Clinical results of proton beam therapy for elderly patients with non-small cell lung cancer

This retrospective study was approved by the ethics committees of our institution (approval number: D17–31). The study was conducted in accordance with the Declaration of Helsinki.

The present study included patients who were diagnosed with lung cancer and treated with PBT between January 2009 and 2015 at the Southern Tohoku Proton Therapy Center. Patients were retrospectively recruited from our database. The clinical stage of the patients’ lung cancer (Union for International Cancer Control, 8th edition) was determined using computed tomography (CT) and positron emission tomography (PET)-CT. Written informed consent was obtained from all of the patients. The inclusion criteria were as follows: patients aged ≥80 years when the patint received PBT; a solitary lung tumor; pathologically proven non-small cell lung cancer (NSCLC); a World Health Organization performance status of 0–2; no lymph node metastasis; and the absence of distant other organ metastasis or other sites of uncontrolled cancer. Any patients who received concurrent chemotherapy, and those with interstitial pneumonitis were excluded. The judgment as to the operability was made by a conference of lung surgeons. All operable patients who received PBT refused to receive lung surgery.

Treatment planning for PBT was based on three-dimensional CT images that were taken at 2 mm intervals in the exhalation phase while using a respiratory gating system (Anzai Medical, Tokyo, Japan). A custom-indexed vacuum-lock bag was used to immobilize the patients. An XiO-M (CMS Japan, Tokyo, Japan; and Mitsubishi Electric) treatment planning system was used to calculate the dose distributions for PBT. The gross tumor volume (GTV) included the lung tumor. The clinical target volume (CTV) was defined as the GTV plus a margin of 0.5 cm. The planning target volume (PTV) was the CTV plus a 0.5 cm margin. The proton energy levels of 150 MeV and 210 MeV for 2–3 portals, and a spread-out Bragg peak were tuned as much as possible until the PTV was exposed to a 90% isodose of the prescribed dose. Proximal margins, distal margins, and smearing margins were calculated using strategy 2, which Moyers et al. reported [19]. The PBT system at our institute (Proton Beam System, Mitsubishi, Tokyo, Japan) used a synchrotron and a passive scattering method in which a proton beam passes a bar ridge filter, a range shifter, and a customized compensator before entering the patient. The treatment was administered during the exhalation phase using a respiratory gating system. A multileaf collimator, which consisted of 40 iron plates with a width of 3.75 mm, and which could be formed into an irregular shape, was used. Daily front and lateral X-ray imaging was used for positioning. The PBT schedule was 66 Gy relative biological dose effectiveness (RBE) in 10 fractions over 2 weeks for peripheral lung tumors, and 80 Gy (RBE) in 25 fractions over 5 weeks for centrally located lung tumors. Patients with lung tumors that were located near the large intestine or small intestine received 60.0–79.2 Gy (RBE) in 25–33 fractions over 7 weeks.

Comorbidities were evaluated as previously reported by Charlson et al. [10], and shown in the index. All patients underwent either CT or PET-CT to evaluate the initial tumor response within three months after the completion of treatment. The follow-up interval was every 1–3 months for the first year and every 3–6 months thereafter. Pneumonitis, excluding infection, was evaluated using the Common Terminology Criteria for Adverse Events version 4.0 [20].

All statistical analyses were performed using the IBM SPSS Statistics software program (version 22, SPSS Inc., Chicago, IL, USA). The overall survival (OS) time was defined as the time between the start of PBT and the time of the last follow-up examination or death. The Kaplan–Meier method and a log rank test were used to estimate the survival probability and compare survival, respectively. The relationships between the occurrence of lung toxicities and the dose volume histogram factors were examined using the Mann–Whitney U test. The dosimetric factor of lung was examined in 2Gy per fraction using lung alpha/beta ratio was 3.1 [21]. Lung V20 (ratio of lung volume irradiated at leaset 20 Gy) and mean lung dose using a dose volume histogram. The ratio of the lung volume spared from 0.05 Gy (RBE) dose (total lung volume minus lung volume irradiated at least 0.05 Gy [RBE]) was also examined, as Tsujino et al. [22] reported that the lung volume speared from low irradiation dose. All p-values were two sided, and p values of < 0.05 were considered to indicate statistical significance.

The initial study population included 78 patients aged ≥80 years who had received PBT for a lung tumor. Patients were excluded from the analysis for the following reasons: lymph node metastasis (n = 28); distant other organ metastasis (n = 3); interstitial pneumonitis (n = 4); and absence of NSCLC pathology (n = 8). Thus, the characteristics of 35 patients, including 25 (71%) with clinically inoperable NSCLC, were analyzed (Table 1). All patients completed treatments. The cohort comprised 26 men and 9 women, with a median age of 82 years (range: 80–87 years). The comorbidity index of 30 patients (86%) was ≥1. The median follow-up time was 34 months (range: 10–72 months). The median dose of PBT was 80.0 Gy (range: 60.0–80.0 Gy [RBE]).

All patients were followed for at least 23 months or until their death. The 1-year, 2-year, and 3-year OS rates were 97.1% (95% CI: 91.6–100%), 74.3% (95% CI: 59.8–88.8%), and 67.2% (95% CI: 50.3–83.3%), respectively (Fig. 1). The median survival time was 56 months (95% CI: 33.1–78.9 months). The 3-year cancer specific survival rate was 76.3% (95% CI: 60.4–92.2%). Nine patients died due to lung cancer (metastasis, n = 7; local recurrence, n = 2), and 8 patients died due to other causes (another newly diagnosed cancer after PBT, n = 4; other diseases, n = 4). The 3-year OS rate was significantly different between operable and inoperable patients (90% vs 58.2%, p = 0.008) (Fig. 2).

The 3-year local control rate was 86.5% (95% CI: 74.0–99.0%) (Fig. 3). Four patients had local recurrence at 9–33 months. Two had lymph node metastasis, 6 had lung metastasis outside of the PBT field. Regarding other organ metastasis, 1 patient had liver metastasis, 1 patient had brain metastasis, and 4 had pleural dissemination.

There were no cases involving grade 4 or 5 toxicities after PBT treatment (Table 2). The toxicities of the 35 patients included 2 (5.6%) cases of grade 2 pneumonitis, 4 (11.1%) with grade 2 rib fractures, and 1 (2.8%) with grade 3 dermatitis radiation. A high ratio of V 20 (18.7% vs 10.9%, p = 0.030), high dose of mean lung dose (12.4Gy vs 7.5Gy p = 0.030), and low ratio of lung volume spared from 0.05 Gy (RBE) dose (62.9% vs 77.7%, p = 0.030) were significantly correlated with the occurrence of grade2 pneumonia.