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Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: The potential risk of extensive radiation pneumonitis
Lung Cancer 82 (2013) 260–265
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Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: The potential risk of extensive radiation pneumonitis Shinsaku Yamaguchi a , Takayuki Ohguri a,∗ , Satoru Ide a , Takatoshi Aoki a , Hajime Imada b , Katsuya Yahara a , Hiroyuki Narisada b , Yukunori Korogi a a b
Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan Department of Cancer Therapy Center, Tobata Kyoritsu Hospital, Kitakyushu, Japan
a r t i c l e
i n f o
Article history: Received 28 March 2013 Received in revised form 18 July 2013 Accepted 29 August 2013 Keywords: Stereotactic body radiotherapy Interstitial lung disease Radiation pneumonitis Lung cancer Computed tomography Bronchoalveolar lavage
a b s t r a c t Purpose: To evaluate the toxicity and efficacy of thoracic stereotactic body radiotherapy (SBRT) in patients with subclinical interstitial lung disease (ILD). Methods and materials: One hundred patients with 124 lung tumors were treated with SBRT at our institution according to our own protocols; patients with subclinical (untreated and oxygen-free) ILD were treated with SBRT, while those with clinical ILD (post- or under treatment) were not. The administration of 48 Gy in four fractions was used in 103 (83%) of the 124 tumors. The presence of subclinical ILD in the pre-SBRT CT findings was reviewed by two chest radiologists. The relationships between radiation pneumonitis (RP) and clinical factors were investigated. Results: Subclinical ILD was recognized in 16 (16%) of 100 patients. Grade 2–5 RP was recognized in 13 (13%) of 100 patients. Grade 2–5 RP was observed in three (19%) of 16 patients with subclinical ILD. Subclinical ILD was not found to be a significant factor influencing Grade 2–5 RP; however, extensive RP beyond the irradiated field, including the contralateral lung, was recognized in only three patients with subclinical ILD, and the rate of extensive RP was significantly high in the patients with subclinical ILD. Grade 4 or 5 extensive RP was recognized in only two patients with subclinical ILD. Dosimetric factors of the lungs (V5, V10, V15, V20, V25, MLD) were significantly associated with Grade 2–5 RP. The threeyear overall survival and local control rates of all patients were 53% and 86%, respectively. No significant differences were seen in either overall survival or local control rates between the patients with ILD and those without ILD. Conclusions: Subclinical ILD was not found to be a significant factor for Grade 2–5 RP or clinical outcomes in the current study; however, uncommon extensive RP can occur in patients with subclinical ILD. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Stereotactic body radiotherapy (SBRT) has become widespread as a new treatment modality for pulmonary lesions in recent years due to its high local control rate and completely painless and ambulatory treatment. Although adverse reactions are not recognized in most patients treated with SBRT, radiation pneumonitis (RP) is an occasional complication of SBRT. Previous reports have shown a correlation between severe RP and dose–volume parameters, such as the mean lung dose (MLD), V20 (percentage of the lung volume receiving > 20 Gy) and V5 [1,2].
∗ Corresponding author at: Department of Radiology, University of Occupational and Environmental Health, Iseigaoka 1-1, Yahatanisi-ku, Kitakyushu-shi 807-8555, Japan. Tel.: +81 93 691 7264; fax: +81 93 692 0249. E-mail address: [email protected] (T. Ohguri). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.08.024
A group of noninfectious, acute and chronic diffuse parenchymal lung disorders are classified as interstitial lung disease (ILD). More than 150 clinical conditions and/or causes are associated with ILD [3]. The COPD Gene Study group previously demonstrated both chest computed tomographic (CT) and pathologic evidence of subclinical ILD in asymptomatic members; 194 (8%) of 2416 screening HRCT scans in a cohort of smokers showed interstitial lung abnormalities [4]. The frequency of acute exacerbation following conventional radiotherapy in patients with ILD has been reported to be around 25% [5,6]. The eligibility criteria for patients in a phase I/II study of SBRT to treat primary lung cancer showed that active ILD is a factor for patient exclusion [7]. The clinical guidelines for SBRT published by the Japanese Society for Therapeutic Radiology and Oncology also recommend that SBRT should be relatively contraindicated in patients with severe ILD. Beginning in August 2005, at our institution, the use of SBRT to treat patients with stage I non-small cell lung cancer (NSCLC) or
S. Yamaguchi et al. / Lung Cancer 82 (2013) 260–265 Table 1 Background of the 100 patients with 124 tumors. n Gender (m/f) Age (years, median) PS (0/1/2/3/4) Patients Primary lung cancer Metastatic lung tumor Tumor size ≤3 cm >3 cm Tumor location Right upper lobe Right middle lobe Right lower lobe Left upper lobe Left lower lobe Histology in primary lung cancers Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Unclassified NSCLC Clinically diagnosed Primary tumor in 37 patients with metastatic lung tumors Colorectum Lung Others Operability of surgery Medically operable Inoperable
65/35 53–88, 78 7/56/28/9/0 63 37 103 21 32 5 23 40 24 17 15 1 1 35
14 13 10 35 65
metastatic lung tumors was initiated according to our own protocols. Patients with subclinical (untreated and oxygen-free) ILD were treated with SBRT, while those with clinical ILD were not. To our knowledge, there are only a few case series evaluating SBRT in patients with subclinical ILD [8–10]. The purpose of our study was to evaluate the toxicity and efficacy of thoracic SBRT in patients with subclinical ILD and to investigate whether subclinical ILD is a predictor of RP. 2. Materials and methods 2.1. Patients Between August 2005 and February 2011, SBRT was performed to treat lung tumors at our institution in 109 consecutive patients with 138 lung tumors. For this study, we retrospectively collected data for patients who received follow-up for a minimum of six months. Nine patients who were followed up for less than six months were excluded. One hundred patients with 124 lung tumors were included in this study. According to our own protocols for SBRT, during the same period, patients with subclinical ILD, which was defined as the presence of untreated and asymptomatic ILD on computed tomography (CT), were indicated for SBRT. However, SBRT was not performed in patients with clinical ILD, which was defined as a status of post- or under treatment or symptomatic disease. The patients’ backgrounds are shown in Table 1. There were 63 patients with 69 primary lung cancers, 37 patients with 55 metastatic lung tumors. Regarding the primary lung cancers, the histology was pathologically proven in 34 tumors. The remaining 35 tumors were considered to be lung cancer without pathologically proven evidence. These tumors were diagnosed based on successive increases in the tumor size obtained on computed tomography (CT), as well as according to the uptake on positron emission tomography and/or elevated levels of tumor markers, including carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC), cytokeratin 19 fragment (CYFRA), sialyl Lewis X-i antigen (SLX)
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[11], neuron specific enolase (NSE) and progastrin releasing peptide (proGRP) [12]. Among the metastatic lung tumors, the primary sites were the colorectum (n = 14), lungs (n = 13) and other sites (n = 10). The time interval between the primary treatment and subsequent diagnosis of metastasis was 1.6–11.1 months (median 9.7). All patients with metastatic lung tumors met the following criteria: (1) one or two pulmonary metastases, (2) a locally controlled primary tumor and (3) no other metastatic sites. Thirteen of 37 patients were treated with chemotherapy for the metastatic lung tumor before SBRT, and 10 patients received chemotherapy after SBRT. This study was approved by the Institutional Review Board of the authors’ institution. 2.2. Diagnosis of interstitial lung abnormalities The presence, extent and distribution of ILD were determined based on CT criteria used in a previous study [13]: pre-SBRT CT findings were reviewed by two chest radiologists and thus were found to show no evidence of ILD (score 0), slight ILD (score 1), mild ILD (score 2) and moderate ILD (score 3). Slight ILD was defined as focal or unilateral ground glass attenuation, focal or unilateral reticulation and patchy ground glass abnormalities (less than 5% of the lungs). Mild ILD was defined as follows: nondependent ground glass abnormalities affecting more than 5% of any lung zone, nondependent reticular abnormalities, diffuse centrilobular nodularity with ground glass abnormalities, honeycombing, traction bronchiectasis, nonemphysematous cysts and architectural distortion. Moderate ILD was defined as bilateral fibrosis in multiple lobes associated with honeycombing and traction bronchiectasis in a subpleural distribution. Pulmonary infections were excluded by a blood test, the response to antibiotics, sputum cultures or by bronchoalveolar lavage (BAL). The presence of pulmonary emphysema was also reviewed by two chest radiologists. 2.3. Treatment SBRT was delivered using a linear accelerator with 6-MV photons. The patient’s body was immobilized using a stereotactic body frame. In each case, the SBRT plan was created using commercial treatment planning systems (Xio; CMS Japan, Tokyo, Japan). The gross tumor volume (GTV) was initially defined for each patient as the pulmonary lesion observed on 2-mm-thick axial CT imaging. In 26 of the 100 patients, the internal target volume (ITV) was determined based on CT with a slow scan technique, which can visualize the major part of the trajectory of the tumor by scanning each slice for a time longer than the respiratory cycle. In the remaining 74 patients, the ITVs were estimated based on the reproducibility of the breath-holding method on X-ray fluoroscopy. The planned target volume (PTV) consisted of the imaged volume, defined as the GTV plus an internal margin plus a 5- to 10-mm setup margin; 48 patients in the early years of the current study were treated with a 10 mm set-up margin, and 52 patients in more recent years were treated with a 5 mm set-up margin. The shape of the field was adjusted dynamically according to the tumor shape using a multileaf collimator. Dose calculation was performed using a superposition algorithm. Our dose-prescription policies were based on the D95 (the percentage of the prescribed dose covering 95% of the volume) of the PTV. Six to 14 coplanar/noncoplanar static ports were used, and the irradiation dose generally consisted of 48 Gy in four fractions administered over four to seven days. When the tumor was adjacent to critical organs (e.g., the spinal cord or esophagus) or was relatively large, the fractionated dose was reduced to 6–10 Gy, and the total dose was limited to 30.0–62.5 Gy. A dose of 48 Gy was administered in four fractions to 103 tumors, while 50 Gy was
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Table 2 RP grade in the patients with subclinical ILD and PE. RP gradea
All patients (n = 100) (%) With subclinical ILD (n = 16) (%) With PE (n = 41) (%) With both subclinical ILD and PE (n = 11) (%)
0–1
2
3
4
5
87 (87) 13 (81) 33 (80) 9 (82)
7 (7) 0 (0) 3 (7) 0 (0)
4 (4) 1 (6) 4 (10) 1 (9)
1 (1) 1 (6) 0 (0) 0 (0)
1 (1) 1 (6) 1 (2) 1 (9)
RP, radiation pneumonitis; ILD, interstitial lung disease; PE, pulmonary emphysema. a CTCAE ver.3.
administered in four fractions for six tumors, 52 Gy was administered in four fractions for six tumors, 30 Gy was administered in three fractions for four tumors, 60 Gy was administered in 10 fractions for two tumors, 50.4 Gy was administered in four fractions for two tumors and 62.5 Gy was administered in 10 fractions for one tumor. Between October 2008 and February 2011, escalated radiation doses of more than BED 100 Gy10 (biological effective dose based on ˛/ˇ = 10 Gy) were delivered to the tumor in four or ten fractions based on published clinical results [14]. Verification was performed with anteroposterior and lateral portal images and digitally reconstructed radiographs, which were calculated from the planning CT scans relative to bony landmarks, the diaphragm, and the isocenter, before every treatment. 2.4. Follow-up In all patients, the development of RP was monitored on an outpatient basis using chest X-ray examinations. Additionally, CT scans were performed at one and three months after SBRT and at three to four month intervals during the first two years and at four to six month intervals thereafter, even in the absence of clinical symptoms. The National Cancer Institute Common Toxicity Criteria version 3 (CTCAE) were used to score patient toxicity. The highest toxicity grade for each patient was used for the toxicity analysis. 2.5. Statistical analysis The relationships between RP and the clinical factors were investigated using Fisher’s exact probability test and the Mann–Whitney U test. For dosimetric factors, the total normal lung volume was defined as the total lung volume including the ITV. The following dosimetric parameters were generated from a dose volume histogram (DVH) of the total normal lungs: mean lung dose (MLD) and the volumes of the lungs receiving more than a threshold dose, D, of radiation (VD), where the D values considered ranged from 5 to 25 Gy in increments of 5 Gy. The associations between these factors and the occurrence of RP were examined. The relationships between the ILD score and RP grade were assessed using Spearman’s correlation test. The overall patient survival, local control and disease-specific survival rates after SBRT were calculated from the first day of SBRT using the Kaplan–Meier method. The statistical significance of any differences between the actuarial curves was assessed using the log-rank test.
Grade 2 or higher RP was recognized in 13 (13%) of 100 patients: Grade 5 in one patient, Grade 4 in one patient, Grade 3 in four patients and Grade 2 in seven patents. Symptomatic Grade 2 or higher RP was seen 2.9 months (range, 1.4–6.9 months) after SBRT. The frequency of Grade 2 or higher RP is summarized in Table 2. Grade 2 or higher RP was seen in three (19%) of 16 patients with subclinical ILD and eight (20%) of 41 patients with pulmonary emphysema. Subclinical ILD was not found to be a significant factor for the occurrence of Grade 2 or higher RP, and the rate of pulmonary emphysema was also not significant. The CT appearance of Grade 2 or higher RP is listed in Table 3. Extensive RP beyond the irradiated field, including the contralateral lung, was recognized in three patients, and all of them had subclinical ILD on pre-SBRT CT. There was a significant difference in the occurrence rate of extensive RP between the patients with and those without subclinical ILD (p = 0.0035) (Table 4). Two patients suffered from Grade 4 or 5 with extensive RP: one patient required the administration of home oxygen therapy and the other died of respiratory failure after some relapses and remissions (Fig. 1). All six patients suffering from Grade 3 or higher RP were treated with steroids and oxygen. There was no significant correlation between the ILD score on CT findings and the RP grade (p = 0.19). Other adverse events of Grade 2 or higher were as follows: Grade 2 chest wall pain in one patient and Grade 2 dermatitis in three patients. Table 5 shows the relationships between the clinical/dosimetric factors and Grade 2 or higher RP. In the univariate analyses, all dosimetric factors (lung doses V5, V10, V15, V20, V25 and MLD) were significantly associated with Grade 2 or higher RP. None of the other factors exhibited significant relationships. With regard to the dosimetric relationships between the patients with ILD and those without ILD, no dosimetric factors (lung doses V5, V10, V15, V20, V25 and MLD) were found to be significant in the univariate analyses. A multivariate analysis was not performed because of the small number of patients. The median overall survival time was 17.3 months in all 100 patients: 19.0 months in 63 patients with primary NSCLC and 14.3 months in 37 patients with metastatic lung tumors. The overall survival, cause-specific survival and local control rates in patients with primary NSCLC were 91%, 96% and 96% at one year and 52%, 60% and 84% at three years, and in patients with metastatic lung tumors were 90%, 93% and 90% at one year and 54%, 56% and 90% at Table 3 CT appearance of symptomatic RP. RP gradea
3. Results The median follow-up period after SBRT was 17.1 months (range, 6.0–71.5 months). Subclinical ILD on the pre-SBRT CT findings was recognized in 16 (16%) of 100 patients: 84 patients with no evidence of ILD (score 0), two patient with a status of slight ILD (score 1), five patients with a status of mild ILD (score 2) and nine patients with moderate ILD (score 3).
CT appearance Diffuse consolidation Patchy consolidation and GGO GGO alone
2 (n = 7)
3 (n = 4)
4 (n = 1)
5 (n = 1)
2 5
2 1b
0 1b
0 1b
0
1
0
0
RP, radiation pneumonitis; GGO, ground glass opacity. a CTCAE ver. 3. b Extensive RP beyond the irradiated field, including the contralateral lung.
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Table 4 Characteristics of the patients with extensive RP. Case
Tumor
Tumor size (cm)
Subclinical ILD, scorea
PE
V20 (%)
Lung MLD (Gy)
Contra-lateral MLD Total dose (Gy) (Gy/fraction)
Toxicity grade
Latent period (mos)
1 2 3
Primary Primary Primary
2.2 3.7 3.7
Yesb , 1 Yesb , 1 Yesb , 2
Yes No Yes
3.0 9.5 11.5
2.2 5.3 6.8
0.5 0.8 0.7
3 4 5
2.4 3.8 5.9
48/4 48/4 48/4
RP, radiation pneumonitis; ILD, interstitial lung disease; PE, pulmonary emphysema; MLD, mean lung dose. a Score of CT criteria for ILD determined on the basis of a previous study [11]. b There was a significant difference in the rate of extensive RP between the patients with and those without subclinical ILD (p = 0.0035, Fisher’s exact test).
three years, respectively. No significant differences were observed in either the overall survival or local control rates between the patients with ILD and those without. The overall survival rates at three years in the patients with ILD and those without ILD were 48% and 54%, respectively (p = 0.39). The local control rates at three years in the patients with ILD and those without ILD were 94% and 88%, respectively (p = 0.64). No significant differences were observed in either the overall survival or local control rates between the patients with pulmonary emphysema and those without.
4. Discussion Promising clinical results of thoracic SBRT with high local control rates and the absence of severe toxicities have been demonstrated [7,15]. Recently, thoracic SBRT has been performed as a standard treatment method in patients with medically inoperative NSCLC or those who refuse surgery, especially to treat peripheral lesions. Previous studies of thoracic SBRT have reported a 9–28% incidence of Grade 2 or higher RP [2,16–19]. To our knowledge, however, only a few papers have reported the results of
Fig. 1. (a–d) Grade 3 of extensive radiation pneumonitis (case 1 in Table 4); (a) CT with dose distribution. Red and blue lines are 48 Gy and 2 Gy, respectively. (b) CT image of pre-stereotactic body radiation therapy. CT at level of bilateral lower lobes shows focal subpleural ground-glass abnormalities. In this case the abnormality was less than 5% of the lung (ILD score 1). (c and d) 2 months after stereotactic body radiation therapy. CT at level of upper lobes (c) and at bilateral lower lobes (d) shows extensive ground-glass abnormalities and focal consolidations. (e–g) Grade 4 of extensive radiation pneumonitis (case 2 in Table 4); (e) CT with dose distribution. Red and blue lines are 48 Gy and 2 Gy, respectively. (f) CT image of pre-stereotactic body radiation therapy (ILD score 1). (g) CT image of extensive ground-glass abnormalities and focal consolidations 4 months after stereotactic body radiation therapy. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
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Table 5 Clinical and dosimetric factors associated with RP. Grade 0–1 RP (n = 87) Clinical factors Gender (m/f) Age PS (0–1/2–4) Operable/inoperable Subclinical ILD (yes/no) PE (yes/no) Dosimetric factors of the lung (%), median (range) V5 V10 V15 V20 V25 MLD (Gy)
Grade 2–5 RP (n = 13)
55/32 78 (53–88) 57/30 32/55 13/74 33/54
10/3 74 (58–87) 7/6 3/10 3/10 8/5
15.8 (4.3–38.4) 10.0 (2.1–27.2) 6.4 (1.3–19.3) 4.4 (0.9–16.4) 3.3 (0.7–13.7) 3.1 (1.0–8.3)
24.0 (10.2–37.6) 17.5 (5.9–25.3) 11.9 (4.2–18.1) 8.4 (3.0–12.2) 6.9 (2.3–9.7) 5.3 (2.2–7.2)
p 0.53 0.66 0.53 0.76 0.43 0.16 0.002 0.0005 0.0005 <0.0001 <0.0001 0.0002
RP, radiation pneumonitis; ILD, interstitial lung disease; PE, pulmonary emphysema; MLD, mean lung dose.
SBRT in patients with ILD [8–10]. Yamashita et al. reported that Grade 4-5 RP was observed in nine (8%) of 117 patients who had undergone SBRT, seven (78%) of whom demonstrated CT appearance of IP before receiving SBRT [8]. A significant correlation was found between the incidence of RP and IP shadows. Takeda et al. reported a case associated with acute exacerbation of subclinical ILD that exhibited slightly focal honeycombing triggered by SBRT [10]. Similarly, acute exacerbation of subclinical ILD triggered by surgery in patients with lung tumors has been demonstrated [20]. In our series, relationship between subclinical ILD and Grade 2–5 RP was not significant, the rate of extensive RP beyond the irradiated field was significantly high in the patients with subclinical ILD. Our results also implied that uncommon extensive and fatal RP can occur in patients with subclinical ILD even if CT appearance of subclinical ILD was slight, the risk of extensive RP should be considered in patients with subclinical ILD and that careful observation and management of RP must be provided after SBRT in such patients. Classical RP changes in the lungs are considered to be confined to the site of irradiation. However, there are several reports of extensive RP occurring beyond the irradiated field in the early literature [21,22]. Morgan et al. indicated that sporadic pneumonitis, including extensive RP, appears to be an entirely different disease process involving immune modulation and genetic factors, as opposed to classical RP, which is characterized by the inflammatory consequences of direct irradiation injury to pulmonary tissue [23]. Roberts et al. demonstrated that lymphocytic alveolitis develops in both lung fields after strictly unilateral thoracic irradiation and is more pronounced in patients who develop clinical pneumonitis. They concluded that radiotherapy might cause generalized lymphocyte-mediated hypersensitivity reactions [24]. In the current study, the contribution of the above described unclassical disease process was suggested in the three patients with extensive RP involving the contralateral lung because the mean irradiation dose of the contralateral lung was as low as 0.5–0.8 Gy. The relationships between the dosimetric factors of the lungs and the occurrence of symptomatic RP have been investigated in patients treated with thoracic radiotherapy [18,25]. Matsuo et al. reported that the rate of symptomatic RP after SBRT was 15.0% in patients with Lung V20 of <5.8% and 42.9% in the remaining patients [18]. In the current study, dosimetric factors were also significantly correlated with Grade 2 or higher RP, and both of the two patients with Grade 4–5 extensive RP exhibited high Lung V20 (9.5% and 11.5%) and MLD (5.3 and 6.8 Gy) values (Table 4). Therefore, we propose that SBRT should be administered in patients with subclinical ILD using safer values of dosimetric factors and increasing fractionation schedules to prevent the risk of extensive RP.
Rancati et al. evaluated clinical and lung dose-volume histogram-based factors as predictors of RP in patients with lung tumors, and concluded that the presence of chronic obstructive pulmonary disease was significantly associated with a higher risk of RP after three-dimensional conventional radiotherapy [26]. On the other hand, Kimura et al. reported the relationship between pulmonary emphysema and RP in 45 patients treated with SBRT. The rate of Grade 2 or higher RP was rather low in patients with pulmonary emphysema [27]. In the current study of SBRT, pulmonary emphysema was not found to be a significant factor related to the occurrence of Grade 2 or higher RP. Regarding limitations associated with this study. Due to the fact that the current study was a retrospective series, the possibility of selection bias with regard to the predictive factors cannot be ruled out. In addition, we could not analyze the data in patients with active ILD excluded from SBRT, because they had not been properly recorded. A formal prospective study is consequently needed to determine the toxicity, efficacy and prognostic factors of SBRT in patients with subclinical ILD. In summary, this is the first report attempting to investigate whether subclinical ILD is a predictor of RP in patients treated with thoracic SBRT. Subclinical ILD was not found to be a predictor of Grade 2–5 RP in patients treated with thoracic SBRT; however, uncommon extensive and fatal RP extending beyond the irradiated field can occur in patients with subclinical ILD, and the rate of extensive RP was significantly higher in the patients with subclinical ILD in this study. There were no significant differences in the survival rates between the patients with and those without subclinical ILD. The risk of extensive RP should be considered and obtaining sufficient informed consent is required in patients with subclinical ILD. In addition, careful observation and management of RP should be carried out after SBRT in such patients.
Conflict of interest statement Potential conflicts of interest do not exist in this study.
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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: The potential risk of extensive radiation pneumonitis Shinsaku Yamaguchi a , Takayuki Ohguri a,∗ , Satoru Ide a , Takatoshi Aoki a , Hajime Imada b , Katsuya Yahara a , Hiroyuki Narisada b , Yukunori Korogi a a b
Department of Radiology, University of Occupational and Environmental Health, Kitakyushu, Japan Department of Cancer Therapy Center, Tobata Kyoritsu Hospital, Kitakyushu, Japan
a r t i c l e
i n f o
Article history: Received 28 March 2013 Received in revised form 18 July 2013 Accepted 29 August 2013 Keywords: Stereotactic body radiotherapy Interstitial lung disease Radiation pneumonitis Lung cancer Computed tomography Bronchoalveolar lavage
a b s t r a c t Purpose: To evaluate the toxicity and efficacy of thoracic stereotactic body radiotherapy (SBRT) in patients with subclinical interstitial lung disease (ILD). Methods and materials: One hundred patients with 124 lung tumors were treated with SBRT at our institution according to our own protocols; patients with subclinical (untreated and oxygen-free) ILD were treated with SBRT, while those with clinical ILD (post- or under treatment) were not. The administration of 48 Gy in four fractions was used in 103 (83%) of the 124 tumors. The presence of subclinical ILD in the pre-SBRT CT findings was reviewed by two chest radiologists. The relationships between radiation pneumonitis (RP) and clinical factors were investigated. Results: Subclinical ILD was recognized in 16 (16%) of 100 patients. Grade 2–5 RP was recognized in 13 (13%) of 100 patients. Grade 2–5 RP was observed in three (19%) of 16 patients with subclinical ILD. Subclinical ILD was not found to be a significant factor influencing Grade 2–5 RP; however, extensive RP beyond the irradiated field, including the contralateral lung, was recognized in only three patients with subclinical ILD, and the rate of extensive RP was significantly high in the patients with subclinical ILD. Grade 4 or 5 extensive RP was recognized in only two patients with subclinical ILD. Dosimetric factors of the lungs (V5, V10, V15, V20, V25, MLD) were significantly associated with Grade 2–5 RP. The threeyear overall survival and local control rates of all patients were 53% and 86%, respectively. No significant differences were seen in either overall survival or local control rates between the patients with ILD and those without ILD. Conclusions: Subclinical ILD was not found to be a significant factor for Grade 2–5 RP or clinical outcomes in the current study; however, uncommon extensive RP can occur in patients with subclinical ILD. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Stereotactic body radiotherapy (SBRT) has become widespread as a new treatment modality for pulmonary lesions in recent years due to its high local control rate and completely painless and ambulatory treatment. Although adverse reactions are not recognized in most patients treated with SBRT, radiation pneumonitis (RP) is an occasional complication of SBRT. Previous reports have shown a correlation between severe RP and dose–volume parameters, such as the mean lung dose (MLD), V20 (percentage of the lung volume receiving > 20 Gy) and V5 [1,2].
∗ Corresponding author at: Department of Radiology, University of Occupational and Environmental Health, Iseigaoka 1-1, Yahatanisi-ku, Kitakyushu-shi 807-8555, Japan. Tel.: +81 93 691 7264; fax: +81 93 692 0249. E-mail address: [email protected] (T. Ohguri). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.08.024
A group of noninfectious, acute and chronic diffuse parenchymal lung disorders are classified as interstitial lung disease (ILD). More than 150 clinical conditions and/or causes are associated with ILD [3]. The COPD Gene Study group previously demonstrated both chest computed tomographic (CT) and pathologic evidence of subclinical ILD in asymptomatic members; 194 (8%) of 2416 screening HRCT scans in a cohort of smokers showed interstitial lung abnormalities [4]. The frequency of acute exacerbation following conventional radiotherapy in patients with ILD has been reported to be around 25% [5,6]. The eligibility criteria for patients in a phase I/II study of SBRT to treat primary lung cancer showed that active ILD is a factor for patient exclusion [7]. The clinical guidelines for SBRT published by the Japanese Society for Therapeutic Radiology and Oncology also recommend that SBRT should be relatively contraindicated in patients with severe ILD. Beginning in August 2005, at our institution, the use of SBRT to treat patients with stage I non-small cell lung cancer (NSCLC) or
S. Yamaguchi et al. / Lung Cancer 82 (2013) 260–265 Table 1 Background of the 100 patients with 124 tumors. n Gender (m/f) Age (years, median) PS (0/1/2/3/4) Patients Primary lung cancer Metastatic lung tumor Tumor size ≤3 cm >3 cm Tumor location Right upper lobe Right middle lobe Right lower lobe Left upper lobe Left lower lobe Histology in primary lung cancers Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Unclassified NSCLC Clinically diagnosed Primary tumor in 37 patients with metastatic lung tumors Colorectum Lung Others Operability of surgery Medically operable Inoperable
65/35 53–88, 78 7/56/28/9/0 63 37 103 21 32 5 23 40 24 17 15 1 1 35
14 13 10 35 65
metastatic lung tumors was initiated according to our own protocols. Patients with subclinical (untreated and oxygen-free) ILD were treated with SBRT, while those with clinical ILD were not. To our knowledge, there are only a few case series evaluating SBRT in patients with subclinical ILD [8–10]. The purpose of our study was to evaluate the toxicity and efficacy of thoracic SBRT in patients with subclinical ILD and to investigate whether subclinical ILD is a predictor of RP. 2. Materials and methods 2.1. Patients Between August 2005 and February 2011, SBRT was performed to treat lung tumors at our institution in 109 consecutive patients with 138 lung tumors. For this study, we retrospectively collected data for patients who received follow-up for a minimum of six months. Nine patients who were followed up for less than six months were excluded. One hundred patients with 124 lung tumors were included in this study. According to our own protocols for SBRT, during the same period, patients with subclinical ILD, which was defined as the presence of untreated and asymptomatic ILD on computed tomography (CT), were indicated for SBRT. However, SBRT was not performed in patients with clinical ILD, which was defined as a status of post- or under treatment or symptomatic disease. The patients’ backgrounds are shown in Table 1. There were 63 patients with 69 primary lung cancers, 37 patients with 55 metastatic lung tumors. Regarding the primary lung cancers, the histology was pathologically proven in 34 tumors. The remaining 35 tumors were considered to be lung cancer without pathologically proven evidence. These tumors were diagnosed based on successive increases in the tumor size obtained on computed tomography (CT), as well as according to the uptake on positron emission tomography and/or elevated levels of tumor markers, including carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC), cytokeratin 19 fragment (CYFRA), sialyl Lewis X-i antigen (SLX)
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[11], neuron specific enolase (NSE) and progastrin releasing peptide (proGRP) [12]. Among the metastatic lung tumors, the primary sites were the colorectum (n = 14), lungs (n = 13) and other sites (n = 10). The time interval between the primary treatment and subsequent diagnosis of metastasis was 1.6–11.1 months (median 9.7). All patients with metastatic lung tumors met the following criteria: (1) one or two pulmonary metastases, (2) a locally controlled primary tumor and (3) no other metastatic sites. Thirteen of 37 patients were treated with chemotherapy for the metastatic lung tumor before SBRT, and 10 patients received chemotherapy after SBRT. This study was approved by the Institutional Review Board of the authors’ institution. 2.2. Diagnosis of interstitial lung abnormalities The presence, extent and distribution of ILD were determined based on CT criteria used in a previous study [13]: pre-SBRT CT findings were reviewed by two chest radiologists and thus were found to show no evidence of ILD (score 0), slight ILD (score 1), mild ILD (score 2) and moderate ILD (score 3). Slight ILD was defined as focal or unilateral ground glass attenuation, focal or unilateral reticulation and patchy ground glass abnormalities (less than 5% of the lungs). Mild ILD was defined as follows: nondependent ground glass abnormalities affecting more than 5% of any lung zone, nondependent reticular abnormalities, diffuse centrilobular nodularity with ground glass abnormalities, honeycombing, traction bronchiectasis, nonemphysematous cysts and architectural distortion. Moderate ILD was defined as bilateral fibrosis in multiple lobes associated with honeycombing and traction bronchiectasis in a subpleural distribution. Pulmonary infections were excluded by a blood test, the response to antibiotics, sputum cultures or by bronchoalveolar lavage (BAL). The presence of pulmonary emphysema was also reviewed by two chest radiologists. 2.3. Treatment SBRT was delivered using a linear accelerator with 6-MV photons. The patient’s body was immobilized using a stereotactic body frame. In each case, the SBRT plan was created using commercial treatment planning systems (Xio; CMS Japan, Tokyo, Japan). The gross tumor volume (GTV) was initially defined for each patient as the pulmonary lesion observed on 2-mm-thick axial CT imaging. In 26 of the 100 patients, the internal target volume (ITV) was determined based on CT with a slow scan technique, which can visualize the major part of the trajectory of the tumor by scanning each slice for a time longer than the respiratory cycle. In the remaining 74 patients, the ITVs were estimated based on the reproducibility of the breath-holding method on X-ray fluoroscopy. The planned target volume (PTV) consisted of the imaged volume, defined as the GTV plus an internal margin plus a 5- to 10-mm setup margin; 48 patients in the early years of the current study were treated with a 10 mm set-up margin, and 52 patients in more recent years were treated with a 5 mm set-up margin. The shape of the field was adjusted dynamically according to the tumor shape using a multileaf collimator. Dose calculation was performed using a superposition algorithm. Our dose-prescription policies were based on the D95 (the percentage of the prescribed dose covering 95% of the volume) of the PTV. Six to 14 coplanar/noncoplanar static ports were used, and the irradiation dose generally consisted of 48 Gy in four fractions administered over four to seven days. When the tumor was adjacent to critical organs (e.g., the spinal cord or esophagus) or was relatively large, the fractionated dose was reduced to 6–10 Gy, and the total dose was limited to 30.0–62.5 Gy. A dose of 48 Gy was administered in four fractions to 103 tumors, while 50 Gy was
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Table 2 RP grade in the patients with subclinical ILD and PE. RP gradea
All patients (n = 100) (%) With subclinical ILD (n = 16) (%) With PE (n = 41) (%) With both subclinical ILD and PE (n = 11) (%)
0–1
2
3
4
5
87 (87) 13 (81) 33 (80) 9 (82)
7 (7) 0 (0) 3 (7) 0 (0)
4 (4) 1 (6) 4 (10) 1 (9)
1 (1) 1 (6) 0 (0) 0 (0)
1 (1) 1 (6) 1 (2) 1 (9)
RP, radiation pneumonitis; ILD, interstitial lung disease; PE, pulmonary emphysema. a CTCAE ver.3.
administered in four fractions for six tumors, 52 Gy was administered in four fractions for six tumors, 30 Gy was administered in three fractions for four tumors, 60 Gy was administered in 10 fractions for two tumors, 50.4 Gy was administered in four fractions for two tumors and 62.5 Gy was administered in 10 fractions for one tumor. Between October 2008 and February 2011, escalated radiation doses of more than BED 100 Gy10 (biological effective dose based on ˛/ˇ = 10 Gy) were delivered to the tumor in four or ten fractions based on published clinical results [14]. Verification was performed with anteroposterior and lateral portal images and digitally reconstructed radiographs, which were calculated from the planning CT scans relative to bony landmarks, the diaphragm, and the isocenter, before every treatment. 2.4. Follow-up In all patients, the development of RP was monitored on an outpatient basis using chest X-ray examinations. Additionally, CT scans were performed at one and three months after SBRT and at three to four month intervals during the first two years and at four to six month intervals thereafter, even in the absence of clinical symptoms. The National Cancer Institute Common Toxicity Criteria version 3 (CTCAE) were used to score patient toxicity. The highest toxicity grade for each patient was used for the toxicity analysis. 2.5. Statistical analysis The relationships between RP and the clinical factors were investigated using Fisher’s exact probability test and the Mann–Whitney U test. For dosimetric factors, the total normal lung volume was defined as the total lung volume including the ITV. The following dosimetric parameters were generated from a dose volume histogram (DVH) of the total normal lungs: mean lung dose (MLD) and the volumes of the lungs receiving more than a threshold dose, D, of radiation (VD), where the D values considered ranged from 5 to 25 Gy in increments of 5 Gy. The associations between these factors and the occurrence of RP were examined. The relationships between the ILD score and RP grade were assessed using Spearman’s correlation test. The overall patient survival, local control and disease-specific survival rates after SBRT were calculated from the first day of SBRT using the Kaplan–Meier method. The statistical significance of any differences between the actuarial curves was assessed using the log-rank test.
Grade 2 or higher RP was recognized in 13 (13%) of 100 patients: Grade 5 in one patient, Grade 4 in one patient, Grade 3 in four patients and Grade 2 in seven patents. Symptomatic Grade 2 or higher RP was seen 2.9 months (range, 1.4–6.9 months) after SBRT. The frequency of Grade 2 or higher RP is summarized in Table 2. Grade 2 or higher RP was seen in three (19%) of 16 patients with subclinical ILD and eight (20%) of 41 patients with pulmonary emphysema. Subclinical ILD was not found to be a significant factor for the occurrence of Grade 2 or higher RP, and the rate of pulmonary emphysema was also not significant. The CT appearance of Grade 2 or higher RP is listed in Table 3. Extensive RP beyond the irradiated field, including the contralateral lung, was recognized in three patients, and all of them had subclinical ILD on pre-SBRT CT. There was a significant difference in the occurrence rate of extensive RP between the patients with and those without subclinical ILD (p = 0.0035) (Table 4). Two patients suffered from Grade 4 or 5 with extensive RP: one patient required the administration of home oxygen therapy and the other died of respiratory failure after some relapses and remissions (Fig. 1). All six patients suffering from Grade 3 or higher RP were treated with steroids and oxygen. There was no significant correlation between the ILD score on CT findings and the RP grade (p = 0.19). Other adverse events of Grade 2 or higher were as follows: Grade 2 chest wall pain in one patient and Grade 2 dermatitis in three patients. Table 5 shows the relationships between the clinical/dosimetric factors and Grade 2 or higher RP. In the univariate analyses, all dosimetric factors (lung doses V5, V10, V15, V20, V25 and MLD) were significantly associated with Grade 2 or higher RP. None of the other factors exhibited significant relationships. With regard to the dosimetric relationships between the patients with ILD and those without ILD, no dosimetric factors (lung doses V5, V10, V15, V20, V25 and MLD) were found to be significant in the univariate analyses. A multivariate analysis was not performed because of the small number of patients. The median overall survival time was 17.3 months in all 100 patients: 19.0 months in 63 patients with primary NSCLC and 14.3 months in 37 patients with metastatic lung tumors. The overall survival, cause-specific survival and local control rates in patients with primary NSCLC were 91%, 96% and 96% at one year and 52%, 60% and 84% at three years, and in patients with metastatic lung tumors were 90%, 93% and 90% at one year and 54%, 56% and 90% at Table 3 CT appearance of symptomatic RP. RP gradea
3. Results The median follow-up period after SBRT was 17.1 months (range, 6.0–71.5 months). Subclinical ILD on the pre-SBRT CT findings was recognized in 16 (16%) of 100 patients: 84 patients with no evidence of ILD (score 0), two patient with a status of slight ILD (score 1), five patients with a status of mild ILD (score 2) and nine patients with moderate ILD (score 3).
CT appearance Diffuse consolidation Patchy consolidation and GGO GGO alone
2 (n = 7)
3 (n = 4)
4 (n = 1)
5 (n = 1)
2 5
2 1b
0 1b
0 1b
0
1
0
0
RP, radiation pneumonitis; GGO, ground glass opacity. a CTCAE ver. 3. b Extensive RP beyond the irradiated field, including the contralateral lung.
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Table 4 Characteristics of the patients with extensive RP. Case
Tumor
Tumor size (cm)
Subclinical ILD, scorea
PE
V20 (%)
Lung MLD (Gy)
Contra-lateral MLD Total dose (Gy) (Gy/fraction)
Toxicity grade
Latent period (mos)
1 2 3
Primary Primary Primary
2.2 3.7 3.7
Yesb , 1 Yesb , 1 Yesb , 2
Yes No Yes
3.0 9.5 11.5
2.2 5.3 6.8
0.5 0.8 0.7
3 4 5
2.4 3.8 5.9
48/4 48/4 48/4
RP, radiation pneumonitis; ILD, interstitial lung disease; PE, pulmonary emphysema; MLD, mean lung dose. a Score of CT criteria for ILD determined on the basis of a previous study [11]. b There was a significant difference in the rate of extensive RP between the patients with and those without subclinical ILD (p = 0.0035, Fisher’s exact test).
three years, respectively. No significant differences were observed in either the overall survival or local control rates between the patients with ILD and those without. The overall survival rates at three years in the patients with ILD and those without ILD were 48% and 54%, respectively (p = 0.39). The local control rates at three years in the patients with ILD and those without ILD were 94% and 88%, respectively (p = 0.64). No significant differences were observed in either the overall survival or local control rates between the patients with pulmonary emphysema and those without.
4. Discussion Promising clinical results of thoracic SBRT with high local control rates and the absence of severe toxicities have been demonstrated [7,15]. Recently, thoracic SBRT has been performed as a standard treatment method in patients with medically inoperative NSCLC or those who refuse surgery, especially to treat peripheral lesions. Previous studies of thoracic SBRT have reported a 9–28% incidence of Grade 2 or higher RP [2,16–19]. To our knowledge, however, only a few papers have reported the results of
Fig. 1. (a–d) Grade 3 of extensive radiation pneumonitis (case 1 in Table 4); (a) CT with dose distribution. Red and blue lines are 48 Gy and 2 Gy, respectively. (b) CT image of pre-stereotactic body radiation therapy. CT at level of bilateral lower lobes shows focal subpleural ground-glass abnormalities. In this case the abnormality was less than 5% of the lung (ILD score 1). (c and d) 2 months after stereotactic body radiation therapy. CT at level of upper lobes (c) and at bilateral lower lobes (d) shows extensive ground-glass abnormalities and focal consolidations. (e–g) Grade 4 of extensive radiation pneumonitis (case 2 in Table 4); (e) CT with dose distribution. Red and blue lines are 48 Gy and 2 Gy, respectively. (f) CT image of pre-stereotactic body radiation therapy (ILD score 1). (g) CT image of extensive ground-glass abnormalities and focal consolidations 4 months after stereotactic body radiation therapy. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
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Table 5 Clinical and dosimetric factors associated with RP. Grade 0–1 RP (n = 87) Clinical factors Gender (m/f) Age PS (0–1/2–4) Operable/inoperable Subclinical ILD (yes/no) PE (yes/no) Dosimetric factors of the lung (%), median (range) V5 V10 V15 V20 V25 MLD (Gy)
Grade 2–5 RP (n = 13)
55/32 78 (53–88) 57/30 32/55 13/74 33/54
10/3 74 (58–87) 7/6 3/10 3/10 8/5
15.8 (4.3–38.4) 10.0 (2.1–27.2) 6.4 (1.3–19.3) 4.4 (0.9–16.4) 3.3 (0.7–13.7) 3.1 (1.0–8.3)
24.0 (10.2–37.6) 17.5 (5.9–25.3) 11.9 (4.2–18.1) 8.4 (3.0–12.2) 6.9 (2.3–9.7) 5.3 (2.2–7.2)
p 0.53 0.66 0.53 0.76 0.43 0.16 0.002 0.0005 0.0005 <0.0001 <0.0001 0.0002
RP, radiation pneumonitis; ILD, interstitial lung disease; PE, pulmonary emphysema; MLD, mean lung dose.
SBRT in patients with ILD [8–10]. Yamashita et al. reported that Grade 4-5 RP was observed in nine (8%) of 117 patients who had undergone SBRT, seven (78%) of whom demonstrated CT appearance of IP before receiving SBRT [8]. A significant correlation was found between the incidence of RP and IP shadows. Takeda et al. reported a case associated with acute exacerbation of subclinical ILD that exhibited slightly focal honeycombing triggered by SBRT [10]. Similarly, acute exacerbation of subclinical ILD triggered by surgery in patients with lung tumors has been demonstrated [20]. In our series, relationship between subclinical ILD and Grade 2–5 RP was not significant, the rate of extensive RP beyond the irradiated field was significantly high in the patients with subclinical ILD. Our results also implied that uncommon extensive and fatal RP can occur in patients with subclinical ILD even if CT appearance of subclinical ILD was slight, the risk of extensive RP should be considered in patients with subclinical ILD and that careful observation and management of RP must be provided after SBRT in such patients. Classical RP changes in the lungs are considered to be confined to the site of irradiation. However, there are several reports of extensive RP occurring beyond the irradiated field in the early literature [21,22]. Morgan et al. indicated that sporadic pneumonitis, including extensive RP, appears to be an entirely different disease process involving immune modulation and genetic factors, as opposed to classical RP, which is characterized by the inflammatory consequences of direct irradiation injury to pulmonary tissue [23]. Roberts et al. demonstrated that lymphocytic alveolitis develops in both lung fields after strictly unilateral thoracic irradiation and is more pronounced in patients who develop clinical pneumonitis. They concluded that radiotherapy might cause generalized lymphocyte-mediated hypersensitivity reactions [24]. In the current study, the contribution of the above described unclassical disease process was suggested in the three patients with extensive RP involving the contralateral lung because the mean irradiation dose of the contralateral lung was as low as 0.5–0.8 Gy. The relationships between the dosimetric factors of the lungs and the occurrence of symptomatic RP have been investigated in patients treated with thoracic radiotherapy [18,25]. Matsuo et al. reported that the rate of symptomatic RP after SBRT was 15.0% in patients with Lung V20 of <5.8% and 42.9% in the remaining patients [18]. In the current study, dosimetric factors were also significantly correlated with Grade 2 or higher RP, and both of the two patients with Grade 4–5 extensive RP exhibited high Lung V20 (9.5% and 11.5%) and MLD (5.3 and 6.8 Gy) values (Table 4). Therefore, we propose that SBRT should be administered in patients with subclinical ILD using safer values of dosimetric factors and increasing fractionation schedules to prevent the risk of extensive RP.
Rancati et al. evaluated clinical and lung dose-volume histogram-based factors as predictors of RP in patients with lung tumors, and concluded that the presence of chronic obstructive pulmonary disease was significantly associated with a higher risk of RP after three-dimensional conventional radiotherapy [26]. On the other hand, Kimura et al. reported the relationship between pulmonary emphysema and RP in 45 patients treated with SBRT. The rate of Grade 2 or higher RP was rather low in patients with pulmonary emphysema [27]. In the current study of SBRT, pulmonary emphysema was not found to be a significant factor related to the occurrence of Grade 2 or higher RP. Regarding limitations associated with this study. Due to the fact that the current study was a retrospective series, the possibility of selection bias with regard to the predictive factors cannot be ruled out. In addition, we could not analyze the data in patients with active ILD excluded from SBRT, because they had not been properly recorded. A formal prospective study is consequently needed to determine the toxicity, efficacy and prognostic factors of SBRT in patients with subclinical ILD. In summary, this is the first report attempting to investigate whether subclinical ILD is a predictor of RP in patients treated with thoracic SBRT. Subclinical ILD was not found to be a predictor of Grade 2–5 RP in patients treated with thoracic SBRT; however, uncommon extensive and fatal RP extending beyond the irradiated field can occur in patients with subclinical ILD, and the rate of extensive RP was significantly higher in the patients with subclinical ILD in this study. There were no significant differences in the survival rates between the patients with and those without subclinical ILD. The risk of extensive RP should be considered and obtaining sufficient informed consent is required in patients with subclinical ILD. In addition, careful observation and management of RP should be carried out after SBRT in such patients.
Conflict of interest statement Potential conflicts of interest do not exist in this study.
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