Mio Nakajima

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.

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.

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.

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 oligo-recurrence in the lung.

The clinical results after carbon ion radiotherapy for the metastatic lung tumors believed to be in the state of oligo-recurrence were evaluated. One hundred and sixteen lesions in 91 patients with lung cancer metastasis were treated with carbon ion radiotherapy at our institute from April 1997 to February 2011. Regarding the prescribed dose, total dose ranged between 40 gray equivalents (GyE) and 80 GyE, and fraction size ranged from 1 to 16 fractions. After a median followup period of 2.3 years (range, 0.3–13.1 years), the statistical overall survival rate and local control rate were 71.2% and 91.9% at 2 years after treatment, respectively. Treatment-related side effects were not a clinical problem. When classified by the primary organ, there were 49 cases of lung cancer, 20 cases of colorectal cancer, and 22 cases of others. The overall survival rate and local control rate for lung metastasis cases from lung cancer at 2 years after treatment were 81.5% and 92.4%, respectively, and 65.0% and 92.0% regarding lung metastasis from colorectal cancer. Carbon ion beam therapy for the metastatic lung tumors is a safe therapy, and the therapeutic effect is comparable to the outcome obtained from reported surgical resections.

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.

Salvage surgery for local recurrence after carbon ion radiotherapy for patients with lung cancer.

OBJECTIVES Carbon ion radiotherapy (CIRT) has been expected to be an alternative for surgery for early-stage non-small-cell lung cancer (NSCLC) and adopted as the second-best choice even in operable patients although local recurrence after CIRT is sometimes experienced. The purpose of this study was to investigate the demographic data, perioperative courses and therapeutic outcomes of patients who underwent salvage resection for local recurrence after CIRT. METHODS From November 1994 to February 2012, CIRT was applied for 602 c-T1/T2/T3N0M0 NSCLC lesions of 599 patients at the National Institute of Radiological Science. A total of 95 (16%) patients were diagnosed as having local recurrence, of whom 12 underwent salvage surgeries. The medical records were retrospectively reviewed. RESULTS There were 7 men and 5 women (mean age, 63 ± 7.4 years). The clinical stages upon initial presentation with NSCLC were as follows: 4 IA, 7 IB and 1 IIB. All the patients were operable, but refused surgery and underwent CIRT. The median progression-free survival time after CIRT was 20 months (range, 7.1-77 months), and salvage surgery was performed at a median of 24 months (range, 9-78 months) after CIRT. All surgeries were successfully performed without any significant CIRT-related adhesions during the surgery, resulting in no mortality or Clavien-Dindo grade 3-4 postoperative complications. However, the distribution of pathological stages was as follows: 4 IA, 3 IB, 2 IIB, 2 IIIA and 1 IV, which included 6 upstages from the clinical stages before CIRT. The Kaplan-Meier estimate of overall survival after the salvage surgery showed that the 3-year survival rate was 82%. CONCLUSIONS The dose intensity of CIRT spared the hilum of the lungs and parietal pleura, none of the patients developed adhesions outside of the radiation field, such that the salvage surgeries for local recurrence after CIRT were safe and feasible.