Naoyoshi Yamamoto

Carbon ion radiotherapy for stage I non-small cell lung cancer.

BACKGROUND AND PURPOSE Heavy ion radiotherapy is a promising modality because of its excellent dose localization and high biological effect on tumors. Using carbon beams, a dose escalation study was conducted for the treatment of stage I non-small cell lung cancer (NSCLC) to determine the optimal dose. MATERIALS AND METHODS The first stage phase I/II trial using 18 fractions over 6 weeks for 47 patients and the second one using nine fractions over 3 weeks for 34 patients were conducted by the dose escalation method from 59.4 to 95.4 Gray equivalents (GyE) in incremental steps of 10% and from 68.4 to 79.2 GyE in 5% increments, respectively. The local control and survival rates were obtained using the Kaplan-Meier method. RESULTS Radiation pneumonitis at grade III occurred in three of 81 patients, but they fully recovered. This was not a dose-limiting factor. The local control rates in the first and second trials were 64% and 84%, respectively. The total recurrence rate in both trials was 23.2%. The infield local recurrence in the first trial was significantly dependent on carbon dose. The doses greater than 86.4 GyE at 18 fractions and 72 GyE at nine fractions achieved a local control of 90% and 95%, respectively. The 5 year overall and cause-specific survivals in 81 patients were 42% and 60%, respectively. CONCLUSIONS With our dose escalation study, the optimum safety and efficacy dose of carbon beams was determined. Carbon beam therapy attained almost the same results as surgery for stage I NSCLC although this was a I/II study.

Carbon ion radiotherapy for elderly patients 80 years and older with stage I non-small cell lung cancer.

Surgical resection is the standard treatment for stage I non-small cell lung cancer (NSCLC). However, elderly patients with NSCLC often suffer from other conditions, such as chronic obstructive pulmonary disease (COPD) or cardiovascular disease, and are not suitable candidates for surgery. Different modalities to treat stage I NSCLC have been developed, such as stereotactic radiotherapy (SRT), proton beam radiotherapy and carbon ion radiotherapy (CIRT). Between April 1999 and November 2003, we treated 129 patients with stage I NSCLC using CIRT. In this study, we focused on 28 patients aged 80 years and older who underwent CIRT, and analyzed the effectiveness of CIRT in treating their lung cancer and the impact on their activity of daily life (ADL). The 5-year local control rate for these patients was 95.8%, and the 5-year overall survival rate was 30.7%, but there were no patients who started home oxygen therapy or had decreased ADL. Our data demonstrate that CIRT was effective in treating elderly patients with stage I NSCLC.

Radiographic pulmonary and pleural changes after carbon ion irradiation

PURPOSE For the treatment of Stage I non-small-cell lung cancers, a Phase I/II study of carbon ion irradiation was undertaken. In the present study, we focus on posttreatment radiographic lung damage: specifically, its timing, features, and relation to dose-volume factors. MATERIALS AND METHODS Forty-three patients with 44 Stage I non-small-cell lung cancers were treated with carbon ion irradiation ranging from 59.4 to 95.4 photon Gy equivalent dose (GyE) in 18 fractions over 6 weeks, according to our dose escalation protocols. Primary lesions were irradiated by 2-4 portals. Follow-up evaluation with computed tomography (CT) was sequentially performed to assess changes in the lung. CT findings were classified into two categories: pulmonary reaction and pleural reaction. A dose-volume histogram for each patient was calculated, using a three-dimensional CT planning system. Statistical analysis was conducted using Spearmans rank test. RESULTS The median appearance period of pulmonary reactions was 3 months after the start of carbon ion irradiation, whereas the maximum period was 6 months. The severity of pulmonary reactions statistically correlated with lung volumes irradiated no less than 20 GyE (vol. 20) and 40 GyE (vol. 40) (p = 0.017 and p = 0.0089). Geometrically unique findings in the irradiated fields were observed in 7 patients (16%). The median appearance period of pleural reactions was 4 months after the start of carbon ion irradiation. The occurrence of pleural reactions significantly correlated with planning target volume (p = 0.000098), vol. 20 (p = 0.00011), and vol. 40 (p = 0.00097). CONCLUSIONS Lung damage after carbon ion irradiation was observed in the parenchyma and in the pleura. The severity of pulmonary reactions was correlated with dose-volume factors. These findings might provide useful information in the planning and management of carbon ion irradiation.

Amplitude-based gated phase-controlled rescanning in carbon-ion scanning beam treatment planning under irregular breathing conditions using lung and liver 4DCTs

Amplitude-based gating aids treatment planning in scanned particle therapy because it gives better control of uncertainty with the gate window. We have installed an X-ray fluoroscopic imaging system in our treatment room for clinical use with an amplitude-based gating strategy. We evaluated the effects of this gating under realistic organ motion conditions using 4DCT data of lung and liver tumors. 4DCT imaging was done for 24 lung and liver patients using the area-detector CT. We calculated the field-specific target volume (FTV) for the gating window, which was defined for a single respiratory cycle. Prescribed doses of 48 Gy relative biological effectiveness (RBE)/fraction/four fields and 45 Gy RBE/two fractions/two fields were delivered to the FTVs for lung and liver treatments, respectively. Dose distributions were calculated for the repeated first respiratory cycle (= planning dose) and the whole respiratory data (= treatment dose). We applied eight phase-controlled rescannings with the amplitude-based gating. For the lung cases, D95 of the treatment dose (= 96.0 ± 1.0%) was almost the same as that of the planning dose (= 96.6 ± 0.9%). Dmax/Dmin of the treatment dose (= 104.5 ± 2.2%/89.4 ± 2.6%) was slightly increased over that of the planning dose (= 102.1 ± 1.0%/89.8 ± 2.5%) due to hot spots. For the liver cases, D95 of the treatment dose (= 97.6 ± 0.5%) was decreased by ∼ 1% when compared with the planning dose (= 98.5 ± 0.4%). Dmax/Dmin of the treatment dose was degraded by 3.0%/0.4% compared with the planning dose. Average treatment times were extended by 46.5 s and 65.9 s from those of the planning dose for lung and liver cases, respectively. As with regular respiratory patterns, amplitude-based gated multiple phase-controlled rescanning preserves target coverage to a moving target under irregular respiratory patterns.

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.

A prospective nonrandomized phase I/II study of carbon ion radiotherapy in a favorable subset of locally advanced non-small cell lung cancer (NSCLC).

Although concurrent chemoradiotherapy (CCRT) has become the standard approach for unresectable locally advanced non–small cell lung cancer (LA‐NSCLC), most patients are not candidates for this treatment because of comorbidities. We evaluated the safety and efficacy of carbon ion radiotherapy (CIRT) in LA‐NSCLC patients.

Four-Dimensional Lung Treatment Planning in Layer-Stacking Carbon Ion Beam Treatment: Comparison of Layer-Stacking and Conventional Ungated/Gated Irradiation

PURPOSE We compared four-dimensional (4D) layer-stacking and conventional carbon ion beam distribution in the treatment of lung cancer between ungated and gated respiratory strategies using 4DCT data sets. METHODS AND MATERIALS Twenty lung patients underwent 4DCT imaging under free-breathing conditions. Using planning target volumes (PTVs) at respective respiratory phases, two types of compensating bolus were designed, a full single respiratory cycle for the ungated strategy and an approximately 30% duty cycle for the exhalation-gated strategy. Beams were delivered to the PTVs for the ungated and gated strategies, PTV(ungated) and PTV(gated), respectively, which were calculated by combining the respective PTV(Tn)s by layer-stacking and conventional irradiation. Carbon ion beam dose distribution was calculated as a function of respiratory phase by applying a compensating bolus to 4DCT. Accumulated dose distributions were calculated by applying deformable registration. RESULTS With the ungated strategy, accumulated dose distributions were satisfactorily provided to the PTV, with D95 values for layer-stacking and conventional irradiation of 94.0% and 96.2%, respectively. V20 for the lung and Dmax for the spinal cord were lower with layer-stacking than with conventional irradiation, whereas Dmax for the skin (14.1 GyE) was significantly lower (21.9 GyE). In addition, dose conformation to the GTV/PTV with layer-stacking irradiation was better with the gated than with the ungated strategy. CONCLUSIONS Gated layer-stacking irradiation allows the delivery of a carbon ion beam to a moving target without significant degradation of dose conformity or the development of hot spots.

Carbon-ion scanning lung treatment planning with respiratory-gated phase-controlled rescanning: simulation study using 4-dimensional CT data

BackgroundTo moving lung tumors, we applied a respiratory-gated strategy to carbon-ion pencil beam scanning with multiple phase-controlled rescanning (PCR). In this simulation study, we quantitatively evaluated dose distributions based on 4-dimensional CT (4DCT) treatment planning.MethodsVolumetric 4DCTs were acquired for 14 patients with lung tumors. Gross tumor volume, clinical target volume (CTV) and organs at risk (OARs) were delineated. Field-specific target volumes (FTVs) were calculated, and 48Gy(RBE) in a single fraction was prescribed to the FTVs delivered from four beam angles. The dose assessment metrics were quantified by changing the number of PCR and the results for the ungated and gated scenarios were then compared.ResultsFor the ungated strategy, the mean dose delivered to 95% of the volume of the CTV (CTV-D95) was in average 45.3 ± 0.9 Gy(RBE) even with a single rescanning (1 × PCR). Using 4 × PCR or more achieved adequate target coverage (CTV-D95 = 46.6 ± 0.3 Gy(RBE) for ungated 4 × PCR) and excellent dose homogeneity (homogeneity index =1.0 ± 0.2% for ungated 4 × PCR). Applying respiratory gating, percentage of lung receiving at least 20 Gy(RBE) (lung-V20) and heart maximal dose, averaged over all patients, significantly decreased by 12% (p < 0.05) and 13% (p < 0.05), respectively.ConclusionsFour or more PCR during PBS-CIRT improved dose conformation to moving lung tumors without gating. The use of a respiratory-gated strategy in combination with PCR reduced excessive doses to OARs.

Carbon ion radiotherapy in a hypofractionation regimen for stage I non-small-cell lung cancer

Introduction: In 1994, we started carbon-ion radiotherapy (CIRT) for peripheral stage I non-small-cell lung cancer (NSCLC). First, two phase I/II clinical trials demonstrated the optimal doses of 90.0 GyE in 18 fractions over 6 weeks (Protocol 9303) and 72.0 GyE in 9 fractions over 3 weeks (Protocol 9701) for achieving more than 95% local control with minimal pulmonary toxicity. As a next step, we conducted two successive phase II trials. The first trial (Protocol 9802) used a regimen of 72 GyE per 9 fractions over 3 weeks and the second trial (Protocol 0001) used a regimen of 4 fractions over 1 week, at a fixed dose of 52.8 GyE for stage IA and 60 GyE for IB. In these Phase II trials, the local control rate (LCR) for all patients was 91.5%, and those for T1 and T2 tumors were 96.3 and 84.7%, respectively. The 5-year cause-specific survival rate (CSS) was 67.0% (IA: 84.4, IB: 43.7), and overall survival (OS) was 45.3% (IA: 53.9, IB: 34.2). No adverse events greater than grade 2 occurred in the lung. In 2003, we also started a phase I/II clinical trial (Protocol 0201) as a dose escalation study using single fraction. The initial total dose was 28.0 GyE administered and escalated in increments of 2.0 GyE each, up to 50.0 GyE. This clinical trial ended in February 2012 and is still followed up. In this article, we investigated the preliminary results of this phase I/II trial. Materials and methods: In this prospective study, 151 primary stage I NSCLC were treated by CIRT monotherapy using a total dose of 36.0 GyE (n = 18), 38.0 GyE (n = 14), 40.0 GyE (n = 20), 42.0 GyE (n = 15), 44.0 GyE (n = 44), 46.0 GyE (n = 20), 48.0 GyE (n = 10) and 50.0 GyE (n = 10) using single fractionation. Mean age was 73.9 years, and size of tumor included T1 (n = 91) and T2 (n = 60). By type (cancer type was determined by biopsy), there were 104 adenocarcinomas, 46 squamous cell carcinomas and 1 large cell carcinoma. Medical inoperability was 55.6%. The patient is fixed on the rotational couch by using a custom-made immobilization device. Under free breathing conditions, planning CT images were acquired for treatment planning. The clinical target volume (CTV) was determined by adding >10-mm margin to the gross tumor volume (GTV). The planning target volume (PTV) was created by adding an internal margin to CTV as 5 mm in craniocaudal direction. The prescribed dose was delivered to PTV with different coplanar four beam angles. A respiratory-gated irradiation system was used in all irradiation sessions. Results: The median follow-up time was 45.6 months (range, 1.6–88.4 months). For 151 patients, the 5-year overall LCR was 79.2%, and those for T1 (n = 91) and T2 (n = 60) tumors were 83.6 and 72.2%, respectively. Also, local control in T1a, T1b, T2a and T2b were 96.8, 84.4, 80.2 and 20.0%, respectively. The OS was 55.1% and the CSS was 73.1%. No toxicity greater than grade 2 was observed in the lung and the skin. Conclusions: In patients with stage I NSCLC, CIRT using single fraction is considered as a promising curative modality. Especially for elderly and inoperable cases, CIRT could be a minimally invasive therapeutic option as a valid alternative to surgical resection (Fig. 1).Fig 1. Overall survival and local control in 151 patients with stage I non-small-cell lung cancer.

Preoperative carbon ion radiotherapy for non-small cell lung cancer with chest wall invasion—pathological findings concerning tumor response and radiation induced lung injury in the resected organs

The purpose of this study was to make a pathological evaluation of the tumor response and the lung injury of non-small cell lung cancer (NSCLC) patients after carbon ion therapy. We enrolled four NSCLC patients with chest wall invasion but without nodal and distant metastasis (T3N0M0). Only primary lesions were irradiated with carbon ions, followed by surgical resection. The patients consisted of three males and one female varying by age from 54 to 73 (average 66.3). Total treatment dose was 59.4 and 64.8 GyE, respectively, administered in 18 fractions over 6 weeks, or 72.0 GyE in 16 fractions over 4 weeks. Resection after radiation therapy was performed as a combination of lobectomy, lymph node dissection and chest wall surgery. After fixation, the lung was sliced into thin sections to match the CT image. Each slice was anatomically identified and the slices were compared with each other subjected to pathological analysis. No tumor cells were observed in two cases. The other two cases exhibited only a few tumor cells sparsely distributed in the lung tissue. There was evidence of dense pulmonary fibrosis in the limited space surrounding primary tumors, but its density was found to rapidly decrease in the narrow area toward the outside. The rate at which its density subsided mirrored the rapid decrease in the planning CT dose distribution. Microscopy showed no evidence of fibrosis in any of the fields irradiated with less than 15 GyE. Microscopy confirmed an outstanding tumor response with limited pulmonary fibrosis. This substantiates the superior dose localization and strong biological effect of carbon ion beams with a Bragg peak in the lung. The pathological findings have thus provided evidence of the safety and effectiveness of carbon beam therapy in the treatment of NSCLC.