Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias

Radiotherapy and Oncology xxx (2017) xxx–xxx

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Original article

Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias Yuichiro Tsurugai a, Atsuya Takeda a,⇑, Naoko Sanuki a, Tatsuji Enomoto b, Takeshi Kaneko c, Yu Hara c, Tomikazu Mizuno d, Noriyuki Saeki e, Yousuke Aoki a, Yohei Oku a, Takeshi Akiba f, Etsuo Kunieda f a Radiation Oncology Center; b Department of Respiratory Medicine, Ofuna Chuo Hospital, Kamakura; c Department of Pulmonology, Yokohama City University Graduate School of Medicine; d Department of Diagnostic Radiology; e Department of Thoracic Surgery, Ofuna Chuo Hospital, Kamakura; and f Department of Radiation Oncology, Tokai University School of Medicine, Isehara, Japan

a r t i c l e

i n f o

Article history: Received 20 February 2017 Received in revised form 19 May 2017 Accepted 5 August 2017 Available online xxxx Keywords: Radiation pneumonitis SBRT SABR Idiopathic interstitial pneumonias Pulmonary toxicity

a b s t r a c t Purpose: To compare toxicity and survival after stereotactic body radiotherapy (SBRT) between lung cancer patients with or without idiopathic interstitial pneumonias (IIPs), and to investigate the potential value of SBRT for the patients. Methods: Among lung cancer patients receiving SBRT between 2005 and 2016, we evaluated those treated with a total dose of 40–60 Gy in five fractions with curative intent who either were staged as cT1-4N0M0 or experienced postoperative isolated local recurrence. We analyzed the incidence of radiation pneumonitis (RP) in all patients and local recurrence and overall survival (OS) in T1a-2a patients. Results: A total of 508 patients were eligible, including 42 with IIPs. The median follow-up was 32.3 (6.0–120.9) months. Significantly more patients with IIPs had grade 3 RP than did those without IIPs (12% vs. 3%, p = 0.009). The 2-year local recurrence rate was low in both groups (3.4% vs. 5.6%, p = 0.38). The 2-year OS rate was significantly lower in the patients with IIPs (42.2% vs. 80.9%, p < 0.001), although death from lung cancer was comparable (p = 0.74). Conclusion: SBRT achieved excellent local control with acceptable pulmonary toxicity in lung cancer patients with IIPs. SBRT can be a reasonable option for early lung cancer patients with IIPs. Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx

Abbreviations: ILD, interstitial lung disease; SBRT, stereotactic body radiotherapy; IIPs, idiopathic interstitial pneumonias; 18F-FDG PET/CT, [18F]fluorodeoxyglucose positron emission tomography/computed tomography; UIP, usual interstitial pneumonia; CPFE, combined pulmonary fibrosis with emphysema; ITV, internal target volume; PTV, planning target volume; KL-6, Krebs von den Lungen-6; SP-D, surfactant protein D; CRP, C reactive protein; OS, overall survival; ATS/ERS/JRS/ALAT, American thoracic society/European respiratory society/Japanese respiratory society/Latin American thoracic association; AE, acute exacerbation; RP, radiation pneumonitis; NSCLC, non-small cell lung cancer; CRP, C reactive protein; SUV, standardized uptake value; CI, confidence interval; FEV1.0, forced expiratory volume in 1 s; GOLD, global initiative for chronic obstructive lung disease; V20, lung volume irradiated with 20 Gy; MLD, mean lung dose; HRCT, high resolution computed tomography; NSIP, nonspecific interstitial pneumonia; RTKs, receptor tyrosine kinases; ILD, interstitial lung disease. ⇑ Corresponding author at: Radiation Oncology Center, Ofuna Chuo Hospital, 6-224 Ofuna, Kamakura, Kanagawa 247-0056, Japan. E-mail addresses: [email protected] (Y. Tsurugai), [email protected]. keio.ac.jp (A. Takeda), [email protected] (N. Sanuki), [email protected] (T. Enomoto), [email protected] (T. Kaneko), [email protected]. jp (Y. Hara), [email protected] (T. Mizuno), [email protected] (N. Saeki), [email protected] (Y. Aoki), [email protected] (Y. Oku), [email protected] (T. Akiba), [email protected] (E. Kunieda).

Idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of non-neoplastic disorders resulting from damage to the lung parenchyma, with varying patterns of inflammation and fibrosis [1]. The median survival of patients with idiopathic pulmonary fibrosis (IPF), the most common subtype of IIPs, is only 2–3 years on the whole; however, some patients with stable disease survive relatively long [1,2]. Various comorbidities, such as cardiovascular disease [3], and lung cancer [4], can occur during the course of IIPs. The incidence of lung cancer is markedly increased among patients with IIPs, ranging from 6% to 17% [4]. Treatment decision-making for lung cancer patients with IIPs is difficult. Treatments for lung cancer in the patients, including resection, chemotherapy, and radiotherapy, are often contraindicated due to poor pulmonary function prior to treatment and may trigger severe pulmonary toxicities, such as acute exacerbation (AE) [5] or radiation pneumonitis (RP) [6]. The optimal treatment should be determined with consideration of potential disease progression of IIPs and lung cancer and the balance between treatment benefit and toxicity. Stereotactic body radiotherapy (SBRT) is a high-precision conformal external-beam radiation technique that delivers high-dose

http://dx.doi.org/10.1016/j.radonc.2017.08.026 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.

Please cite this article in press as: Tsurugai Y et al. Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.08.026

2

SBRT for lung cancer patients with IIPs

radiation, showing excellent local control rates with minimal toxicity in patients with medically inoperable stage I non-small cell lung cancer (NSCLC) [7,8]. We performed SBRT for lung cancer patients with IIPs after deliberate multidisciplinary discussion and informed consent in scant data regarding the role of SBRT for the patients. We retrospectively investigated the tolerability of SBRT for lung cancer patients with IIPs comparing toxicity and survival after SBRT for them to those for patients without IIPs. Materials and methods Patients Of consecutive lung cancer patients treated with SBRT in our hospital between February 2005 and March 2016, we retrospectively identified patients who were treated with a total dose of 40–60 Gy in five fractions with curative intent, who were either staged as cT1-4N0M0 using the 7th edition of the International Union Against Cancer (UICC) TNM staging system for lung cancer or who experienced postoperative isolated local recurrence. Although biopsy was proposed to most patients, some refused or could not undergo biopsy because of technical or clinical difficulties, and others were examined but failed in pathological confirmation. For patients without pathological confirmation, the diagnoses of lung cancer were determined by a lung cancer board based on clinical information, such as an increase in the maximum standardized uptake value (SUVmax) on [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), successive enlargements on CT images and elevated tumor marker levels. Patients with less than 6 months of follow-up without death or those with interstitial lung disease (ILD) other than IIPs, e.g., connective tissue disease-associated interstitial pneumonia and pneumoconiosis, were excluded. Small cell carcinoma cases were also excluded. Two pulmonologists (T.E. and T.K.) with expertise in IIPs and a diagnostic radiologist (T.M.) reviewed the patients’ image data, including pretreatment high resolution computed tomography (HRCT) images, and classified the IIPs into usual interstitial pneumonia (UIP) and non-UIP according to the 2011 ATS/ERS/JRS/ALAT guidelines [2]. UIP pattern and possible UIP pattern were regarded as UIP, and inconsistent with UIP pattern was regarded as non-UIP. UIP patients were subclassified into UIP-alone and combined pulmonary fibrosis with emphysema (CPFE). CPFE was defined as UIP with 10% emphysema [9]. Visual analysis was performed to quantify the extent of fibrosis. The fibrosis score was calculated as the percentage of the lung affected by fibrosis (including the extent of reticular abnormality and honeycombing) and scored to the nearest 5% [10]. All patients’ data were collected prospectively and retrospectively reviewed for this study. This retrospective study was approved by The Ofuna Chuo Hospital Review Board (No. 2016-8). Treatment We have previously reported the details of our SBRT technique [11]. After immobilization using a vacuum pillow and abdominal compression corset, long-scan-time CT was performed for treatment planning to visualize the internal target volume (ITV) directly. The planning target volume (PTV) was determined by adding 6–8 mm margins to the ITV. Treatment-planning methods, systems and the calculation algorithm consisted of the following: dynamic conformal multiple arc therapy, FOCUS XiO version 4.2.0–4.3.3 (Computerized Medical Systems, St Louis, MO, USA) and a multigrid superposition algorithm with heterogeneity correction until January 2012; after which non-coplanar volumetric modulated arc therapy, Eclipse version 10.0.0 (Varian Medical

Systems, Palo Alto, CA, USA) and an Acuros XB algorithm with heterogeneity correction. SBRT was delivered using risk-adapted total doses in five fractions, over 5–7 days, depending on the location of the lesion. Total doses were set to enclose the PTV surface by the 80% or 60% isodose line of the maximum dose. Until April 2011, we prescribed 50 Gy for peripherally located lesions and 40 Gy for centrally located lesions to enclose the PTV by the 80% isodose line of the maximum dose. The maximum doses were 62.5 Gy and 50 Gy for prescribed doses of 50 Gy and 40 Gy, respectively. Since May 2011, we routinely prescribe three total doses in five fractions to enclose the PTV by the 60% isodose line of the maximum dose: (1) 60 Gy for peripherally located lesions non-adjacent to the chest wall, (2) 50 Gy for peripherally located lesions adjacent to the chest wall and for centrally located lesions not including the main bronchus and/or main pulmonary artery within the PTV and (3) 40 Gy for centrally located lesions including the main bronchus and/or main pulmonary artery within the PTV. In this risk adapted approach, the maximum doses were 100 Gy, 83.3 Gy and 66.7 Gy for prescribed doses of 60 Gy, 50 Gy and 40 Gy, respectively. Follow-up Our follow-up procedures were previously described in detail [11]. In brief, all patients were followed up monthly during the first 6 months with interviews, laboratory data review, and chest X-ray examinations or high-resolution CT. CT scans were scheduled at 1 and 3 months post-SBRT and at 3-month intervals during the first 2 years thereafter. Subsequently, follow-up interviews, laboratory data review and CT scans were obtained at 4- to 6-month intervals. In addition, 18F-FDG PET/CT and brain magnetic resonance imaging were performed 1 year post-SBRT and when recurrence was suspected. Statistical analysis We divided the patients into the IIPs and non-IIP groups and compared the characteristics, treatment outcomes and RP grades of the patients between the two groups. Local recurrence was defined as recurrence within or adjacent to the PTV and was diagnosed by pathological confirmation or by tumor size enlargement that could not clearly be attributable to lung fibsosis on serial CT scans. We also considered 18F-FDG PET/CT findings [12] when recurrence was highly suspected. Local recurrence was analyzed using death as a competing risk, and cumulative incidences were compared using Gray’s test. Overall survival (OS) was estimated using the Kaplan–Meier method, and differences between groups were assessed using the log-rank test. Univariate analysis was used to identify independent predictors of OS by employing a Cox proportional hazards model. Multivariate analysis was performed by including all covariates potentially associated with OS in the univariate analyses with p < 0.20. Adverse events were graded using the Common Terminology Criteria for Adverse Events, version 4. Logistic regression analysis was used to assess correlations between the patient groups and RP. All statistical analyses were two-sided, and p values <0.05 were considered statistically significant. Analyses were performed using JMP 11Ò (SAS Institute Inc., Cary, NC, USA) and EZR software [13] (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, version 3.2.2). Results Between February 2005 and March 2016, 520 patients received SBRT for lung cancer at a total dose of 40–60 Gy in five fractions.

Please cite this article in press as: Tsurugai Y et al. Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.08.026

Y. Tsurugai et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx

Among these patients, 12 were excluded for the following reasons: a short follow-up duration (less than 6 months) not due to death (n = 2), having ILD other than IIPs (n = 2; 1 with connective tissue disease-associated interstitial pneumonia and 1 with pneumoconiosis) and small cell carcinoma (n = 8). The remaining 508 patients were eligible for this study: 42 patients in the IIP group and 466 patients in the non-IIP group (Fig. 1). Table 1 shows the patient and tumor characteristics. Pathological confirmation before SBRT was obtained in 257 (51%) of 508 patients. The median follow-up for all patients was 32.3 months (range, 6.0–120.9 months). The baseline KL-6, SP-D, CRP, smoking history, pack-years and sex were significantly different between the IIP and non-IIP groups, which is expected considering that these characteristics are related to IIPs. With regard to the IIP subtype, among the 42 patients in the IIP group, 16 had UIP alone, 19 had CPFE, 7 had non-UIP. Table 2 shows the distribution of the different RP grades. None of the patients experienced grade 3 RP within 30 days. Although the presence of IIPs did not significantly affect the incidence of grade 2 RP (19% (95% CI, 10–33) vs. 15% (95% CI, 12–18), p = 0.46), grade 3 RP was significantly more frequent in the IIP group than in the non-IIP group (12% (95% CI, 5.2–25) vs. 2.6% (95% CI, 1.5–4.4), p = 0.009). In the IIP group, grade 3 RP was observed only in patients with UIP alone or CPFE. One of the IIP patients had grade 5 RP at 7.4 months post-SBRT. Of the T1a-2a patients, 197 (46%) had died, and 32 (7%) experienced local recurrence post-SBRT at the time of writing this report. In the IIP and non-IIP groups, the 2-year local recurrence rates were 3.4% (95% confidence interval (CI): 0.2–15.1) and 5.6% (95% CI: 3.5–8.3) (p = 0.38, Fig. 2a), and the 2-year OS rates were 42.2% (95% CI: 23.0–60.3) and 80.9% (95% CI: 76.4–84.6) (p < 0.001, Fig. 2b), respectively. No differences in OS were found among the IIP subtypes (p = 0.97). The rate of death from lung cancer showed no statistical difference between the groups (p = 0.74). In contrast, death from intercurrent disease was statistically more frequent in the IIP group (p < 0.001) (Fig. 2c).

3

Table 3 shows the results of univariate and multivariate analyses of factors potentially related to OS. Univariate analyses indicated that age, sex, pack-years, elevated KL-6/SP-D, CRP, vital capacity (% predicted), T stage, maximum tumor diameter, ITV, PTV, SUVmax and IIPs were significantly associated with OS. On multivariate analysis, age (p = 0.014), vital capacity (% predicted) (p = 0.001) and IIPs (p < 0.001) remained significant factors. SUVmax (p = 0.076) and CRP (p = 0.099) showed a tendency toward an association with OS. Discussion The treatment of lung cancer patients with IIPs requires careful decision-making not only because such patients commonly have a poor prognosis [2] but also because therapeutic interventions for lung cancer may provoke AE of IIPs [14,15]. In an analysis of resection cases from multiple institutions in Japan, AE occurred in 164 patients (9%), with a mortality rate of 44%, and was the leading cause of 30-day mortality (72%) among patients with ILD (n = 1763) [16]. Those results suggested that the 30-day rate of grade 3 pulmonary toxicity was 9% or greater, and that the 30-day rate of grade 5 toxicity was 4%. In addition, they found that the risk of AE gradually increased with the volume of the lung removed. SBRT is less toxic than resection especially during the acute phase, although historically, radiotherapy has been considered unsuitable for patients with IIPs. Following conventional radiation therapy for patients with IIPs, the frequency of AE is reported to be approximately 25% in Japan [17,18]. Therefore, IPF is often considered a contraindication to conventional radiation. Based on the evidence from those studies, previous prospective SBRT studies also excluded patients with IIPs [19,20]. In this study, the rate of grade 3 RP was 12%, and that of grade 5 RP was 2% (one patient) in the IIP group. Grade 3 RP did not occur within 30 days. These rates of RP were equivalent to those of previous studies in patients

Fig. 1. Flowchart of the patient recruitment and analyses.

Please cite this article in press as: Tsurugai Y et al. Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.08.026

4

SBRT for lung cancer patients with IIPs

Table 1 Patients and tumor characteristics. Abbreviations: IIPs: idiopathic interstitial pneumonias; KL-6: Krebs von den Lungen-6; SP-D: surfactant protein D; CRP: C reactive protein; FEV1.0: forced expiratory volume in 1 s; GOLD: global initiative for chronic obstructive lung disease; ad; adenocarcinoma; sq; squamous cell carcinoma; NSCLC: unclassified nonsmall cell carcinoma; ITV: internal target volume; PTV: planning target volume; SUV: standardized uptake value; V20: lung volumes irradiated with 20 Gy; MLD: mean lung dose. IIPs (n = 42) Age, median (range), years Sex, male/female Fibrosis score, median (range),% KL-6, median (range), U/ml SP-D, median (range), ng/ml CRP, median (range), mg/dl Vital capacity, % predicted median (range) FEV1.0, % predicted median (range)

non-IIPs (n = 466)

78 39/3 5 458 99 0.2 82.8 76.9

Condition of COPD non-COPD/GOLD criteria I/II/III/IV+unmeasurable Smoking history, yes/no/unknown Pack-years, median (range) Clarithromycin administration Histology ad/sq/NSCLC/unproven

(64–91) (93%/7%) (5–55) (213–1506) (41–277) (0–3.7) (52.5–108.2) (41.8–120.7)

(53–93) (67%/33%)

0.94 <0.001

300 63 0.1 80.1 72.9

(124–1568) (17–401) (0–8.9) (29.4–136.2) (18.1–146.3)

<0.001 <0.001 0.02 0.77 0.12

25/2/12/3/0 (60%/5%/29%/7%/0%)

238/32/98/76/21 (51%/7%/21%/16%/5%)

41/1/0 52 15

348/109/9 37 57

(98%/1%) (0–200) 36%

p value

79 314/152

0.22 (75%/23%/2%) (0–228) 12%

Maximum tumor diameter, median (range), cm ITV, median (range), cm3 PTV, median (range), cm3 SUVmax, median (range) Location, central/peripheral Total prescribed dose, 60/50/40 Gy 50/40 Gy, 80% isodose level 60/50/40 Gy, 60% isodose level

7/13/3/19 (17%/31%/7%/45%) 9/9/16/2/4/2 (21%/21%/38%/5%/10%/5%) 2.8 (1.3–5.3) 12.2 (2.6–63.9) 45.0 (15.8–128.4) 5.8 (0–14.7) 7/35 (17%/83%) 2/36/4 (5%/86%/10%) 19/2 (90%/10%) 2/17/2 (9.5%/81%/9.5%)

140/65/29/232 (30%/14%/6%/50%) 152/132/113/8/28/33 (33%/28%/24%/2%/6%/7%) 2.4 (0.5–6.7) 8.0 (0.2–141.0) 33.3 (6.1–238.2) 3.2 (0–30.1) 138/328 (30%/70%) 58/323/85 0.08 198/45 58/125/40

Lung V20, median (range), % MLD, median (range), Gy

4.5 3.8

4.6 3.8

T stage, 1a/1b/2a/2b/3-4/rT1-4

(1.4–13.1) (1.3–7.7)

<0.001 <0.001 <0.001 0.02 0.31 0.006 <0.001 <0.001 0.004 0.11

(0–17.6) (0.7–10.3)

0.74 0.94

Table 2 Radiation pneumonitis grade after SBRT. Abbreviations: IIPs: idiopathic interstitial pneumonias; UIP: usual interstitial pneumonia; CPFE: combined pulmonary fibrosis with emphysema. Radiation pneumonitis grade 0–1 IIPs group UIP -UIP alone -UIP-CPFE non-UIP non-IIPs group

(n = 42) (n = 35) (n = 16) (n = 19) (n = 7) (n = 466)

34 27 11 16 6 397

2 81% 77%

86% 85%

3 2 2 0 1 57

following SBRT (grade 3 RP rate of 10–39%) [21–24] and proton beam therapy (grade 3 RP rate of 12.5%) [25]. The range of grade 5 RP rates was 0–21%; however, no grade 5 toxicities within 30 days have been reported [21–24]. Several medications to mitigate RP have been evaluated, including corticosteroids, amifostine and angiotensin-converting enzyme inhibitors [26]. However, the efficacy of those medications remains to be determined. Recently, some studies reported that angiotensin-converting enzyme inhibitors decreased the risk of RP after radiotherapy [27,28]. We have used clarithromycin to treat RP in some high-risk patients because of its immunomodulatory and anti-inflammatory effects [29,30]. This drug was effective for treatment of inflammatory pulmonary diseases including diffuse panbronchiolitis [31], cystic fibrosis [32] and chronic obstructive pulmonary disease [33]. It was also reported to be effective for radiation-related organizing pneumonia [34,35], although its efficacy is uncertain. This study also suggested that severe RP may occur more frequently in patients with UIP. This may be because patients with

3 7.1% 5.7%

14% 12%

4 4 1 3 0 10

9.5% 11%

0% 2.2%

4

5

0 0 0 0 0 0

1 1 1 0 0 2

2.4% 2.9%

0% 0.4%

non-UIP commonly have nonspecific interstitial pneumonia (NSIP), which has a favorable prognosis and is less frequently associated with AE compared with IPF [36–39]. We found that grade 3 RP was observed only in patients with UIP alone or CPFE within the IIP group. This is consistent with findings from surgical studies [16,40] in which patients with UIP had a higher risk of developing postoperative AE than did those without UIP. According to the abovementioned multi-institutional analysis of resection cases in Japan, the incidence of AE in patients with UIP was significantly higher than that of those with non-UIP (10.3% vs. 6.5%, p = 0.01; OR, 0.59). Further evaluation of the relationship between severe RP and these risk factors in patients with IIPs is required. The prognosis of lung cancer patients with IIPs is poor. It remains controversial as to which local treatment, resection or SBRT, is suitable for such patients. According to the abovementioned analysis of resection cases from multiple institutions in Japan [41], the 5-year OS rates of NSCLC patients with ILD (n = 1763) staged as IA, IB, or IIA were 59%, 42%, or 43%, respectively. These OS rates were substantially lower than those of the

Please cite this article in press as: Tsurugai Y et al. Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.08.026

Y. Tsurugai et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx

Fig. 2a. Cumulative incidence of local recurrence. Abbreviations: IIPs: idiopathic interstitial pneumonias.

Fig. 2b. Overall survival curves. Abbreviations: IIPs: idiopathic interstitial pneumonias.

NSCLC patient population overall reported by the Japanese Joint Committee for Lung Cancer Registration (87%, 74% and 62% for stage IA, IB and IIA patients, respectively) [42]. The outcomes after SBRT were also poorer compared with those of patients without IIPs. The 2-year OS rates in stage I lung cancer patients with ILD were 44.4–70% in previous studies [22,23,25] and 42.2% in this study. Those outcomes after resection and SBRT are associated with substantial selection bias. Outcomes of lung cancer treatment have been extremely poor regardless of the tumor stage or severity of IPF [43]. Such poor prognoses may be because of not only the separate effects of the individual diseases, IIPs and lung cancer, but also their synergistic effects. The multi-institutional resection analysis in Japan suggested that patients with ILD have a high incidence of cancer recurrence [41]. Even among patients with pathologic stage IA NSCLC, the rate of cancer-related death was significantly higher in patients with IPF than in those without IPF (17.9% vs. 3.7%, p = 0.001) [44]. Also in this study, early death from lung cancer occurred more frequently in the IIP group, which was due to distant metastases, despite that 18F-FDG PET/CT staging was performed in the

5

Fig. 2c. Cumulative incidence of each cause of death. Abbreviations: IIPs: idiopathic interstitial pneumonias.

majority of patients (83.8%), and local recurrence was rare (2-year local recurrence rate of 3.4%). Stella et al. suggested similar molecular biological behaviors between IPF and cancer [45]. According to a pathogenic perspective, the aberrant proliferative events in IPF resemble those occurring in malignant transformation. Receptor tyrosine kinases (RTKs) are key players in cancer onset, spread and metastasis. The expression of certain RTK family members, e.g., the MET proto-oncogene, is also activated in IPF to enhance organ regeneration as a reaction to inappropriate persistent lung damage. Although the biological significance of RTK activation may differ between the two diseases, their common aberrant activation may induce synergistically poor outcomes. We consider that IIPs are not an absolute contraindication for SBRT but rather a poor prognostic factor, in light of acceptable pulmonary toxicities: grade 3 RP rate of 12%, grade 5 RP rate of 2% and 30-day mortality rate of 0%. We believe that the decision to perform SBRT should be discussed on a per-patient basis as well as among multidisciplinary teams for the following reasons. First, SBRT itself may reduce survival duration due to severe toxicities. Second, IIPs are a heterogeneous disorder in terms of their clinical course. Some patients deteriorate rapidly, and others survive relatively long with stable disease [2,46]. Third, there is no other treatment option for lung cancer in most patients who are not candidates for SBRT. Fourth, the natural course of stage I NSCLC is poor even in patients without IIPs. The median survival of patients with untreated stage I NSCLC was reported to be 14–27 months [47–49]. Although predicting the natural history is difficult, we have evidence regarding the prognosis of such patients. The prognosis depends on the subtype of IIPs. The overall prognosis and response to therapy of NSIP, the second most common type of chronic IIPs, is favorable compared with those of IPF [36,39]. Some clinical variables have been shown to predict mortality in patients with IPF (e.g., number of comorbidities, older age and weak pulmonary function) [2,46]. In addition, we compare the progression of between cancer and IIPs by referring to serial images, additionally estimate which disease is more likely to diminish quality of life and be cause of death. If IIPs’-related symptoms and prognosis are likely to be more critical, we can take course observation for cancer. Taking these clinical features and SBRT-induced benefits and toxicities into account, clinicians should have adequate information for discussing the treatment course with their patients.

Please cite this article in press as: Tsurugai Y et al. Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.08.026

6

SBRT for lung cancer patients with IIPs

Table 3 Univariate and multivariate analyses for overall survival. Abbreviations: IIPs: idiopathic interstitial pneumonias; KL-6: Krebs von den Lungen-6; SP-D: surfactant protein D; CRP: C reactive protein; FEV1.0: forced expiratory volume in 1 s; GOLD: Global Initiative for Chronic Obstructive Lung Disease; ITV: internal target volume; PTV: planning target volume; SUV: standardized uptake value; V20: lung volumes irradiated with 20 Gy; MLD: mean lung dose. Characteristic

Age Sex Male (n = 296) Female (n = 135) IIPs No (n = 397) Yes (n = 34) Elevated KL-6/SP-D No (n = 314) Yes (n = 117) CRP, mg/dl Vital capacity, % predicted Condition of COPD non-COPD (n = 228) GOLD I-II (n = 115) GOLD III-IV + unmeasurable (n = 88) Pack-years Clarithromycin administration Histology Proven NSCLC (n = 373) Clinical NSCLC (n = 58) T stage 1a (n = 161) 1b (n = 141) 2a (n = 129) Maximum tumor diameter, cm ITV, cm3 PTV, cm3 SUVmax, median (range) Location Peripheral (n = 323) Central (n = 108) Total dose 40 Gy (n = 59) 50 Gy (n = 317) 60 Gy (n = 55)

Univariate analysis

Multivariate analysis

HR

95% CI

p value

HR

95% CI

p value

1.03

1.01–1.05

0.005 0.002

1.03

1.00–1.06

0.014 0.70

1 0.61

0.44–0.85

1 0.92

0.61–1.36

<0.001 1 2.94

1.83–4.49

<0.001 1 2.77

1.69–4.35

1.13 0.98

0.98–1.26 0.97–0.99

0.099 0.001

1

1.00–1.01

0.16

0.02 1 1.44 1.19 0.98

1.06–1.93 1.05–1.32 0.97–0.99

1 1.01 1.32 1.01 0.91

0.71–1.41 0.93–1.86 1.00–1.01 0.48–1.58

1 1.05

0.79–1.39

0.01 <0.001 0.27 0.97 0.12 0.002 0.76 0.75

0.02 1 1.44 1.57 1.32 1.03 1.01 1.08

1.02–2.03 1.11–2.21 1.13–1.54 1.01–1.04 1.00–1.02 1.04–1.12

1 1.03

0.74–1.41

1.29 1 0.82

0.04 0.01 <0.001 <0.001 <0.001 <0.001 0.86

0.87–1.85

0.30 0.20

0.45–1.38

0.48

SBRT can be a reasonable option for early lung cancer with IIPs. A propensity score matching analysis suggested that oncologic outcomes are comparable between patients treated with limited resection and those treated with SBRT plus lymph node evaluation [50]. Moreover, quality of life could be maintained after SBRT in contrast to after pulmonary resection [51–53]. We showed excellent local control and acceptable pulmonary toxicities. These outcomes suggest that SBRT has comparable outcomes to those of resection, with less toxicity, especially during the acute phase. Despite this being the largest study involving SBRT for patients with IIPs to our knowledge, the sample size of patients with IIPs and events of severe toxicities (grade 3–5 RP) might still be too small to generalize our findings in terms of survival, incidence of RP and outcomes of IIP subtypes. In conclusion, we showed that SBRT achieved excellent local control with acceptable pulmonary toxicity in lung cancer patients with IIPs. SBRT provides a reasonable option for early lung cancer with IIPs. Clinicians should deliberately discuss the treatment course for individual lung cancer patients with IIPs via multidisciplinary teams, taking these clinical features and SBRT-induced benefits and toxicities into account.

Funding/Support We received no funding source, financial or material support.

0.12 1 1.5 1.18

1.02–2.20 0.77–1.79

0.03 0.44

1.04

1.00–1.09

0.076

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Please cite this article in press as: Tsurugai Y et al. Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.08.026

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Please cite this article in press as: Tsurugai Y et al. Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.08.026