Study design and patients
This single-center retrospective study was approved by the Institutional Review Board of our institution (16–027) and was conducted according to the tenets of the Helsinki Declaration and its later amendments. The subjects were octogenarians who underwent CIRT alone between June 1997 and December 2015 at our institution. They were identified from a previously reported prospective phase Ι/ΙΙ study of 72 patients of all ages and a previously reported retrospective study of 69 patients of all ages who were deemed ineligible for the phase Ι/ΙΙ study at our institution [8, 13]. The studies have been described in detail previously [8, 13]. The inclusion criteria were as follows: (1) histologically or clinically diagnosed LA-NSCLC of stages ΙΙA to ΙΙΙB (the UICC’s TNM 7th Classification) , (2) Eastern Cooperative Oncology Group performance status of 0–2, (3) measurable tumors, (4) inoperable or refusal of surgery, (5) definitive treatments, (6) no other active cancers, and (7) no history of radiotherapy to the concerned region. The exclusion criteria included lung tumors with suspected invasion to the trachea, great vessels, heart, or carina. Consequently, data of 32 patients (18 patients from the prospective phase Ι/ΙΙ study and 12 patients from the retrospective study) who met the inclusion criteria were analyzed.
Tumor stage was evaluated using computed tomography (CT) imaging of the chest and whole abdomen, enhanced magnetic resonance imaging (MRI) of the brain, chest radiography, and blood tests. Bone scans or [18F]-fluorodeoxyglucose positron emission tomography combined with CT (18F-FDG PET/CT) were also performed. Histological or cytological diagnosis was confirmed via bronchoscopic biopsy, CT-guided biopsy, or sputum cytology in 28 (87.5%) patients and via CT, radiography, and/or 18F-FDG PET/CT in the remaining patients.
We collected information on grade ≥ 2 toxicities. Treatment-related toxicities were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 4.0) .
Patients were fixed using an individually tailored immobilization device (Moldcare; Alcare, Tokyo, Japan; Shellfitter; Kuraray, Osaka, Japan), and CT images were obtained in the supine or prone position using respiratory sensors to monitor the respiratory phase [7, 8]. Target delineation was performed as previously reported [8, 13]. The primary lung lesion and metastatic lymph nodes were contoured as the gross tumor volume (GTV) on CT images. The GTV with a 10 mm margin and any prophylactic lymph nodes (ipsilateral hilar and/or mediastinal lymph nodes) were defined as the clinical target volume (CTV). For N0 cases, prophylactic lymph nodes irradiation was omitted irrespective of T-stage. Planning target volume (PTV) was defined as the CTV + 5 mm safety margin. In cases where the PTV was close to the organs at risk, the margins for creating PTV was reduced.
The prescribed dose ranged from 68.0 to 76.0 Gy [relative biological effectiveness (RBE)] in 12–16 fractions, 4 days per week. Their prescribed doses were converted to 96.9 to 115.0 Gy (RBE) as the biologically effective dose using α/β = 10. A dose escalation study conducted during our investigation showed the potential of short-course CIRT alone at 72 Gy (RBE) , and thus the recommended dose was fixed at 72 Gy (RBE) in 16 fractions. Subsequently, this dose was adopted for all remaining patients (n = 21, 65.6%). The total dose was applied to the isocenter, and it enclosed the PTV conformably, with a 95% isodose line. The patients with lymph node metastasis underwent metastatic and prophylactic lymph node irradiation at a median dose of 49.5 Gy (RBE) [8, 13, 16]. The following irradiation dose constraints were applied: main bronchus, 60 Gy (RBE); esophagus, 50 Gy (RBE); and spinal cord, 30 Gy (RBE). Irradiation was performed in 2–5 fields with 250 or 290 meV carbon ions.
Regarding chemotherapy, 2 patients were administered induction chemotherapy, but none of the 32 patients received concurrent or adjuvant chemotherapy.
After treatment, follow-up observations were performed at 1, 3, 6, 9, and 12 months, and every 3–6 months thereafter if serious complications had not occurred. Follow-up comprised chest CT, chest radiography, and blood tests during each evaluation. Brain MRI or F18-FDG PET/CT was performed as necessary.
LC, progression-free survival (PFS), and OS were calculated using the Kaplan–Meier method. LC was defined as the time interval between irradiation commencement date and the local tumor regrowth at the PTV date or the last follow-up. PFS was defined as the time interval between irradiation commencement date and the date of disease progression at any site, death from any cause, or the last follow-up. OS was defined as the time interval between the start of irradiation and death or the last follow-up.
All statistical analyses were conducted using JMP statistical software (version 14.0; SAS Institute Inc., Cary, NC, USA).