Feasibility of carbon-ion radiotherapy for re-irradiation of locoregionally recurrent, metastatic, or secondary lung tumors.

Intrathoracic recurrence after carbon-ion radiotherapy for primary or metastatic lung tumors remains a major cause of cancer-related deaths. However, treatment options are limited. Herein, we report on the toxicity and efficacy of re-irradiation with carbon-ion radiotherapy for locoregionally recurrent, metastatic, or secondary lung tumors. Data of 95 patients with prior intrathoracic carbon-ion radiotherapy who were treated with re-irradiation with carbon-ion radiotherapy at our institution between 2006 and 2016 were retrospectively analyzed. Seventy-three patients (76.8%) had primary lung tumors and 22 patients (23.2%) had metastatic lung tumors. The median dose of initial carbon-ion radiotherapy was 52.8 Gy (relative biological effectiveness) and the median dose of re-irradiation was 66.0 Gy (relative biological effectiveness). None of the patients received concurrent chemotherapy. The median follow-up period after re-irradiation was 18 months. In terms of grade ≥3 toxicities, one patient experienced each of the following: grade 5 bronchopleural fistula, grade 4 radiation pneumonitis, grade 3 chest pain, and grade 3 radiation pneumonitis. The 2-year local control and overall survival rates were 54.0% and 61.9%, respectively. In conclusion, re-irradiation with carbon-ion radiotherapy was associated with relatively low toxicity and moderate efficacy. Re-irradiation with carbon-ion radiotherapy might be an effective treatment option for patients with locoregionally recurrent, metastatic, or secondary lung tumors.

Comparative Analysis of Photon Stereotactic Radiotherapy and Carbon-Ion Radiotherapy for Elderly Patients with Stage I Non-Small-Cell Lung Cancer: A Multicenter Retrospective Study.

The emergence of an aging society and technological advances have made radiotherapy, especially stereotactic body radiotherapy (SBRT), a common alternative to surgery for elderly patients with early stage non-small-cell lung cancer (NSCLC). Carbon-ion radiotherapy (CIRT) is also an attractive treatment option with potentially lower toxicity for elderly patients with comorbidities. We compared the clinical outcomes of the two modalities using Japanese multicenter data. SBRT (n = 420) and single-fraction CIRT (n = 70) data for patients with stage I NSCLC from 20 centers were retrospectively analyzed. Contiguous patients ≥ 80 years of age were enrolled, and overall survival (OS), disease-specific survival (DSS), local control (LC), and adverse event rates were compared. The median age was 83 years in both groups and the median follow-up periods were 28.5 and 42.7 months for SBRT and CIRT, respectively. The 3-year OS, DSS, and LC rates were 76.0% vs. 72.3% (p = 0.21), 87.5% vs. 81.6% (p = 0.46), and 79.2% vs. 78.2% (p = 0.87), respectively, for the SBRT vs. CIRT groups. Regarding toxicity, 2.9% of the SBRT group developed grade ≥ 3 radiation pneumonitis, whereas none of the CIRT group developed grade ≥ 2 radiation pneumonitis. SBRT and CIRT in elderly patients showed similar survival and LC rates, although CIRT was associated with less severe radiation pneumonitis.

Proton therapy for patients with esophageal cancer: History, characteristics, clinical outcome and future direction of proton beam therapy.

After the second war, Wilson who participated in development of the atomic bomb in Los Alamos studied peaceful use of atomic energy and proposed a property of proton beam that has potential to treat cancer. According to his proposal, the first patient was treated with proton beam therapy at the University of California Berkley in 1954. The first series of proton beam therapy for patients with esophageal cancer was reported from Japan in 1993. After that many proton facilities in Japan reported the clinical outcome of patients with esophageal cancer. Many dosimetric and clinical studies showed proton beam therapy for esophageal cancer was less toxic than photon beam therapy, however there is a paucity of randomized trials and evidence that proton beam therapy has clearly superior survival compared to photon therapy. Only one randomized trial has been conducted to study less toxicity for proton beam compared with intensity modulated radiotherapy (IMRT), which was stopped early because toxicities of IMRT were higher. A phase III study comparing overall survival between proton beam therapy and IMRT is now activated. A cost reduction for proton therapy is necessary to facilitate patient care and establishment of clinical evidence.

Transvaginal artificial ascites infusion as a spacer in gynecological brachytherapy: a novel technique.

This is a first paper to report on artificial ascites infusion via vaginal wall for pelvic interstitial brachytherapy. Artificial ascites is commonly used for treating liver tumors, with radiofrequency ablation and percutaneous artificial ascites infusion through the abdominal wall for pelvic brachytherapy has been previously reported by our group. However, the trans-abdominal needle approach under ultrasound guidance is unreliable due to poor visualization resulting in fluid injection into the abdominal wall or mesenterium and the rate of successful artificial ascites infusion was low. Target tumor of the vaginal cuff brachytherapy is usually adjacent to the intestine, and transvaginal artificial ascites infusion under trans-rectal ultrasonography is considered as a rational and simpler method to create a space between target volume and organs at risk, such as intestines or sigmoid colon, by increased visualization of the needle compared to trans-abdominal approach. Here, we report a practical experience of transvaginal artificial ascites infusion.

Prevention of calpain-dependent degradation of STK38 by MEKK2-mediated phosphorylation.

Serine-threonine kinase 38 (STK38) is a member of the protein kinase A (PKA)/PKG/PKC-family implicated in the regulation of cell division and morphogenesis. However, the molecular mechanisms underlying STK38 stability remain largely unknown. Here, we show that treatment of cells with either heat or the calcium ionophore A23187 induced STK38 degradation. The calpain inhibitor calpeptin suppressed hyperthermia-induced degradation or the appearance of A23187-induced cleaved form of STK38. An in vitro cleavage assay was then used to demonstrate that calpain I directly cleaves STK38 at the proximal N-terminal region. Deletion of the N-terminal region of STK38 increased its stability against hyperthermia. We further demonstrated that the MAPKK kinase (MAP3K) MEKK2 prevented both heat- and calpain-induced cleavage of STK38. MEKK2 knockdown enhanced hyperthermia-induced degradation of STK38. We performed an in vitro MEKK2 assay and identified the key regulatory site in STK38 phosphorylated by MEKK2. Experiments with a phosphorylation-defective mutant demonstrated that phosphorylation of Ser 91 is important for STK38 stability, as the enzyme is susceptible to degradation by the calpain pathway unless this residue is phosphorylated. In summary, we demonstrated that STK38 is a calpain substrate and revealed a novel role of MEKK2 in the process of STK38 degradation by calpain.

Gating window dependency on scanned carbon-ion beam dose distribution and imaging dose for thoracoabdominal treatment.

OBJECTIVE: To explore the trade-off between dose assessment and imaging dose in respiratory gating with radiographic fluoroscopic imaging, we evaluated the relationship between dose assessment and fluoroscopic imaging dose in various gating windows, retrospectively. METHODS: Four-dimensional (4D) CT images acquired for 10 patients with lung and liver tumours were used for 4D treatment planning for scanned carbon ion beam. Imaging dose from two oblique directions was calculated by the number of images multiplied by the air kerma per image. Necessary beam-on time was calculated from the treatment log file. Accumulated dose distribution was calculated. The gating window was defined as tumour position not respiratory phase and changed from 0-100% duty cycle on 4DCT. These metrics were individually evaluated for every case. RESULTS: For lung cases, sufficient dose conformation was achieved in respective gating windows [D95-clinical target volume (CTV) > 99%]. V20-lung values for 50%- and 30%-duty cycles were 2.5% and 6.0% of that for 100%-duty cycle. Maximum doses (cord/oesophagus) for 30%-duty cycle decreased 6.8%/7.4% to those for 100%-duty cycle. For liver cases, V10-liver values for 50%- and 30%-duty cycles were 9.4% and 12.8% of those for 100%-duty cycle, respectively. Maximum doses (cord/oesophagus) for 50%- and 30%-duty cycles also decreased 17.2%/19.3% and 24.6%/29.8% to those for 100%-duty cycle, respectively. Total imaging doses increased 43.5% and 115.8% for 50%- and 30%-duty cycles to that for the 100%-duty cycle. CONCLUSION: When normal tissue doses are below the tolerance level, the gating window should be expanded to minimize imaging dose and treatment time. Advances in knowledge: The skin dose from imaging might not be counterbalanced to the OAR dose; however, imaging dose is a particularly important factor.

Carbon-ion re-irradiation for recurrences after initial treatment of stage I non-small cell lung cancer with carbon-ion radiotherapy.

PURPOSE: To investigate carbon-ion radiotherapy (CIRT) for in-field recurrence of stage I non-small cell lung cancer (NSCLC) initially treated with CIRT. MATERIALS AND METHODS: From January 2007 to March 2014, patients initially treated for stage I NSCLC with CIRT and relapsed in-field were candidates. Overall survival (OS) rate, local control (LC) rate, progressive free survival (PFS) rate, dose to the lungs and skin, and adverse effects were analyzed. RESULTS: Twenty-nine patients were eligible. Median age at re-irradiation was 74years (range 53-90). Median observation period from the first day of re-irradiation was 29months (4-88months). Median prescribed dose was 46.0Gy (RBE) as initial treatment and 66.0Gy (RBE) in 12 fractions as re-irradiation. Two-year OS, LC, and PFS rates after re-irradiation were 69.0% (95% CI: 50.3-83.0), 66.9% (95% CI: 47.5-81.9), and 51.7% (95% CI: 34.1-68.9). Median skin maximum dose was 53.8Gy (RBE) (range 4.4-103.1) and median of mean lung dose was 7.3Gy (RBE) (range 2.6-14.0). There were no severer than grade 2 adverse effects except one (3.4%) grade 3 bacterial pneumonia, which was not considered radiation-induced. CONCLUSION: CIRT for stage I NSCLC local recurrence is an acceptable definitive re-treatment.

Prognostic analysis of radiation pneumonitis: carbon-ion radiotherapy in patients with locally advanced lung cancer.

BACKGROUND: Carbon-ion radiotherapy (CIRT) is a promising treatment for locally advanced non-small-cell lung cancer, especially for patients with inoperable lung cancer. Although the incidence of CIRT-induced radiation pneumonitis (RP) ≥ grade 2 ranges from 2.5 to 9.9%, the association between CIRT-induced RP and dosimetric parameters is not clear. Herein, we identified prognostic factors associated with symptomatic RP after CIRT for patients with non-small-cell lung cancer. METHODS: Clinical results of 65 patients treated with CIRT between 2000 and 2015 at the National Institute of Radiological Sciences were retrospectively analyzed. Clinical stage II B disease (TNM classification) was the most common stage among the patients (45%). The median radiation dose was 72 Gy (68-76) relative biological effectiveness (RBE) in 16 fractions. In cases involving metastatic lymph nodes, prophylactic irradiation of mediastinal lymph nodes was performed at a median dose of 49.5 Gy (RBE). The median follow-up was 22 months. RESULTS: Grade 2 and grade 3 RP occurred in 6 and 3 patients (9 and 5%), respectively. No patients developed grade 4 or 5 RP. Using univariate analysis, vital capacity as a percentage of predicted (%VC), forced expiratory volume in 1 s (FEV1), mean lung dose (MLD), volume of lung receiving ≥5 Gy (RBE) (V5), V10, V20 and V30 were determined to be the significant predictive factors for ≥ grade 2 RP. The receiver operating characteristic (ROC) analysis revealed the cutoff values for %VC, FEV1, MLD, V5, V10, V20 and V30 for ≥ grade 2 RP, which were 86.9%, 1.16 L, 12.5 Gy (RBE), 28.8, 29.9, 20.1 and 15.0%, respectively. In addition, the multivariate analysis revealed that %VC <86.9% (odds ratio = 13.7; p = 0.0041) and V30 ≥ 15% (odds ratio = 6.1; p = 0.0221) were significant risk factors. CONCLUSIONS: Our study demonstrated the risk factors for ≥ grade 2 RP after carbon-ion radiotherapy for patients with locally advanced lung cancer.

A Dose Escalation Clinical Trial of Single-Fraction Carbon Ion Radiotherapy for Peripheral Stage I Non-Small Cell Lung Cancer.

OBJECTIVES: Our objective was to report initial results of a dose escalation trial of single-fraction carbon ion radiotherapy for peripheral stage I NSCLC. METHODS: Between April 2003 and February 2012, a total of 218 patients were treated. The total dose was raised from 28 to 50 Gy (relative biological effectiveness [RBE]). There were 157 male and 61 female patients, with a median age of 75 years. Of the tumors, 123 were stage T1 and 95 were stage T2. A total of 134 patients (61.5%) were medically inoperable. By histological type, there were 146 adenocarcinomas, 68 squamous cell carcinomas, three large cell carcinomas, and one mucoepidermoid carcinoma. RESULTS: The median follow-up was 57.8 months (range 1.6-160.7). The overall survival rate at 5 years was 49.4%. The local control (LC) rate was 72.7%. A statistically significant difference in LC rate (p = 0.0001, log-rank test) was seen between patients receiving 36 Gy (RBE) or more and those receiving less than 36 Gy (RBE). In 20 patients irradiated with 48 to 50 Gy (RBE), the LC rate at 5 years was 95.0%, the overall survival rate was 69.2%, and the progression-free survival rate was 60.0% (median follow-up was 58.6 months). With dose escalation, LC tended to improve. As for adverse lung and skin reactions, there were no patients with grade 3 or higher reactions, and less than 2% had a grade 2 reaction. Regarding chest wall pain, only one patient had grade 3 late toxicity. CONCLUSIONS: We have reported the outcome of a dose escalation study of single-fraction carbon ion radiotherapy for stage I NSCLC, showing the feasibility of obtaining excellent results comparable to those with previous fractionated regimens.

Carbon-ion radiotherapy for patients with advanced stage non-small-cell lung cancer at multicenters.

Carbon-ion radiation therapy (CIRT) for advanced non-small-cell lung cancer (NSCLC) has not been well studied to date. This paper aimed to analyze a retrospective multicenter survey for detecting problems with the use of CIRT for Stage II and III NSCLC (7th UICC TNM Staging System). Inclusion was restricted to patients with Stage II and III NSCLC who received CIRT from November 2003 to December 2014. We gathered the data from three CIRT operating centers on July 2015. Patients with radiotherapy history, patients with cancers other than lung cancer, and those receiving palliative therapies were excluded. The patient characteristics, prescribed dose/fraction, survival rates, and adverse effects were analyzed. The total number of patients was 64 (male: 49, female: 15). Of these, 53 patients were medically inoperable. The median age was 76 years (range 46-91), and the median follow-up period was 18.5 months (range 3.2-121.5). The clinical staging consisted of 10 Stage IIA, 30 Stage IIB, 23 Stage IIIA and 1 Stage IIIB. The median prescribed dose was 72.0 Gy (RBE) (range 52.8-72.0) in 16 fractions (range 4-16). The 2-year overall survival, progression-free survival, and local control rates were 62.2% [confidence interval (CI): 47.5-76.9], 42.3% (CI: 28.8-55.8) and 81.8% (CI: 69.9-94.0), respectively. There were no higher than Grade 2 adverse effects observed. CIRT for inoperable Stage II and III NSCLC could be implemented without severe adverse effects, but the clinical staging (including lymph node status) was inhomogeneous. In addition, the prescribed dose and fractionation were not standardized. Further data accumulation and a multiple centers prospective trial for evaluating clinical stage-based results are required.

Carbon-ion radiotherapy for non-small cell lung cancer with interstitial lung disease: a retrospective analysis.

BACKGROUND: Lung cancer is frequently complicated by interstitial lung disease (ILD). Treatment protocols for lung cancer patients with ILD have not been established; surgery, chemotherapy, and radiotherapy can all cause acute exacerbation of ILD. This study evaluated the toxicity and efficacy of carbon ion radiotherapy (CIRT) in patients with non-small cell lung cancer (NSCLC) and ILD. METHODS: Between June 2004 and November 2014, 29 patients diagnosed with NSCLC and ILD were treated with CIRT. No patient was eligible for curative surgery or conventional radiotherapy secondary to ILD. Owing to prior symptomology, radiation pneumonitis (RP) and symptom progression pre- and post-treatment were evaluated. The relationships between RP and clinical factors were investigated. RESULTS: Twenty-eight men and one woman, aged 62 to 90 years old, were followed for 2.7-77.1 months (median: 22.8 months). Single-grade symptomatic progression (grade 2-3) was observed in 4 patients, while 1 patient experiencedtwo-grade progression. Two patients experienced radiation-induced acute exacerbation. Local control at 3 years was 63.3% (72.2% for stage I disease); survival at 3 years was 46.3% (57.2% for stage I disease). Eighteen patients had died by the time of this writing, 10 of lung cancer progression. Radiation pneumonitis post-treatment progression correlated with dosimetric factors of the lungs (V5, V10) and a low pre-treatment serum surfactant protein-D. CONCLUSIONS: We found that CIRT may be useful as a low-risk, curative option for NSCLC patients with ILD, a population that is typically ineligible for conventional therapy. The DVH analysis showed that minimizing the low-dose region is important for reducing the risk of severe RP. TRIAL REGISTRATION: NIRS-9404 . Registered 1 March 1994.

Dosimetric impact of 4DCT artifact in carbon-ion scanning beam treatment: Worst case analysis in lung and liver treatments.

INTRODUCTION: We evaluated the impact of 4DCT artifacts on carbon-ion pencil beam scanning dose distributions in lung and liver treatment. METHODS & MATERIALS: 4DCT was performed in 20 liver and lung patients using area-detector CT (original 4DCT). 4DCT acquisition by multi-detector row CT was simulated using original 4DCT by selecting other phases randomly (plus/minus 20% phases). Since tumor position can move over the respiratory range in original 4DCT, mid-exhalation was set as reference phase. Total prescribed dose of 60Gy (RBE) was delivered to the clinical target volume (CTV). Reference dose distribution was calculated with the original CT, and actual dose distributions were calculated with treatment planning parameters optimized using the simulated CT (simulated dose). Dose distribution was calculated by substituting these parameters into the original CT. RESULTS: For liver cases, CTV-D95 and CTV-Dmin values for the reference dose were 97.6±0.5% and 89.8±0.6% of prescribed dose, respectively. Values for the simulated dose were significantly degraded, to 88.6±14.0% and 46.3±26.7%, respectively. Dose assessment results for lung cases were 84.8±12.8% and 58.0±24.5% for the simulated dose, showing significant degradation over the reference dose of 95.1±1.5% and 87.0±2.2%, respectively. CONCLUSIONS: 4DCT image quality should be closely checked to minimize degradation of dose conformation due to 4DCT artifacts. Medical staff should pay particular attention to checking the quality of 4DCT images as a function of respiratory phase, because it is difficult to recognize 4DCT artifact on a single phase in some cases.

Carbon-ion pencil beam scanning for thoracic treatment - initiation report and dose metrics evaluation.

Carbon-ion beam scanning has not previously been used for moving tumor treatments. We have commenced respiratory-gated carbon-ion radiotherapy (CIRT) in the thoracic and abdominal regions under free-breathing conditions as a clinical trial. This study aimed to investigate this treatment in the lungs in comparison with passive scattering CIRT. Five patients had thoracic tumors treated with carbon-ion scanned beams using respiratory gating. We analyzed the actual treatments and calculated passive scattering treatment plans based on the same planning CT. We evaluated tumor size until 3 months post treatment and each treatment plan regarding dose delivered to 95% of the clinical target volume (CTV-D95), mean lung dose, percentage of lung receiving at least 5 Gy (RBE) (Lung-V5), Lung-V10, Lung-V20, heart maximum dose (Dmax), esophagus Dmax, cord Dmax and skin Dmax. Obvious tumor deterioration was not observed up to 3 months post treatment. The dose evaluation metrics were similar item by item between respiratory-gated scanned CIRT and passive scattering CIRT. In conclusion, scanned beam CIRT provided treatments equivalent to passive scattering CIRT for thoracic tumors. Increased sample numbers and longer-term observation are needed.

Single-Fraction Carbon-Ion Radiation Therapy for Patients 80 Years of Age and Older With Stage I Non-Small Cell Lung Cancer.

PURPOSE: In an aging society, many senior citizens want less invasive treatment because of potential medical complications. The National Institute of Radiological Sciences has started to treat stage I lung cancer with single-fraction carbon-ion radiation therapy (CIRT) as a dose escalation prospective phase 1/2 trial. We evaluated the efficacy and safety of CIRT for patients 80 years of age and older, undergoing single-fraction CIRT. METHODS AND MATERIALS: Peripheral non-small cell lung cancer patients who were treated with single-fraction CIRT were prospectively followed. We analyzed the data from among these patients 80 years of age and older. RESULTS: There were 70 patients. Median age was 83 years (range: 80-89) and median follow-up period was 42.7 months (range: 12-128 months). Three-year local control, cause-specific survival, and overall survival rates were 88.0%, 81.6%, and 72.4%, respectively. Five-year local control, cause-specific survival, and overall survival rates were 85.8%, 64.9%, and 39.7%, respectively. There were no adverse effects higher than grade 2 either in the acute or late phase in terms of skin and lung. Analgesic agents were necessary for only 5 patients (7.1%), to relieve muscular or rib fracture pain caused by irradiation. CONCLUSIONS: Single-fraction CIRT was low-risk and effective, even for the elderly.

Carbon-Ion Pencil Beam Scanning Treatment With Gated Markerless Tumor Tracking: An Analysis of Positional Accuracy.

PURPOSE: Having implemented amplitude-based respiratory gating for scanned carbon-ion beam therapy, we sought to evaluate its effect on positional accuracy and throughput. METHODS AND MATERIALS: A total of 10 patients with tumors of the lung and liver participated in the first clinical trials at our center. Treatment planning was conducted with 4-dimensional computed tomography (4DCT) under free-breathing conditions. The planning target volume (PTV) was calculated by adding a 2- to 3-mm setup margin outside the clinical target volume (CTV) within the gating window. The treatment beam was on when the CTV was within the PTV. Tumor position was detected in real time with a markerless tumor tracking system using paired x-ray fluoroscopic imaging units. RESULTS: The patient setup error (mean ± SD) was 1.1 ± 1.2 mm/0.6 ± 0.4°. The mean internal gating accuracy (95% confidence interval [CI]) was 0.5 mm. If external gating had been applied to this treatment, the mean gating accuracy (95% CI) would have been 4.1 mm. The fluoroscopic radiation doses (mean ± SD) were 23.7 ± 21.8 mGy per beam and less than 487.5 mGy total throughout the treatment course. The setup, preparation, and irradiation times (mean ± SD) were 8.9 ± 8.2 min, 9.5 ± 4.6 min, and 4.0 ± 2.4 min, respectively. The treatment room occupation time was 36.7 ± 67.5 min. CONCLUSIONS: Internal gating had a much higher accuracy than external gating. By the addition of a setup margin of 2 to 3 mm, internal gating positional error was less than 2.2 mm at 95% CI.