High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer

The treatment methods and procedures were approved by the Ethics committee of our institution. The study was conducted in accordance with the Declaration of Helsinki. Patients signed informed consent.

The present study enrolled patients who were diagnosed with central lung cancer and were treated with PBT between January 2009 and February 2015 at the Southern Tohoku Proton Therapy Center. Central lung cancer was defined as tumors located less than 2 cm from the trachea, mainstem bronchus, or lobe bronchus.⁷ Patients were retrospectively recruited from our database.

Whether or not the pathology of the lung tumor was histologically confirmed did not matter. If the pathology was not confirmed, an increase in the size of the lung tumor or high positron emission tomography (PET) uptake was regarded as a clinical malignancy. The clinical stage of the lung cancer was determined using computed tomography (CT) and PET-CT. Written informed consent was obtained from all of patients.

The inclusion criteria were as follows: (1) a solitary lung tumor without any previous treatment for it, (2) a World Health Organization performance status of 0–2, (3) no lymph node metastasis, and (4) the absence of distant other-organ metastasis or other sites of uncontrolled cancer. Patients with interstitial pneumonia were excluded from this study.

Treatment planning for PBT was based on 3-dimensional CT images 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 (Engineering System Co, Nagano, Japan) was used to immobilize the patients. A Xio-M treatment planning system (CMS Japan, Tokyo, Japan; and Mitsubishi Electric) 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 0.5 cm, and 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 1–3 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, and was not exposed to 110% isodose (upper limit) (Figure 1). The PBT system at our institute (Proton Beam System; Mitsubishi, Tokyo, Japan) uses 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 could be formed into an irregular shape, was used. Daily front and lateral X-ray imaging was used for positioning. The PBT for central lung tumors was set at 80 Gy of relative biological dose effectiveness (RBE) in 25 fractions over 5 weeks inour institution (isocenter prescription); the biological equivalent dose was 105.6 Gy when tumor alpha/beta ratio was regarded 10. The dose constraints were set for the esophagus (≤ 55 Gy [RBE]), spinal cord (≤ 40 Gy [RBE]), and heart (≤ 40 Gy [RBE]) in principle. However, we did not reduce prescribed dose and irradiated over 40 Gy (RBE) to the heart when the lung tumor was too close to it.

Figure 1

All patients underwent either CT or PET-CT to evaluate the initial tumor response within 3 months after the completion of treatment. The initial treatment response was evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1.¹⁶ A complete response was defined as the complete disappearance of all detectable tumors. In this study, a complete metabolic response (extinction of PET uptake) was also defined as a complete response.¹⁷ A partial response was defined as ≥ 30% reduction in the maximal diameter of the tumor. Stable disease was defined as neither a partial response nor progressive disease. Progressive disease was defined as ≥ 20% enlargement of the primary tumor or the appearance of new lesions, including lymph node metastases and distant metastases. The evaluation of comorbidities was performed in accordance with Charlson et al. previously reported.¹⁸ The follow-up interval was every 1–3 months for the first year and every 3–6 months thereafter. Imaging performed every 3–6 months after evaluating the initial tumor response. The cause of death was determined as lung cancer when patients had local recurrence or metastases and no other causes of death except for cancer, were presented. Toxicities were evaluated using the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer criteria.¹⁹ The following dosimetric factors were examined with the use of a dose volume histogram of the lung minus the GTV and heart: mean lung dose, lung V5 (lung irradiated 5 Gy [RBE]), lung V10, lung V15, lung V20, and mean heart dose.

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 the survival, respectively. The relationships between the occurrence of lung or heart toxicities and the dose volume histogram factors were examined using the Mann-Whitney U test. All p-values were two-sided, and p-values of < 0.05 were considered to indicate statistical significance.

The initial study population included 86 patients who received 80 Gy (RBE) for lung cancer. Patients were excluded from the analysis for the following reasons: lymph node metastasis, n = 13; distant other-organ metastasis, n = 13; treatment for lung cancer before PBT n = 7; other sites of uncontrolled cancer n = 5; interstitial pneumonia n = 9; and failure to satisfy the criteria of central lung cancer, n = 19. Thus, the characteristics of 20 patients, including 14 (70%) with clinically inoperable cancer due to poor respiratory function (n = 9), elderly (90 years old, n = 1), comorbidities (n = 4), as well as 9 (45%) with chronic obstructive pulmonary disease, were analyzed (Table 1). The median age was 75 years (range: 63–90 years), the median follow up time was 27.5 months (range: 12–72 months), the median tumor diameter was 39.5 mm (range: 24–81 mm), the median tumor volume 35.7 cc (range: 6.1–151.2 cc), and the median dose of mean PTV coverage was 79.5 Gy (RBE) (range: 75–81 Gy [RBE]).

All patients were followed for at least 20 months (living patients) or until death. The 1- and 2-year overall survival (OS) rates were 95.0% (95% confidence interval [CI]: 87.7–100%), and 73.8% (95% CI: 53.9–93.7%), respectively (Figure 2A). The 2-year OS rates of stage I and II/III were 80% and 53.3%, respectively. Six patients died of lung cancer, due to local recurrence (n = 3) and distant failure (n = 3) and 2 of other disease, due to heart failure (n = 1) and sepsis (n = 1). The 2-year OS rates for operable and inoperable patients were 100%, and 62.5%, respectively (Figure 2B), although the 2-year OS between the two groups was not significantly different (p = 0.109). Thirteen patients (65%) achieved a complete response, 5 (25%) achieved a partial response, and 2 (10%) achieved stable disease. The 2-year local control rate was 78.5% (95% CI: 59.5–97.5%); all local recurrences were in-field recurrence) (Figure 3A). The 2-year local control rates of lung cancers with diameters of ≤ 39.5 mm and > 39.5 mm (39.5 mm was the median tumor diameter) were 90% and 68.6%, respectively (Figure 3B), although the 2-year local control rate between the two groups was not significantly different (p = 0.348).

Figure 2

Figure 3

Table 2 shows the toxicities after PBT. The median dose of mean lung dose and mean heart dose were 7.2 Gy (RBE) and 0.5 Gy (RBE), respectively. There were 2 patients (10%) with Grade 2 lung toxicities (both pneumonitis) and no patients with Grade 3 or higher lung toxicities, including bronchial stricture, obstruction, and fistula. Moreover, there were 2 patients (10%) with Grade 2 bone toxicities (both rib fracture). No Grade 2 or higher heart toxicities were observed, although 4 patients had Grade 1 toxicities (all of them pericardial effusion). Lastly, there were no esophageal toxicities, as no tumor included in the study was close enough to the esophagus. There were no statistically significant differences with regard to the dosimetric factors of mean lung dose (7.4 Gy [RBE] vs 7.0 Gy [RBE], p = 0.830), lung V5 (18.2% vs 16.6%, p = 0.677), lung V10 (16.1% vs 14.5%, p = 0.647), lung V15 (14.8% vs 13.1%, p = 0.625), and lung V20 (13.5% vs 12.0%, p = 0.629) between patients with Grade 2 pneumonitis and those without it. Furthermore the dosimetric factors of mean heart dose (1.3 Gy [RBE] vs 1.9 Gy [RBE], p = 0.667) between patients with Grade 1 pericardial effusion and those without it demonstrated no statistically significant differences.