15.75, 15.84, 15.61, and 15.83 mm, respectively, corresponding to 25.35, 25.96, 25.11, 28.23, and 24.47 mm before the post-processing. With regard to runtime, significant elapsed time growths (about 70s and 230s) were observed both in the mmUNet and gruUNet architectures due to the increasing parameters. But the mmUNet structure showed less growth. CONCLUSION: Our study demonstrated the ability of the deep learning technique to predict iGTVs directly. With the introduction of multi-channel multi-path and convolutional GRU, the segmentation accuracy was improved under certain conditions with a reduced segmentation efficiency and a further research topic when the 3D UNet network would lead to poor performance is elicited. Less efficiency degradation was observed in the mmUNet structure. Besides, the element-wise add fusing strategy was favorable to increase DSC, whereas HD_95 benefited from the concentrate merging approach. Nevertheless, the segmentation accuracy by deep learning still remains to be improved.

Adaptive carbon ion radiotherapy for locally advanced non-small cell lung cancer: Organ-sparing potential and target coverage.

BACKGROUND: The dose distribution of carbon ion radiotherapy (CIRT) for locally advanced non-small cell lung cancer (LANSCLC) is highly sensitive to anatomical changes. PURPOSE: To demonstrate the dosimetric benefits of adaptive CIRT for LANSCLC and compare the differences between patients with and without adaptive plans based on dosimetry and clinical effect factors. MATERIALS AND METHODS: Of the 98 patients with LANSCLC receiving CIRT, 31 patients underwent replanning following re-evaluations that revealed changes that would have compromised the dose coverage of the target volume or violated dose constraints. Dosimetric parameters and clinical factors were compared between patients with and without adaptive plans. Multivariate analysis identified factors influencing the adaptive planning. RESULTS: The median number of fractions delivered using adaptive plans was eight (range: 2-18). Adaptive plans ensured target coverage, and the maximum spinal cord dose was significantly decreased (p = 0.02). The median reduction in the maximum spinal cord dose was 10.4 Gy (relative biological effectiveness). Patients with adaptive plans had larger tumor volumes (p < 0.001); the median initial internal gross tumor volumes (iGTVs) of patients with adaptive and nonadaptive plans were 125.9 and 49.79 cm3 , respectively. Tumor volumes of patients with adaptive plans were altered to a greater extent (p < 0.001); the median absolute percentage of volume changes in patients in the adaptive and in nonadaptive groups were 20.76% and 3.63%, respectively, while the median movements of iGTV centers were 5.75 and 2.44 mm, respectively. Binary logistic regression analysis revealed that the iGTV volume change and iGTV center movements were significantly different between the groups. CONCLUSIONS: An adaptive plan can effectively ensure target area coverage and protect normal tissues, especially in patients with large tumor volumes and substantial changes. iGTV volume changes and iGTV center movements are the main factors influencing adaptive planning. Weekly simulation computed tomography scans are necessary for treatment evaluation in patients with LANSCLC treated with CIRT.

Preliminary Safety and Efficacy of Proton Plus Carbon-Ion Radiotherapy With Concurrent Chemotherapy in Limited-Stage Small Cell Lung Cancer.

OBJECTIVES: This study aimed to investigate the tolerance and effect of proton plus carbon-ion radiotherapy with concurrent chemotherapy in limited-stage small cell lung cancer using the pencil beam scanning technique. MATERIALS AND METHODS: From March 2017 to April 2020, 25 patients with limited-stage small cell lung cancer treated with combined proton and carbon-ion radiotherapy were analyzed. The primary lesions and involved lymph nodes were irradiated using 2-4 portals. Proton and sequential carbon-ion beams were delivered with a median dose of 67.1 (range, 63-74.8) GyE as fraction doses of 2.0-2.2 GyE with proton beams in 20-23 fractions and 3.0-3.8 GyE with carbon ions in 5-8 fractions. Chemotherapy was delivered concurrently with radiotherapy in all patients. RESULTS: At the last follow-up, the 2-year overall and locoregional progression-free survival rates were 81.7% and 66.7%, respectively. Radiochemotherapy was well tolerated, with grade 1, 2, and 3 acute toxicities occurring in 12.0%, 68.0%, and 20.0% of patients, respectively. All grade 3 acute toxicities were hematologically related changes. One patient experienced grade 3 acute non-hematological toxicity in the esophagus, and one other patient had grade 3 bronchial obstruction accompanied by obstructive atelectasis as a late side effect. CONCLUSION: Proton plus carbon-ion radiotherapy using pencil beam scanning yielded promising survival rates and tolerability in patients with limited-stage small cell lung cancer. A prospective clinical study is warranted to validate the therapeutic efficacy of particle radiotherapy in combination with chemotherapy in limited-stage small cell lung cancer.

Clinical Implementation of a 6D Treatment Chair for Fixed Ion Beam Lines.

PURPOSE: To verify the practicality and safety of a treatment chair with six degrees of freedom (6DTC) through demonstrating the efficacy of the workflow in clinical settings and analyzing the obtained technical data, including intra-fraction patient movement during the use of the 6DTC. MATERIALS AND METHODS: A clinical study was designed and conducted to test the clinical treatment workflow and the safety of the 6DTC. Based on the demonstrated dosimetric advantages, fifteen patients with head and neck tumors were selected and treated with the 6DTC. The positional error at the first beam position (PE-B1) and the second beam position (PE-B2) were analyzed and compared with the results from daily quality assurance (QA) procedures of the 6DTC and imaging system performed each day before clinical treatment. The intra-fraction patient movement was derived from the total patient alignment positional error and the QA data based on a Gaussian distribution formulism. RESULTS: The QA results showed sub-millimeter mechanical accuracy of the 6DTC over the course of the clinical study. For 150 patient treatment fractions, the mean deviations between PE-B1 and PE-B2 were 0.13mm (SD 0.88mm), 0.25mm (SD 1.17mm), -0.57mm (SD 0.85mm), 0.02° (SD 0.35°), 0.00° (SD 0.37°), and -0.02° (SD 0.37°) in the x, y, z (translational), and u, v, w (rotational) directions, respectively. The calculated intra-fraction patient movement was -0.08mm (SD 0.56mm), 0.71mm (SD 1.12mm), -0.52mm (SD 0.84mm), 0.10° (SD 0.32°), 0.09° (SD 0.36°), and -0.04° (SD 0.36°) in the x, y, z, u, v, w directions, respectively. CONCLUSIONS: The performance stability of the 6DTC was satisfactory. The position accuracy and intra-fraction patient movement in an upright posture with the 6DTC were verified and found adequate for clinical implementation.

Definitive carbon ion radiotherapy for tracheobronchial adenoid cystic carcinoma: a preliminary report.

BACKGROUND: Tracheobronchial adenoid cystic carcinoma (TACC) is a rare tumour. About one-third of patients miss their chance of surgery or complete resection as it is mostly detected in the advanced stage; hence, photon radiotherapy (RT) is used. However, the outcomes of photon RT remain unsatisfactory. Carbon ion radiotherapy (CIRT) is thought to improve the therapeutic gain ratio; however, the outcomes of CIRT in TACC are unclear. Therefore, we aimed to assess the effects and toxicities of CIRT in patients with TACC. METHODS: The inclusion criteria were as follows: 1) age 18-80 years; 2) Eastern Cooperative Oncology Group Performance Status 0-2; 3) histologically confirmed TACC; 4) stage III-IV disease; 5) visible primary tumour; and 6) no previous RT history. The planned prescription doses of CIRT were 66-72.6 GyE/22-23 fractions. The rates of overall survival (OS), local control (LC), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Treatment-induced toxicities and tumour response were scored according to the Common Terminology Criteria for Adverse Events and Response Evaluation Criteria in Solid Tumors, respectively. RESULTS: Eighteen patients with a median age of 48 (range 30-73) years were enrolled. The median follow-up time was 20.7 (range 5.8-44.1) months. The overall response rate was 88.2%. Five patients developed lung metastasis after 12.2-41.0 months and one of them experienced local recurrence at 31.9 months after CIRT. The rates of 2-year OS, LC, and PFS were 100, 100, and 61.4%, respectively. Except for one patient who experienced grade 4 tracheal stenosis, which was relieved after stent implantation, no other ≥3 grade toxicities were observed. CONCLUSIONS: CIRT might be safe and effective in the management of TACC based on a short observation period. Further studies with more cases and longer observation are warranted.

Dosimetric impact of using a commercial metal artifact reduction tool in carbon ion therapy in patients with hip prostheses.

The study investigated the dosimetric impact of an iterative metal artifact reduction (iMAR) tool on carbon ion therapy for pelvic cancer patients with hip prostheses. An anthropomorphic pelvic phantom with unilateral and bilateral hip prostheses was used to simulate pelvic cancer patients with metal implants. The raw data obtained from phantom CT scanning were reconstructed with a regular filtered back projection (FBP) algorithm and then corrected with iMAR. The phantom without hip prosthesis was also scanned and used as a reference ground truth (GT). The CT images of three prostate and four sarcoma patients with unilateral hip prosthesis were also reconstructed by FBP and iMAR algorithm and compared. iMAR algorithm reduced the metal artifacts and the maximum WEPL deviation in phantom images from -19.1 to -0.4 mm. However, the CT numbers cannot be retrieved using iMAR for periprosthetic bone materials, eventually leading to a WEPL deviation of -3.6 mm. The use of iMAR improved large discrepancies in DVHs of PTVs and the gamma index between FBP and GT images but increased the difference in the bladder DVH for bilateral hip prostheses due to newly introduced artifacts. In the patient study, the discrepancies of dose distribution were small on iMAR images when compared with FBP images for most cases, except for two sarcoma cases where gamma analysis failed and dose coverage in 98% of the PTV maximally reduced due to large volume of dark metal artifacts. iMAR reduced the metal artifacts and improved dose distribution accuracy in carbon ion radiotherapy for pelvic cancer. However, the residual and newly introduced artifacts, especially with bilateral hip prostheses, may potentially increase WEPL inaccuracy and dose uncertainty. The use of iMAR has the potential to improve carbon ion treatment planning of pelvic cancer but should be used with caution.

Sequential boost of intensity-modulated radiotherapy with chemotherapy for inoperable esophageal squamous cell carcinoma: A prospective phase II study.

PURPOSE: This prospective phase II study aimed to determine the efficacy and tolerability of sequential boost of intensity-modulated radiation therapy (IMRT) with chemotherapy for patients with inoperable esophageal squamous cell carcinoma (ESCC). METHODS: Patients with histologically or cytologically proven inoperable ESCC were enrolled in this study (ChiCTR-OIC-17010485). A larger target volume for subclinical lesion was irradiated with 50 Gy, and then, a smaller target volume only including gross tumor was boosted to 66 Gy. The fraction dose was 2 Gy, and no elective node was irradiated. Concurrent and consolidation chemotherapy of fluorouracil (600 mg/m2 , days 1-3) plus cisplatin (25 mg/m2 , days 1-3) was administered every 4 weeks, for 4 cycles in total. The primary endpoint was 2-year progression-free survival (PFS). RESULTS: Eighty-eight patients were enrolled in this study. The median age was 65 years (range: 45-75 years), and 69 patients (78.4%) were men. With the median follow-up of 26 (range: 3-95) months, the 2- and 5-year PFS were 39.3% and 36.9%, respectively, and overall survival (OS) were 57.1% and 39.2%, respectively. Tumor stage and concurrent chemotherapy were independent OS predictors. Major acute adverse events were myelosuppression and esophagitis, most of which were grades 1-2. Nine percent and 2.3% of patients had grade 3 acute esophagitis and late esophageal strictures, respectively. CONCLUSIONS: Sequential boost to 66 Gy by IMRT with chemotherapy was safe and effective for inoperable ESCC. A randomized phase III study to compare with standard dose of 50 Gy is warranted.

Early stage non-small cell lung cancer treated with pencil beam scanning particle therapy: retrospective analysis of early results on safety and efficacy.

BACKGROUND: To evaluate the safety and efficacy of particle therapy (PT) using pencil beam scanning (PBS) technique for early stage non-small cell lung cancer (NSCLC). METHODS: From 08/2014 to 03/2018, 31 consecutive patients with sum of the longest diameters of primary tumor and hilar lymph node < 5 cm, N0-1, M0 NSCLC treated with PT were retrospectively analyzed. Gating/active breathing control techniques were used to control tumor motion in 20 and 7 patients. PBS-based proton radiotherapy (PRT) or carbon ion radiotherapy (CIRT) plans were designed via Syngo® planning system. PRT, PRT + CIRT boost, and CIRT were used in 6, 6 and 19 patients, respectively. Prescriptions were categorized to 3 levels: 5-7.5 GyE * 8-10 Fx, 4-5 GyE * 15-16 Fx and 2.25-3.5 GyE * 20-31 Fx. RESULTS: Thirty-one patients (20 males and 11 females) with a median age of 71 (50-80) years were enrolled with a median follow-up time of 12.1 (2.9-45.2) months. Fourteen were adenocarcinomas, 7 squamous cell carcinomas, 4 non-specified NSCLC and 6 had no histological diagnosis (4/6 had previous resected lung cancer). The median tumor size was 3.1 (1.1-4.7) cm. No grade 4-5 toxicities were observed. One patient experienced grade 3 (per the Common Terminology Criteria for Adverse Events version 4.03) radiation-induced lung injury (RILI) at 6.7 months from radiation started. Grade 2 acute toxicities included hematological toxicities (5 cases), RILI (2), plural pain (1) and dermatitis (1). Grade 2 late toxicities included RILI (3) and asymptomatic rib fracture (1). Three patients had progressed disease at 4.0~10.6 months after the initiation of PT. One experienced local failure with simultaneous distant failure and died of brain metastasis at 10.8 months; one developed regional and distant failure and died of lung infection at 8.7 months; the other experienced isolated distant failure only and his disease was well controlled after salvage systemic therapy. The estimated rates of progression-free survival, local control, cause-specific survival and overall survival at 1, 2 years were 85.5% and 85.5%, 95.2% and 95.2%, 95.0% and 95.0%, 90.7% and 90.7%, respectively. CONCLUSIONS: PBS-based PT appears safe and effective for early stage NSCLC. Further follow-up and investigation is warranted. TRIAL REGISTRATION: ISRCTN, ISRCTN78973763. Registered 14 August 2018- Retrospectively registered, http://www.isrctn.com/ISRCTN78973763 .

Phase 2 study of accelerated hypofractionated thoracic radiation therapy and concurrent chemotherapy in patients with limited-stage small-cell lung cancer.

PURPOSE: To prospectively investigate the efficacy and toxicity of accelerated hypofractionated thoracic radiation therapy (HypoTRT) combined with concurrent chemotherapy in the treatment of limited-stage small-cell lung cancer (LS-SCLC), with the hypothesis that both high radiation dose and short radiation time are important in this setting. METHODS AND MATERIALS: Patients with previously untreated LS-SCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. HypoTRT of 55 Gy at 2.5 Gy per fraction over 30 days was given on the first day of the second or third cycle of chemotherapy. An etoposide/cisplatin regimen was given to 4 to 6 cycles. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 2-year progression-free survival rate. RESULTS: Fifty-nine patients were enrolled from July 2007 through February 2012 (median age, 58 years; 86% male). The 2-year progression-free survival rate was 49.0% (95% confidence interval [CI] 35.3%-62.7%). Median survival time was 28.5 months (95% CI 9.0-48.0 months); the 2-year overall survival rate was 58.2% (95% CI 44.5%-71.9%). The 2-year local control rate was 76.4% (95% CI 63.7%-89.1%). The severe hematologic toxicities (grade 3 or 4) were leukopenia (32%), neutropenia (25%), and thrombocytopenia (15%). Acute esophagitis and pneumonitis of grade ≥3 occurred in 25% and 10% of the patients, respectively. Thirty-eight patients (64%) received prophylactic cranial irradiation. CONCLUSION: Our study showed that HypoTRT of 55 Gy at 2.5 Gy per fraction daily concurrently with etoposide/cisplatin chemotherapy has favorable survival and acceptable toxicity. This radiation schedule deserves further investigation in LS-SCLC.

Simultaneous integrated boost intensity-modulated radiotherapy in esophageal carcinoma: early results of a phase II study.

PURPOSE: The safety and efficacy of using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with esophageal squamous cell carcinoma were evaluated in a single-institution phase II setting. METHODS AND MATERIALS: Between June 2007 and October 2009, 45 patients underwent concurrent chemoradiotherapy (n = 27) or radiotherapy alone (n = 18). Two planning target volumes (PTV) were defined for the SIB: PTVC and PTVG, with prescribed doses of 50.4 Gy to the PTVC (1.8 Gy/fraction) and 63 Gy to the PTVG (2.25 Gy/fraction), both given in 28 fractions. RESULTS: At a median follow-up interval of 20.3 months, the 3-year overall survival (OS) and progression-free survival (PFS) rates were 42.2 and 40.7 %, respectively. The median overall survival time was 21 months; locoregional control rates were 83.3 % at 1 year and 67.5 % at 3 years. According to CTCAE (version 3.0) criteria, none of the patients developed grade 4-5 toxicity. The most common grade 2 and 3 radiation-related toxicity was radiation esophagitis, occurring in 64 % of all patients (but only 13 % as grade 3). No patient developed grade > 2 pulmonary complications. CONCLUSION: SIB-IMRT is a feasible therapeutic approach for esophageal carcinoma patients and provides encouraging locoregional control with a low toxicity profile. Further investigations should focus on dose escalation and optimization of the combination with systemic therapies.

Prognostic predictors and long-term outcome of postoperative irradiation in thymoma: a study of 241 patients.

The purpose of this study was to identify the prognostic predictors treated with postoperative irradiation in patients with thymoma. Two hundred forty-one patients with histologically confirmed thymoma were collected and retrospectively reviewed in this study. Fifty-four patients had stage I disease; 57, stage II; 120, stage III; 10, stage IV. One hundred sixty patients underwent total thymectomy; 63, partial resection; 18, debulking or biopsy. Patients were irradiated after surgery with median dose of 50 Gy by conventional fractionation. The overall survival rates at 5 and 10 years were 83.1% and 72.6%, respectively. The 10-year overall survival was 87% for stage I, 78.7% for stage II, 57.4% for stage III, and 24.3% for stage IV. The conclusions were drawn from this analysis. For stage I, the role of postoperative irradiation needed further investigation. For stage II-III, surgery and postoperative irradiation should be part of standard care. The favorable prognostic predictors were female, early stage, and surgical extirpation.

Observation of normal appearance and wall thickness of esophagus on CT images.

PURPOSE: This study sought to observe the appearance of normal esophagus, measure and record the thickness of esophageal wall in order to offer reference for estimating esophageal wall abnormalities and delineating gross tumor target of esophageal carcinomas on CT images. MATERIALS AND METHODS: From September 2006 to February 2007, 110 consecutive CT films from adult patients without esophageal diseases were collected and studied. On CT images the entire esophagus was divided into cervical, thoracic, retrocardiac and intraabdominal segments. The appearance of esophagus was described when the esophagus contracted or dilated. Thickness of esophageal wall and diameters of esophageal cavities were measured by hard-copy reading with a magnifying glass. Age, sex and the thickness of subcutaneous fat of each patient were recorded. RESULTS: It was observed that the esophagus presented both contracted and dilated status on CT images. In each segment there were certain portions of esophagus in complete contraction or dilatation. 47 images (42.7%) showed contracted esophagus in each segment available for measurement. The largest wall thickness when esophagus was in contraction and dilatation was 4.70 (95%CI: 4.44-4.95)mm and 2.11 (95%CI: 2.00-2.23)mm, respectively. When contracting, the intraabdominal esophagus was thicker than the cervical, thoracic and retrocardiac parts, and the average thickness was 5.68 (95%CI: 5.28-6.09)mm, 4.67 (95%CI: 4.36-4.86)mm, 4.56 (95%CI: 4.31-4.87)mm, and 4.05 (95%CI: 3.71-4.21)mm, respectively. When the esophagus was dilating, the average esophageal wall thickness was between 1.87 and 2.70 mm. The thickest part was cervical esophagus. Thickness of esophageal wall was larger in males than that of females (5.26 mm vs. 4.34 mm p<0.001). Age and the thickness of subcutaneous fat had no significant impact on the thickness of esophageal wall (p-value was 0.056 and 0.173, respectively). CONCLUSION: The Observation of normal appearance and wall thickness of esophagus helps us to identify thickened esophageal wall on CT images using new CT scan technologies. Thus it is probably helpful in judging esophageal diseases and delineating gross tumor target of esophageal carcinomas in modern radiotherapy.