Carbon-ion radiotherapy for non-small cell lung cancer with interstitial lung disease: a retrospective analysis

We performed a retrospective evaluation of all patients with ILD-LC who were treated with CIRT at our hospital. Owing to the presense of ILD, all enrolled patients were ineligible for curative surgery and conventional radiotherapy.We diagnosed ILD was according to medical history, physical examination, respiratory function test, and evaluation of abnormalities compatible with bilateral lung fibrosis on chest computed tomography (CT) or high-resolution CT, such as peripheral reticular opacities. Biochemical tests for levels of lactate dehydrogenase, surfactant protein-D (SP-D), and serum Krebs von den Lungen-6 (KL-6) were also performed.

The treatment method and procedure were approved by the ethics committees of our institute, and written informed consent was obtained from all patients included in the study.

Initial workup included clinical and laboratory examinations, contrast-enhanced CT of the chest, contrast-enhanced magnetic resonance imaging (MRI) of the brain, and [11C]-acetate or [18F]-fluorodeoxyglucose (¹⁸F–FDG) positron emission tomography (PET)/CT scanning for detecting involved lymph nodes and distant metastases. The severity of ILD was evaluated according to the criteria of the Japanese Respiratory Society classifications [20].

Carbon ion beams with 290, 350, and 400 MeV of nucleon energy were generated in the Heavy Ion Medical Accelerator in Chiba (HIMAC) synchrotron and delivered to the treatment room. The details of CIRT planning and delivery at our institution have been described previously [16, 18, 19, 21].

Between June 2004 and November 2014, CIRT was performed on 637 patients with primary NSCLC lesions at our institution; among them, 29 patients had ILD. Two patients were diagnosed with hilar lymph node metastasis. Three patients had suspected mediastinal lymph node metastasis on PET/CT, and 1 had suspected accessory nerve lymph node metastasis. We treated only the primary lesions of these patients, as Konishi et al. and Roberts et al. reported that inflammatory pulmonary lesions may show increased uptake of 18F–FDG [22, 23]. Additionally, 1 patient was diagnosed with an intrapulmonary metastatic lesion near their primary tumor. Both primary and metastatic lesions were treated in the same field.

For stage I LC patients and 4 patients with suspected lymph node metastases, the primary tumors were irradiated with carbon-ion beams at a fixed dose of 52.8 Gy (relative biological effectiveness [RBE]) (13.2 Gy[RBE]/fraction) for T1 (≤3 cm) tumors and 60.0 Gy (RBE) (15 Gy[RBE]/fraction) for T2 (>3 cm) tumors, delivered in 4 fractions over the course of 1 week. A single T4 patient was included in the T2 tumor group; this patient’s primary tumor and nearby intrapulmonary metastatic lesion were irradiated. After February 2012, primary tumors in stage I LC patients were irradiated in a single fraction at doses prescribed by the NIRS Lung Cancer Single Fraction Clinical Trial [19]. For single fraction delivery, tumors were normally irradiated from 4 ports consecutively. The HIMAC delivery system allowed for patients to be rotated a maximum of ±20 degrees, allowing for four different treatment angles between the horizontal and vertical particle beams.

In accordance with routine practice at our institute for stage I NSCLC, all CIRT plans utilized 4 coplanar and oblique beam fields at mutual angles of 40 or 50 degrees.

For two patients with stage II NSCLC who had hilar lymph node metastases, the primary tumor and involved lymph nodes were contoured as the gross tumor volume. The clinical target volume included the primary tumor with 10-mm margins in all directions. Prophylactic regional nodal irradiation that included targeting the ipsilateral hilar and mediastinal lymph nodes was chosen for one of the patients with a hilar lymph node metastasis. For the other patient, only the primary tumor and involved lymph node were irradiated. The prescribed dose (72 Gy [RBE]) was administered to the primary tumor, and a reduced dose was delivered to the CTV up to a total dose of 50 Gy (RBE) at the discretion of the treating physician. A fixed dose of 72 Gy (RBE) was delivered over a course of 16 daily fractions administered on four consecutive days per week and over four consecutive weeks.

The planning target volume (PTV) was enclosed by the 95% isodose line for conformal treatment with the prescribed dose. Dose constraints were strictly adhered to, regardless of potential target coverage compromise, as follows: spinal cord, 30 Gy (RBE); esophagus, 50 Gy (RBE); and mainstem bronchus, 60 Gy (RBE). Figure 1 shows a sample of the dose distribution for a patient wih stage I disease.

After the end of radiotherapy, regular follow-up examinations were performed every 3 months for the first 2 years and every 6 months thereafter. Each follow-up session included a physical evaluation, chest CT, brain MRI, respiratory function test, and laboratory tests at a minimum. Additional imaging investigations such as bone scanning and PET/CT were performed upon clinical suspicion of recurrence.

The severity of RP was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. As many patients had respiratory symptoms prior to CIRT, symptoms were graded before and after CIRT, and symptomatic grade change was evaluated. The occurrence of AE was defined according to the revised Japanese criteria for AE of IPF [20], which states that all of the following three conditions must be satisfied during the course of IPF within a single month: 1) worsening or development of dyspnea 2) new ground-glass opacities appear on high-resolution CT in addition to previous honeycomb lesions, new ground-glass abnornalities, and/or consolidation superimposed on a background reticular or honeycomb pattern on high-resolution CT 3) a greater than 10 mmHg reduction of partial pressure of oxygen in the arterial blood under similar conditions. The ruling out of alternative causes, such as infection, pneumothorax, cancer, pulmonary embolism or congestive heart failure is required. Due to the difficulty of distinguishing AE from RP, AE was confirmed when infiltrates were observed outside the radiation field.

All data are presented as median values with ranges. We used JMP statistical software (version 11.0) for all statistical analyses. To investigate the relationships between patients with or without IP grade progression, clinical characteristics and treatment-related factors were compared using the Mann-Whitney U test or Fisher’s exact test.

In total, 637 consecutive patients with NSCLC who underwent CIRT between June 2004 and November 2014 were investigated retrospectively. Of these, 29 patients with ILD were identified; their characteristics are listed in Table 1. Prior to CIRT, 11 grade 1 patients, 6 grade 2 patients, 8 grade 3 patients, and 4 grade 4 patients were identified according to the Modified Medical Research Council Dyspnea Scale [24]. Under the CTCAE v.3.0 criteria, there were 11 grade 1 patients, 14 grade 2 patients, 4 grade 3 patients, and no grade 4 or 5 patients. Four patients were using home oxygen therapy, 4 had a history of AE prior to treatment, and 4 had a prior autoimmune disease.

An evolving series of protocols were employed during the treatment period, the details of which are shown in Table 2. Treatment timeframes ranged between 1 day (46–50 Gy [RBE], single fraction; 13 patients), 4 days (52.8–60 Gy[RBE], 4 fractions; 14 patients), and 4 weeks (72 Gy[RBE], 16 fractions; 2 patients). The PTV ranged from 34.6 mL to 1319.8 mL (median: 145.1 mL).

We detected RP of grades 1, 2, and 3 in 9, 12, and 8 patients, respectively (Table. 3). Five patients experienced RP grade progression. Four patients experienced a single RP grade increase, from 1 to 2 or 2 to 3, following treatment; 1 patient had a 2-degree increase, from 1 to 3. Two patients experienced radiation-induced AE.

The median follow-up period was 26.8 months (range, 2.7–86.5 months) for all patients. The overall survival rates at 3 and 5 years was 46.3 and 30.4% (57.2 and 42.4% for stage I disease), respectively (Fig. 2). Eighteen of 29 patients (62.1%) showed a survival of longer than 2 years. Eighteen patients had died at the time of this writing, 10 of LC progression, 2 of other cancers (1 pancreastic, and 1 myelodysplastic syndrome), and 6 of noncancerous causes (3 of bacterial pneumonia, 2 of hypoxia due to progression of ILD, and 1 of gastrointestinal hemorrhage). The deaths from hypoxia resulting from ILD occurred more than 40 months after undergoing CIRT in both patients. We observed eight local recurrences; the median time between CIRT and diagnosis of local recurrence was 17.2 months. The local control rates at 3 and 5 years were both 63.3% (72.2% for stage I disease only).

Two patients were diagnosed with AE of their ILD post-CIRT. One was a 76-year-old man with stage IA LC, and the other an 80-year-old man with stage IB LC. They were diagnosed with AE by CT scanning following hospital admission due to worsening dyspnea, which revealed ground glass opacities outside the irradiated field. Both were treated with oxygen and steroid pulse therapy. The AE subsided in both patients, although the man with stage IA disease died of gastrointestinal hemorrhage 1 month following admission. The patient with stage IB disease was discharged, but died of bacterial pneumonitis 5 months after radiotherapy.

Table 4 shows the relationships between the RP grade progression and pretreatment clinical factors as well as dosimetric factors in the 29 patients. The lung doses of V5 and V10 were significantly associated with the occurrence of RP grade progression (p = 0.026 and 0.033). Pre-treatment serum SP-D was also found to correlate with grade progression, and was significantly lower in the grade-progressing patient population (p = 0.036).