Long-term survival outcomes and quality of life of image-guided proton therapy for operable stage I non-small cell lung cancer: A phase 2 study.

BACKGROUND AND PURPOSE: This study evaluated long-term efficacy, safety, and changes in quality of life (QOL) of patients after image-guided proton therapy (IGPT) for operable stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This single-institutional prospective phase 2 study enrolled patients with operable histologically confirmed stage IA or IB NSCLC (7th edition of UICC). The prescribed dose was 66 Gy relative biological effectiveness equivalents (GyRBE) in 10 fractions for peripheral lesions, or 72.6 GyRBE in 22 fractions for central lesions. The primary endpoint was the 3-year overall survival (OS). The secondary endpoints included disease control, toxicity, and changes in QOL score. RESULTS: We enrolled 43 patients (median age: 68 years; range, 47-79 years) between July 2013 to January 2021, of whom 41 (95 %) had peripheral lesions and 27 (63 %) were stage IA. OS, local control, and progression-free survival rates were 95 % (95 % CI: 83-99), 95 % (82-99), and 86 % (72-94), respectively, at 3 years, and 83 % (66-92), 95 % (82-99), and 77 % (60-88), respectively, at 7 years. Four patients (9 %) developed grade 2, and one patient (2 %) developed grade 3 radiation pneumonitis. No other grade 3 or higher adverse events were observed. In the QOL analysis, global QOL remained favorable; however, approximately 40 % of patients reported dyspnea at 3 and 24 months. CONCLUSION: Our findings suggest that IGPT provides effective disease control and survival in operable stage I NSCLC, particularly for peripheral lesions. Moreover, toxicity associated with IGPT was minimal, and patients reported favorable QOL.

Spot scanning proton therapy for unresectable bulky retroperitoneal dedifferentiated liposarcoma: a case report.

The development of effective treatment strategies for unresectable retroperitoneal sarcoma is desirable. Herein, we suggest that definitive proton therapy (PT) could be a promising treatment option, regardless of the large size of the tumor. A 52-year-old man presented with a discomfort of the lower abdomen. Computed tomography revealed a retroperitoneal tumor, measuring over 20 cm in the largest dimensions, which was surrounded by the gastrointestinal (GI) tract. Biopsy revealed dedifferentiated liposarcoma. Neoadjuvant chemotherapy was ineffective, and the tumor was ultimately deemed unresectable. The patient opted to receive PT instead of continuation of chemotherapy. Spot scanning PT (SSPT) at a total dose of 60.8 Gy (relative biological effectiveness) in 16 fractions was employed. SSPT administered a dose to the tumor while successfully sparing the surrounding GI tract. He did not receive any maintenance systemic therapy after PT. The tumor gradually shrunk over more than 7 years, with no evidence of recurrence outside the irradiation field. The initial measurable tumor volume of 2925 cc decreased to 214 cc at the final follow-up, seven and a half years after PT. The patient is alive without any severe complications.

Investigation of ionization chamber perturbation factors using proton beam and Fano cavity test for the Monte Carlo simulation code PHITS.

The reference dose for clinical proton beam therapy is based on ionization chamber dosimetry. However, data on uncertainties in proton dosimetry are lacking, and multifaceted studies are required. Monte Carlo simulations are useful tools for calculating ionization chamber dosimetry in radiation fields and are sensitive to the transport algorithm parameters when particles are transported in a heterogeneous region. We aimed to evaluate the proton transport algorithm of the Particle and Heavy Ion Transport Code System (PHITS) using the Fano test. The response of the ionization chamber f Q and beam quality correction factors k Q were calculated using the same parameters as those in the Fano test and compared with those of other Monte Carlo codes for verification. The geometry of the Fano test consisted of a cylindrical gas-filled cavity sandwiched between two cylindrical walls. f Q was calculated as the ratio of the absorbed dose in water to the dose in the cavity in the chamber. We compared the f Q calculated using PHITS with that of a previous study, which was calculated using other Monte Carlo codes (Geant4, FULKA, and PENH) under similar conditions. The flight mesh, a parameter for charged particle transport, passed the Fano test within 0.15%. This was shown to be sufficiently accurate compared with that observed in previous studies. The f Q calculated using PHITS were 1.116 ± 0.002 and 1.124 ± 0.003 for NACP-02 and PTW-30013, respectively, and the k Q were 0.981 ± 0.008 and 1.027 ± 0.008, respectively, at 150 MeV. Our results indicate that PHITS can calculate the f Q and k Q with high precision.

Luminescence imaging of water irradiated by protons under FLASH radiation therapy conditions.

Objective.FLASH radiation therapy with ultrahigh dose rates (UHDR) has the potential to reduce damage to normal tissue while maintaining anti-tumor efficacy. However, rapid and precise dose distribution measurements remain difficult for FLASH radiation therapy with proton beams. To solve this problem, we performed luminescence imaging of water following irradiation by a UHDR proton beam captured using a charge-coupled device camera.Approach. We used 60 MeV proton beams with dose rates of 0.03-837 Gy s-1from a cyclotron. Therapeutic 139.3 MeV proton beams with dose rates of 0.45-4320 Gy s-1delivered by a synchrotron-based proton therapy system were also tested. The luminescent light intensity induced by the UHDR beams was compared with that produced by conventional beams to compare the dose rate dependency of the light intensity and its profile.Main results. Luminescence images of water were clearly visualized under UHDR conditions, with significantly shorter exposure times than those with conventional beams. The light intensity was linearly proportional to the delivered dose, which is similar to that of conventional beams. No significant dose-rate dependency was observed for 0.03-837 Gy s-1. The light-intensity profiles of the UHDR beams agreed with those of conventional beams. The results did not differ between accelerators (synchrotron or cyclotron) and beam energies.Significance. Luminescence imaging of water is achievable with UHDR proton beams as well as with conventional beams. The proposed method should be suitable for rapid and easy quality assurance investigations for proton FLASH therapy, because it facilitates real-time, filmless measurements of dose distributions, and is useful for rapid feedback.

A survey of practice patterns for real-time intrafractional motion-management in particle therapy.

Background and purpose: Organ motion compromises accurate particle therapy delivery. This study reports on the practice patterns for real-time intrafractional motion-management in particle therapy to evaluate current clinical practice and wishes and barriers to implementation. Materials and methods: An institutional questionnaire was distributed to particle therapy centres worldwide (7/2020-6/2021) asking which type(s) of real-time respiratory motion management (RRMM) methods were used, for which treatment sites, and what were the wishes and barriers to implementation. This was followed by a three-round DELPHI consensus analysis (10/2022) to define recommendations on required actions and future vision. With 70 responses from 17 countries, response rate was 100% for Europe (23/23 centres), 96% for Japan (22/23) and 53% for USA (20/38). Results: Of the 68 clinically operational centres, 85% used RRMM, with 41% using both rescanning and active methods. Sixty-four percent used active-RRMM for at least one treatment site, mostly with gating guided by an external marker. Forty-eight percent of active-RRMM users wished to expand or change their RRMM technique. The main barriers were technical limitations and limited resources. From the DELPHI analysis, optimisation of rescanning parameters, improvement of motion models, and pre-treatment 4D evaluation were unanimously considered clinically important future focus. 4D dose calculation was identified as the top requirement for future commercial treatment planning software. Conclusion:  A majority of particle therapy centres have implemented RRMM. Still, further development and clinical integration were desired by most centres. Joint industry, clinical and research efforts are needed to translate innovation into efficient workflows for broad-scale implementation.

A survey of practice patterns for adaptive particle therapy for interfractional changes.

Background and purpose: Anatomical changes may compromise the planned target coverage and organs-at-risk dose in particle therapy. This study reports on the practice patterns for adaptive particle therapy (APT) to evaluate current clinical practice and wishes and barriers to further implementation. Materials and methods: An institutional questionnaire was distributed to PT centres worldwide (7/2020-6/2021) asking which type of APT was used, details of the workflow, and what the wishes and barriers to implementation were. Seventy centres from 17 countries participated. A three-round Delphi consensus analysis (10/2022) among the authors followed to define recommendations on required actions and future vision. Results: Out of the 68 clinically operational centres, 84% were users of APT for at least one treatment site with head and neck being most common. APT was mostly performed offline with only two online APT users (plan-library). No centre used online daily re-planning. Daily 3D imaging was used for APT by 19% of users. Sixty-eight percent of users had plans to increase their use or change their technique for APT. The main barrier was "lack of integrated and efficient workflows". Automation and speed, reliable dose deformation for dose accumulation and higher quality of in-room volumetric imaging were identified as the most urgent task for clinical implementation of online daily APT. Conclusion: Offline APT was implemented by the majority of PT centres. Joint efforts between industry research and clinics are needed to translate innovations into efficient and clinically feasible workflows for broad-scale implementation of online APT.

Deep learning-based in vivo dose verification from proton-induced secondary-electron-bremsstrahlung images with various count level.

PURPOSE: Proton-induced secondary-electron-bremsstrahlung (SEB) imaging is a promising method for estimating the ranges of particle beam. However, SEB images do not directly represent dose distributions of particle beams. In addition, the ranges estimated from measured images were deviated because of limited spatial resolutions of the developed x-ray camera as well as statistical noise in the images. To solve these problems, we proposed a method for predicting high-resolution dose images from SEB images with various count level using a deep learning (DL) approach for range and width verification. METHODS: In this study, we adopted the double U-Net model, which is a previously proposed deep convolutional network model. The first U-Net model in the double U-Net model was used to denoise the SEB images with various count level. The first U-Net model for denoising was trained on 8000 pairs of SEB images with various count level and noise-free images which were created by a sophisticated in-house developed model function. The second U-Net model for dose prediction was trained using 8000 pairs of denoised SEB images from the first U-Net model and high-resolution dose images generated by Monte Carlo simulation. RESULTS: For both simulation and measurement data, the trained DL model could successfully predict high-resolution dose images which showed a clear Bragg peak and no statistical noise. The difference of the range and width was less than 2.1 mm, even from the SEB images measured with a decrease in the number of irradiated protons to less than 11% of 3.2 × 1011 protons. CONCLUSIONS: High-resolution dose images from measured and simulated SEB images were successfully predicted by using the trained DL model for protons. Our proposed DL model was feasible to predict dose images accurately even with smaller number of irradiated protons.

Outcomes of proton therapy for non-small cell lung cancer in patients with interstitial pneumonia.

BACKGROUND: Interstitial pneumonia (IP) is a disease with a poor prognosis. In addition, IP patients are more likely to develop lung cancer. Since IP patients frequently develop toxicities during cancer treatment, minimally invasive cancer treatment is warranted for such patients to maintain their quality of life. This study retrospectively investigated the efficacy and safety of proton therapy (PT) for non-small cell lung cancer (NSCLC) in patients with IP. METHODS: Twenty-nine NSCLC patients with IP were treated with PT between September 2013 and December 2019. The patients had stage IA to IIIB primary NSCLC. Ten of the 29 patients exhibited the usual interstitial pneumonia pattern. The prescribed dose was 66-74 Grays (relative biological effectiveness) in 10-37 fractions. RESULTS: The median follow-up period was 21.1 months [interquartile range (IQR), 15.6-37.3] for all patients and 37.2 months (IQR, 24.0-49.9) for living patients. The median patient age was 77 years (IQR, 71-81). The median planning target volume was 112.0 ml (IQR, 56.1-246.3). The 2-year local control, progression-free survival, and overall survival rates were 85% (95% confidence interval: 57-95), 30% (15-47), and 45% (26-62), respectively. According to the Common Terminology Criteria for Adverse Events (version 4.0), grade 3 acute radiation pneumonitis (RP) was observed in 1 patient. Two patients developed grade 3 late RP, but no other patients experienced serious toxicities. The patients' quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 and SF-36) scores had not changed after 3 months. CONCLUSIONS: PT may be a relatively safe treatment for NSCLC patients with IP, without deteriorating quality of life scores within 3 months.

Patient-Reported Quality of Life Outcomes after Moderately Hypofractionated and Normofractionated Proton Therapy for Localized Prostate Cancer.

We retrospectively evaluated the three-year patient-reported quality of life (QOL) after moderately hypofractionated proton therapy (MHPT) for localized prostate cancer in comparison with that after normofractionated PT (NFPT) using the Expanded Prostate Cancer Index Composite-50. Patients who received MHPT (60-63 Gy (relative biological effectiveness equivalents; RBE)/20-21 fractions) (n = 343) or NFPT (74-78 Gy (RBE)/37-39 fractions) (n = 296) between 2013 and 2016 were analyzed. The minimum clinically important difference (MCID) threshold was defined as one-half of a standard deviation of the baseline value. The median follow-up was 56 months and 83% completed questionnaires at 36 months. Clinically meaningful score deterioration was observed in the urinary domain at 1 month in both groups and in the sexual domain at 6-36 months in the NFPT group, but not observed in the bowel domain. At 36 months, the mean score change for urinary summary was -0.3 (MHPT) and -1.6 points (NFPT), and that for bowel summary was +0.1 and -2.0 points; the proportion of patients with MCID was 21% and 24% for urinary summary and 18% and 29% for bowel summary. Overall, MHPT had small negative impacts on QOL over three years, and the QOL after MHPT and NFPT was similar.

Evaluating the usefulness of the direct density reconstruction algorithm for intensity modulated and passively scattered proton therapy: Validation using an anthropomorphic phantom.

PURPOSE: Accurate calculation of the proton beam range inside a patient is an important topic in proton therapy. In recent times, a computed tomography (CT) image reconstruction algorithm was developed for treatment planning to reduce the impact of the variation of the CT number with changes in imaging conditions. In this study, we investigated the usefulness of this new reconstruction algorithm (DirectDensity™: DD) in proton therapy based on its comparison with filtered back projection (FBP). METHODS: We evaluated the effects of variations in the X-ray tube potential and target size on the FBP- and DD-image values and investigated the usefulness of the DD algorithm based on the range variations and dosimetric quantity variations. RESULTS: For X-ray tube potential variations, the range variation in the case of FBP was up to 12.5 mm (20.8%), whereas that of DD was up to 3.3 mm (5.6%). Meanwhile, for target size variations, the range variation in the case of FBP was up to 2.2 mm (2.5%), whereas that of DD was up to 0.9 mm (1.4%). Moreover, the variations observed in the case of DD were smaller than those of FBP for all dosimetric quantities. CONCLUSION: The dose distributions obtained using DD were more robust against variations in the CT imaging conditions (X-ray tube potential and target size) than those obtained using FBP, and the range variations were often less than the dose calculation grid (2 mm). Therefore, the DD algorithm is effective in a robust workflow and reduces uncertainty in range calculations.

Spot Scanning Proton Therapy for Sinonasal Malignant Tumors.

PURPOSE: Treatment of sinonasal malignant tumors is challenging, and evidence to establish a standard treatment is limited. Our objective was to evaluate the efficacy and safety of spot scanning proton therapy (SSPT) for sinonasal malignant tumors. PATIENTS AND METHODS: We retrospectively analyzed patients with sinonasal malignant tumors (T1-4bN0-2M0) who underwent SSPT between May 2014 and September 2019. The prescription dose was typically either 60 GyRBE in 15 fractions or 60.8 GyRBE in 16 fractions for mucosal melanoma and 70.2 GyRBE in 26 fractions for other histologic subtypes. Endpoints included local control (LC), progression-free survival, overall survival (OS), and incidence of toxicity. Prognostic factors were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Of 62 enrolled patients, the common histologic subtypes were mucosal melanoma (35%), squamous cell carcinoma (27%), adenoid cystic carcinoma (16%), and olfactory neuroblastoma (10%). Locally advanced stages were common (T3 in 42% and T4 in 53%). Treatment-naïve tumors and postsurgical recurrent tumors accounted for 73% and 27%, respectively. No patient had previous radiotherapy. The median follow-up was 17 months (range, 6-66) for all patients and 21.5 months (range, 6-66) for survivors. The 2-year LC, progression-free survival, and OS rates of all patients were 92%, 50%, and 76%, respectively. Univariate analysis revealed histology as a prognostic factor for OS, being higher in adenoid cystic carcinoma and olfactory neuroblastoma than in other tumors. Sixteen grade ≥3 late toxicities were observed in 12 patients (19%), including 11 events resulting in visual impairment; the most common was cataract. There was 1 grade 4 toxicity, and there were no grade 5 toxicities. CONCLUSION: SSPT was well tolerated and yielded good LC for sinonasal malignant tumors. Although we consider SSPT to be a leading treatment modality, further studies are required to establish its status as a standard treatment.

A Phase 2 Study of Image-Guided Proton Therapy for Operable or Ablation-Treatable Primary Hepatocellular Carcinoma.

PURPOSE: Because most previous data on proton therapy for hepatocellular carcinoma (HCC) were retrospectively collected from inoperable or previously treated cases, our aim was to evaluate the outcome of image-guided proton therapy (IGPT) for operable or radiofrequency ablation-treatable primary HCC. METHODS AND MATERIALS: This phase 2 study prospectively investigated the efficacy and safety of IGPT and quality of life (QoL) after IGPT for operable/ablatable HCC. The primary endpoint was overall survival, and the secondary endpoints were local control, incidence of grade ≥3 adverse events, and changes in QoL. Toxicities were evaluated with Common Terminology Criteria for Adverse Events, version 4.0. QoL scores were assessed with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, version 3.0, and Quality of Life Questionnaire-Hepatocellular Carcinoma/Primary Liver Cancer Module. IGPT was performed using respiratory-gated techniques. RESULTS: Forty-five patients (median age: 68 years; range, 36-80 years) were enrolled between June 2013 and February 2016; 38 were considered operable and 14 were indicated for radiofrequency ablation. The major underlying liver diseases were hepatitis B (n = 16), hepatitis C (n = 13), alcoholic hepatitis (n = 3), and nonalcoholic fatty liver disease (n = 13). The Child-Pugh score was A5 in 32 patients, A6 in 9 patients, and B7 in 4 patients. Thirty-seven patients with a peripherally located tumor were given 66 Gy relative biological effectiveness in 10 fractions, and 8 patients with a centrally located tumor received 72.6 Gy relative biological effectiveness in 22 fractions. The median follow-up period of surviving patients was 60 months (range, 42-75 months). Two- and 5-year overall survival rates were 84% (95% confidence interval [CI], 74%-95%) and 70% (95% CI, 56%-84%), respectively, and local control rates were 95% (95% CI, 89%-100%) and 92% (95% CI, 84%-100%), respectively. Grade 3 radiation-induced liver disease was observed in 1 patient. No significant changes were noted in QoL scores 1 year after treatment, except for body image. CONCLUSIONS: Although the primary endpoint did not meet statistical significance as planned in the study design, IGPT is a safe and effective treatment for solitary primary HCC and may become a treatment option.

Changes in sexual function and serum testosterone levels in patients with prostate cancer after image-guided proton therapy.

Since sexual function and testosterone levels after image-guided proton therapy (IGPT) have not yet been examined in detail, we prospectively evaluated changes before and after IGPT. Among patients treated with IGPT with or without combined androgen blockade (CAB) therapy between February 2013 and September 2014, patients who agreed to participate in the study and were followed up for >3 years after IGPT were evaluated. Serum testosterone levels were regularly measured together with prostate-specific antigen (PSA) levels before and after IGPT. The Erection Hardness Score (EHS) and the sexual domain summary, function subscale and bother subscale of the sexual domain in the Expanded Prostate Cancer Index Composite (EPIC) were assessed. There were 38 low-risk, 46 intermediate-risk and 43 high- or very-high-risk patients (NCCN classification). Although serum testosterone levels in low-risk patients did not decrease after IGPT, reductions were observed in the average EHS and the sexual domain summary score of the EPIC. In intermediate-, high- and very-high-risk patients, testosterone and PSA levels both increased following the termination of CAB after IGPT, and the average EHS increased. The sexual domain summary score gradually increased, but not above minimally important differences. In intermediate-risk patients, the function subscale increased from 4.4 to 14.8 (P < 0.05) 12 months after IGPT and reached a plateau after 60 months. The results of the present study would suggest the potential of IGPT, and further prospective studies to directly compare IGPT with other modalities are warranted.

Biological effects of passive scattering and spot scanning proton beams at the distal end of the spread-out Bragg peak in single cells and multicell spheroids.

PURPOSE: The present study investigated the biological effects of spot scanning and passive scattering proton therapies at the distal end region of the spread-out Bragg peak (SOBP) using single cell and multicell spheroids. MATERIALS AND METHODS: The Geant4 Monte Carlo simulation was used to calculate linear energy transfer (LET) values in passive scattering and spot scanning beams. The biological doses of the two beam options at various points of the distal end region of SOBP were investigated using EMT6 single cells and 0.6-mm V79 spheroids irradiated with 6 and 15 Gy, respectively, by inserting the fractions surviving these doses onto dose-survival curves and reading the corresponding dose. RESULTS: LET values in the entrance region of SOBP were similar between the two beam options and increased at the distal end region of SOBP, where the LET value of spot scanning beams was higher than that of passive scattering beams. Increases in biological effects at the distal end region were similarly observed in single cells and spheroids; biological doses at 2-10 mm behind the distal end were 4.5-57% and 5.7-86% higher than physical doses in passive scattering and spot scanning beams, respectively, with the biological doses of spot scanning beams being higher than those of passive scattering beams (p < .05). CONCLUSIONS: In single cells and spheroids, the effects of proton irradiation were stronger than expected from measured physical doses at the distal end of SOBP and were correlated with LET increases.

Dosimetric response of a glass dosimeter in proton beams: LET-dependence and correction factor.

A radiophotoluminescent glass dosimeter (RGD) is widely used in postal audit system for photon beams in Japan. However, proton dosimetry in RGDs is scarcely used owing to a lack of clarity in their response to beam quality. In this study, we investigated RGD response to beam quality for establishing a suitable linear energy transfer (LET)-corrected dosimetry protocol in a therapeutic proton beam. The RGD response was compared with ionization chamber measurement for a 100-225 MeV passive proton beam. LET of the measurement points was calculated by the Monte Carlo method. An LET-correction factor, defined as a ratio between the non-corrected RGD dose and ionization chamber dose, of 1.226×(LET)-0.171 was derived for the RGD response. The magnitude of the LET-dependence of RGD increased with LET; for an LET of 8.2 keV/µm, the RGD under-response was up to 16%. The coefficient of determination, mean difference ± SD of non-corrected RGD dose, residual range-corrected RGD dose, and LET-corrected RGD dose to the ionization chamber are 0.923, 3.7 ± 4.2%, -2.4 ± 7.5%, and 0.04 ± 2.1%, respectively. The LET-corrected RGD dose was within 5% of the corresponding ionization chamber dose at all energies until 200 MeV, where it was 5.3% lower than the ionization chamber dose. A corrected LET-dependence of RGD using a correction factor based on a power function of LET and precise dosimetric verification close to the maximum LET were realized here. We further confirmed establishment of an accurate postal audit under various irradiation conditions.

Image-Guided Proton Therapy for Elderly Patients with Hepatocellular Carcinoma: High Local Control and Quality of Life Preservation.

This study retrospectively investigated the efficacy and safety of image-guided proton therapy (IGPT) for elderly (≥80 years old) hepatocellular carcinoma (HCC) patients. Proton therapy was performed using respiratory-gated and image-guided techniques. Seventy-one elderly HCC patients were treated using IGPT. The Child-Pugh score was A5 in 49 patients, A6 in 15, and B7-9 in 7. Forty-seven patients with a peripherally located tumor were administered 66 gray relative biological effectiveness (GyRBE) in 10 fractions, whereas 24 with a centrally located tumor received 72.6 GyRBE in 22 fractions. The median follow-up period of surviving patients was 33 months (range: 9-68). Two-year overall survival (OS) and local control (LC) rates estimated by the Kaplan-Meier method were 76% (95% confidence interval: 66-87%) and 88% (80-97%), respectively. According to the Common Terminology Criteria for Adverse Events version 4.0, no grade 2 or higher radiation-induced liver disease was observed, and only 1 patient developed grade 3 dermatitis. The quality of life score (European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 version 3.0, QLQ-HCC18, and SF-36) did not change after 1 year, except for the three-mental component summary (SF-36, improvement). IGPT is a safe and effective treatment for HCC in elderly patients.

Concurrent Chemo-Proton Therapy Using Adaptive Planning for Unresectable Stage 3 Non-Small Cell Lung Cancer: A Phase 2 Study.

PURPOSE: This study prospectively evaluated the efficacy and safety of concurrent chemo-proton therapy (CCPT) using adaptive planning for unresectable stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: The primary endpoint was overall survival (OS). Secondary endpoints were local control rate (LCR), progression-free survival (PFS), incidence of grade 3 or higher adverse events, and changes in quality of life (QOL). Patients received cisplatin (60 mg/m2) on day 1 and S-1 (∼40 mg/m2 twice daily) on days 1 to 14, q4w, for up to 4 cycles, plus concurrent proton therapy at a total dose of 70 GyRBE for the primary lesion and 66 GyRBE for lymph node metastasis with 2 GyRBE per day. Proton therapy was performed using respiratory-gated and image guided techniques, and adaptive plans were implemented. RESULTS: Forty-seven patients were enrolled between August 2013 and August 2018. Four cycles of cisplatin plus S-1 were completed in 34 patients. The mean number of cycles was 4 (range, 1-4). The median follow-up of all and surviving patients was 37 (range, 4-84) and 52 months (range, 26-84), respectively. The mean number of replanning sessions was 2.5 (range, 1-4). The 2- and 5-year OS, LCR, and PFS were 77% (95% confidence interval 64%-89%) and 59% (43%-76%), 84% (73%-95%) and 61% (44%-78%), and 43% (28%-57%) and 37% (22%-51%), respectively. The median OS was not reached. No grade 3 or higher radiation pneumonitis was observed. There was no significant deterioration in the QOL scores after 24 months except for alopecia. CONCLUSIONS: CCPT with adaptive planning was well tolerated and yielded remarkable OS for unresectable stage III NSCLC.

Combined effects of cisplatin and photon or proton irradiation in cultured cells: radiosensitization, patterns of cell death and cell cycle distribution.

The purpose of the current study was to investigate the biological effects of protons and photons in combination with cisplatin in cultured cells and elucidate the mechanisms responsible for their combined effects. To evaluate the sensitizing effects of cisplatin against X-rays and proton beams in HSG, EMT6 and V79 cells, the combination index, a simple measure for quantifying synergism, was estimated from cell survival curves using software capable of performing the Monte Carlo calculation. Cell death and apoptosis were assessed using live cell fluorescence imaging. HeLa and HSG cells expressing the fluorescent ubiquitination-based cell cycle indicator system (Fucci) were irradiated with X-rays and protons with cisplatin. Red and green fluorescence in the G1 and S/G2/M phases, respectively, were evaluated and changes in the cell cycle were assessed. The sensitizing effects of ≥1.5 µM cisplatin were observed for both X-ray and proton irradiation (P < 0.05). In the three cell lines, the average combination index was 0.82-1.00 for X-rays and 0.73-0.89 for protons, indicating stronger effects for protons. In time-lapse imaging, apoptosis markedly increased in the groups receiving ≥1.5 µM cisplatin + protons. The percentage of green S/G2/M phase cells at that time was higher when cisplatin was combined with proton beams than with X-rays (P < 0.05), suggesting more significant G2 arrest. Proton therapy plus ≥1.5 µM cisplatin is considered to be very effective. When combined with cisplatin, proton therapy appeared to induce greater apoptotic cell death and G2 arrest, which may partly account for the difference observed in the combined effects.

Prediction of dose distribution from luminescence image of water using a deep convolutional neural network for particle therapy.

PURPOSE: We recently obtained nearly the same depth profiles of luminescence images of water as dose for protons by subtracting the Cerenkov light component emitted by secondary electrons of prompt gamma photons. However, estimating the distribution of Cerenkov light with this correction method is time-consuming, depending on the irradiated energy of protons by Monte Carlo simulation. Therefore, we proposed a method of estimating dose distributions from the measured luminescence images of water using a deep convolutional neural network (DCNN). METHODS: In this study, we adopted the U-Net architectures as the DCNN. To prepare a large amount of image data for DCNN training, we calculated the training data pairs of two-dimensional (2D) dose distributions and luminescence images of water by Monte Carlo simulation for protons and carbon ions. After training the U-Net model for protons or carbon ions using these dose distributions and luminescence images calculated by Monte Carlo simulation, we predicted the dose distributions from the calculated and measured luminescence images of water using the trained U-Net model. RESULTS: All of the U-Net model's predicted images were in good agreement with the MC-calculated dose distributions and showed lower values of the root mean square percentage error (RSMPE) and higher values in the structural similarity index (SSIM) in comparison with these values for calculated or measured luminescence images. CONCLUSION: We confirmed that the DCNN effectively predicts dose distributions in water from the measured as well as calculated luminescence images of water for particle therapy.

Liver phantom design and dosimetric verification in participating institutions for a proton beam therapy in patients with resectable hepatocellular carcinoma: Japan Clinical Oncology Group trial (JCOG1315C).

BACKGROUND AND PURPOSE: In Japan, the first domestic clinical trial of proton beam therapy for the liver was initiated as the Japan Clinical Oncology Group trial (JCOG1315C: Non-randomized controlled study comparing proton beam therapy and hepatectomy for resectable hepatocellular carcinoma). Purposes of this study were to develop a new dosimetric verification system and to carry out a credentialing for the JCOG1315C clinical trial. MATERIALS AND METHODS: Accuracy and differences in doses in proton treatment planning among participating institutions were surveyed and investigated. We designed and developed a suitable water tank-type liver phantom for a dosimetric verification of proton beam therapy for liver. In a visiting survey of five institutions participating in the clinical trial, we performed the dosimetric verification using the liver phantom and an air-filled ionization chamber. RESULTS: The shape of the dose distributions calculated in proton treatment planning was characteristic and dependent on the manufacturers of the proton beam therapy system, the proton treatment planning system and the setup at the participating institutions. Widths of the lateral penumbra were 5.8-12.7 mm among participating institutions. The accuracy between the calculated and the measured doses in the proton irradiation was within 3% at five measurement points including both points on the isocenter and off the isocenter. CONCLUSIONS: These findings confirmed the accuracy of the delivery doses in the institutions participating in the clinical trial, and the clinical trial with integration of all institutions (five institutions) could be initiated.