Volume 77, Issue 3 , Pages 685-690, 1 July 2010
Early Graphical Appearance of Radiation Pneumonitis Correlates With the Severity of Radiation Pneumonitis After Stereotactic Body Radiotherapy (SBRT) in Patients With Lung Tumors
Article Outline
Purpose
To investigate factors associated with Grade ≥3 radiation pneumonitis (RP) in patients with lung tumors treated with stereotactic body radiotherapy (SBRT).
Methods and Materials
We retrospectively analyzed 128 patients with 133 lung tumors treated with SBRT. RP was graded according to the Common Terminology Criteria for Adverse Events version 3.0. Univariate analyses were used to identify predictive factors for RP.
Results
The median follow-up period after SBRT was 12 months (range, 5–45 months). Incidences of Grades 0, 1, 2, and 3 RP were 27%, 52%, 16%, and 5%, respectively. No patients suffered Grade 4 or 5 RP. For all patients with Grade 2 or 3, symptoms occurred either simultaneously with or subsequent to graphical appearances. The latent period was the only significant factor associated with Grade ≥3 RP (p < 0.01). A latent period of 1 or 2 months indicated a 40% (6/15) risk for Grade 3. However, the risk for Grade 3 was 1.2% (1/82) 3 months after SBRT. No pretreatment clinical or dosimetric factors were significantly associated with Grade ≥3 RP. However, 4 of 7 patients with Grade 3 RP had severe pulmonary comorbidities.
Conclusion
Only the latency period was a significant factor in the development of RP. No pretreatment clinical or dosimetric factors were significantly associated with Grade ≥3 RP. Patients, especially those with severe pulmonary comorbidities, should be carefully observed for the graphical appearance of RP within a few months during the follow-up period after SBRT.
Stereotactic body radiotherapy, Radiation pneumonitis, Lung cancer
Introduction
Several reports have suggested that clinical outcomes of hypofractionated stereotactic body radiotherapy (SBRT) for early primary lung cancer are equivalent to surgical outcomes 1, 2, 3, 4; prospective studies are currently underway 5, 6. SBRT not only provides a high local control rate but is also more tolerable for patients because it allows for a completely painless ambulatory treatment with a low incidence of adverse reactions. However, fatalities following the completion of SBRT, although rare, have been reported 7, 8, 9. We have reported a case of acute exacerbation of subclinical idiopathic pulmonary fibrosis (IPF) following SBRT for primary lung cancer in a patient with slight focal honeycomb changes (10). A Japanese survey conducted by Nagata et al. (7) indicated that treatment-related deaths occurred in 14 of 2,390 patients (0.58%) who underwent SBRT for pulmonary lesions (7).
Radiation pneumonitis (RP) is of the greatest concern among the possible toxicities from lung cancer treatment with conventionally fractionated radiotherapy (conventional radiotherapy), and the factors associated with severe RP have been thoroughly discussed (11). Investigation of factors causing severe RP is vital to improve the safety of SBRT. In this study, we analyzed various factors associated with RP of Grade ≥3 after SBRT for lung tumors.
Methods and Materials
Patients
Between February 2005 and November 2008, SBRT was performed at our institutions for 157 patients with 163 lung tumors. All of the patients provided written informed consent. For this study, we retrospectively collected the data for patients who had either a minimum follow-up of 6 months or had Grade ≥1 RP and were followed up for more than 5 month after the appearance of graphical RP. As of February 2009, 128 patients with 133 lung tumors were included in this study. Five patients who had two metachronous lesions were treated twice each with SBRT at different times. Hence, we investigated 133 SBRT series.
The patients' backgrounds are shown in Table 1. There were 111 primary lung cancers and 22 metastatic lung tumors. Regarding primary lung cancer, there were 41 cases of pathologically proven adenocarcinoma, 25 cases of squamous cell carcinoma, 6 cases of non–small cell lung cancer (NSCLC), and 4 cases of small cell lung cancer. The remaining 35 patients were considered to have lung cancer without pathologically proven evidence. They were diagnosed by successive increases in tumor sizes obtained by CT, as well as by uptake on positron emission tomography and/or elevated levels of tumor markers (CEA, SCC, cyfra, SLX, NSE, or proGRP). Among the metastatic lung tumors, the primary sites were colon (10), lung (6), and other sites (6). There were 34 operable and 99 inoperable patients.
Table 1. Background of 133 series of SBRT
| Sex (male/female) | 93/40 |
| Age (years) | 77 (43–92) |
| Disease | |
 Primary lung cancer | 111 |
| Adeno cancer | 41 |
| Squamous cell cancer | 25 |
| NSCLC | 6 |
| Small cell cancer | 4 |
| Clinically diagnosed | 35 |
| Lung metastasis | 22 |
| Operable/inoperable | 34/99 |
| PS(0/1/2) | 26/64/43 |
| 2nd Tx after conv/SBRT | 4/5 |
| Comorbidity | |
| COPD | 36 |
| IPF | 3 |
| Other pulmonary dificiency | 19 |
| Pulmonary function | |
| Vital capacity (1) | 2.33 (1.28–4.50) |
| FEV1.0 (1) | 1.5 (0.46–3.56) |
| Total dose | |
| 60Gy/5 fr | 2 |
| 50Gy/5 fr | 98 |
| 40Gy/5 fr | 29 |
| 50Gy/10 fr | 4 |
Before treatments, pulmonary function tests were performed for all patients. Serum lactate dehydrogenase (LDH) and C-reactive protein (CRP) levels were obtained. Sialylated carbohydrate antigen (KL-6) and surfactant protein D (SP-D) were also monitored beginning in February 2006 and March 2007, respectively.
Treatment
We have described our SBRT methods in previous reports 12, 13. Briefly, long-scan-time CT was employed to visualize the internal target volume (ITV) directly after immobilizing the patient with a vacuum pillow. The planning target volume (PTV) was made by adding a margin of 6–8 mm to the ITV. Dynamic conformal multiple arc irradiation was used for SBRT. The leaf margins were modified to ensure that the PTV was included in the 80% isodose surface. Dose calculation was performed using a superposition algorithm. The prescribed doses were defined as 80% of the maximum dose; in a previous study, they were found to be nearly equivalent to the dose covering 95% of the PTV (D95) (13).
We principally used 50 Gy per 5 fractions in 5–7 days as the prescribed dose for patients with a peripheral NSCLC lesion. For patients with a central NSCLC lesion, we used 50 Gy per 10 fractions until the end of March 2007, after which we used 40 Gy per 5 fractions. For patients with a radioresistant solitary metastatic lung tumor (i.e., one from colon cancer), we employed 60 Gy per 5 fractions. As a result, 2 patients were treated with a prescribed dose of 60 Gy per 5 fractions, 98 received 50 Gy per 5 fractions, 29 received 40 Gy per 5 fractions, and 4 received 50 Gy per 10 fractions.
Follow-up
For all patients, graphical appearances of RP were monitored monthly on an outpatient basis with chest X-ray examinations. Monthly follow-up continued either until clinical and X-ray findings stabilized or for 6 months following SBRT. Additionally CT scans were performed at 1 and 3 months after SBRT and at 3-month intervals during the first 2 years and at 4–6 month intervals thereafter, even in the absence of clinical symptoms. Because most patients with toxic events (87%) developed the endpoint within 6 months of SBRT (14), those without toxic events were additionally required to have a minimum follow-up of 6 months. RP was graded according to the Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE ver. 3.0).
Clinical and dosimetric factors associated with RP
We investigated the following clinical factors associated with RP: sex, age, disease, operability, performance status, pulmonary comorbidity, laboratory results (CRP, LDH, KL-6, and SP-D), pulmonary function results and total dose. Pulmonary functions included vital capacity and forced expiratory volume in 1 s. Performance status was graded using the Karnofsky Performance Status scale.
For dosimetric factors, the total normal lung volume was defined as the total lung volume minus the ITV. The following dosimetric parameters were generated from the DVH for total normal lung: PTV/total normal lung, mean lung dose (MLD), and volumes of lung receiving more than a threshold dose, D, of radiation (VD), where the D values considered ranged from 5 to 30 Gy in increments of 5 Gy. We examined the associations of these factors and GTV with the occurrence of Grade ≥3 RP. We also investigated the latent period for posttreatment factors. The latent period was defined as the interval between the SBRT start date and the onset of RP.
Statistical analysis
The clinical, dosimetric, and posttreatment factors were assessed for correlations with the risk for Grade ≥3 RP. We compared the latent periods between Grades 1–2 RP and Grades ≥3 RP, as well as the other factors between Grades 0–2 RP and Grades ≥3 RP. Univariate analysis was done by independent samples t test using SPSS 16.0 (SPSS, Chicago, IL). Differences with p values <0.05 were considered statistically significant.
Results
The median follow-up period after SBRT was 12 months (range, 5–45 months). For the patients in this study, RP developed as follows: Grade 0 in 36 patients (27%), Grade 1 in 69 patients (52%), Grade 2 in 21 patients (16%), and Grade 3 in 7 patients (5%). No patients suffered RP of Grade ≥4. Patients treated twice because of metachronous metastases did not suffer more than Grade 3 RP. For all patients with Grades 2 and 3 RP, symptoms did not appear earlier than the graphical appearances of RP. Rather, symptoms appeared either simultaneously with or subsequent to graphical appearances.
Of the seven patients suffering Grade 3 RP, 4 patients, including 1 patient with IPF comorbidity, were administered steroids, after which their symptoms resolved. One 80-year-old patient was followed carefully by a respirologist (T.E.) without receiving any treatment. This patient was diagnosed with IPF during the follow-up period after SBRT. The other two patients were given home oxygen therapy without steroid therapy, and they had severe chronic obstructive pulmonary disease (COPD). One of the two patients with severe COPD showed hypoventilation on spirometry (forced expiratory volume [FEV]1.0 = 0.61 L). The other showed hypoxemia (PaO2 = 63 torr) due to an uneven distribution of ventilation-perfusion of the lung, although the FEV1.0 was 2.5 L. Thus, four patients had severe pulmonary comorbidities. Regarding the extent of graphical RP, four patients showed large extents of graphical RP beyond the high-dose irradiated volume. Among them, two patients were diagnosed with IPF. Three of four patients including one IPF patient were administered steroids (Grade ≥3 RP). In the other patients, the extent of graphical RP corresponded to the high-dose irradiated volume.
Table 2 shows the relationships between the clinical, dosimetric, and posttreatment factors with RP. By univariate analyses, the interval between the start of SBRT and the latent period was the only factor significantly associated with Grade ≥3 RP (p < 0.01). None of the other factors showed a significant relationship.
Table 2. Factors associated with radiation pneumonitis
| Mean (range) | |||
|---|---|---|---|
| Grade 0–2 (n=126) | Grade 3 (n=7) | p value | |
| Clinical factor | |||
| Sex (male/female) | 87/39 | 5/2 | 0.89 |
| Age | 75 (43–92) | 77 (70–85) | 0.61 |
| Primary LC/metastasis | 105/21 | 6/1 | 0.87 |
| Operable/inoperable | 33/93 | 1/6 | 0.49 |
| COPD | 34 | 2 | 0.93 |
| PS (0/1/2) | 26/60/40 | 0/4/3 | 0.25 |
| VC | 2.41 (1.28–4.50) | 2.38 (1.76–3.32) | 0.93 |
| FEV1.0 | 1.58 (0.46–3.56) | 1.75 (0.61–2.64) | 0.47 |
| CRP | 1.08 (0.00–57) | 0.73 (0.00–3.85) | 0.87 |
| LDH | 201 (136–429) | 212 (177–277) | 0.5 |
| KL-6 | 327 (124–816) | 404 (177–620) | 0.12 |
| SP-D | 58 (17–158) | 51 (34–64) | 0.71 |
| ITV | 14.0 (0.2–66.8) | 14.5 (2.2–35.0) | 0.92 |
| Upper/lower | 60/66 | 3/4 | 0.81 |
| Central/peripheral | 35/91 | 2/5 | 0.96 |
| Treatment-related factor | |||
| PTV | 45.1 (7.7–139.2) | 42.9 (14.1–77.1) | 0.84 |
| Lung volume | 3522 (1541–7346) | 3155 (1817–5088) | 0.47 |
| PTV/lung volume(%) | 1.48 (0.2–4.9) | 1.57 (0.7–4.4) | 0.83 |
| Total dose (60/50/40) | 2/95/29 | 0/7/0 | 0.21 |
| Dosimetric factor | |||
| MLD | 390 (137–829) | 403 (228–538) | 0.81 |
| V5 | 19.3 (4.54–40.8) | 23.3 (11.5–33.1) | 0.16 |
| V10 | 10.4 (2.52–28.9) | 10.8 (6.1–13.8) | 0.79 |
| V15 | 6.6 (1.18–19.8) | 5.8 (4.0–6.8) | 0.52 |
| V20 | 4.5 (0.65–12.9) | 3.9 (2.9–4.9) | 0.49 |
| V25 | 3.4 (0.38–25.1) | 2.8 (2.2–4.0) | 0.58 |
| V30 | 2.2 (0.2–6.6) | 2.1 (1.6–3.2) | 0.72 |
| Post-treatment factor | Grade 1–2 (n=90) | Grade 3 (n=7) | |
| Latent period=graphical RP | 4.3 (1.0-9.5) | 2.2 (1.2–5.5) | <0.01∗ |
∗Significant P value. |
Figure 1 shows the relationship between the RP grade and the latent period. A short latent period was associated with an early graphical appearance, because RP graphical appearances showed up first for all patients with Grades 2 or 3. This figure indicates a 75% (3/4) risk for Grade 3 RP when graphical RP occurred 1 month after SBRT and a 40% (6/15) risk for Grade 3 RP when graphical RP occurred within 2 months of SBRT. Three months after receiving SBRT, only one patient suffered Grade 3 RP. Therefore, the risk for Grade 3 RP was 1.2% (1/82).
Fig. 1
Relationship between the radiation pneumonitis grade and the latent period.
Discussion
Risk factors for RP after conventional radiotherapy and SBRT
With regard to conventional radiotherapy, the factors correlated with severe RP have frequently been analyzed. Several patient-specific factors (e.g., age, smoking history, tumor location, performance score, gender) and treatment-specific factors (e.g., chemotherapy regimen and dose) have been proposed as predictors for the risk of RP (11). In addition, many dosimetric factors have been studied and reported to be significantly associated with RP 11, 15.
With regard to SBRT, Kyas et al. (14) studied a total of 64 patients with NSCLC who were treated with single doses of 20–30 Gy to estimate the risks of radiation-induced changes. They reported that the mean lung doses V7 and V10 were predictive of a risk for lung toxicity and that no additional factors provided significant associations. The lower part of the lung appears to be more radiosensitive than the upper part. The endpoint studied by Kyas et al. was the occurrence or nonoccurrence of perifocal changes in the lung detected by CT, which were categorized to Grade ≥1 RP by CTCAE ver. 3.0. In contrast, Fujino et al. (16) studied clinical and dosimetric factors for RP that required steroid therapy after SBRT. They evaluated 156 patients with Stage I NSCLC at five institutions in Japan. However, no predictive factors were found in this study. We studied Grade ≥3 RP after SBRT and, similar to the results of Fujino et al., found no significant clinical or dosimetric factors to predict RP before treatment. Early graphical appearance of RP was the only factor that significantly correlated with Grade ≥3 RP.
However, SBRT for lung tumor is a treatment method that is still under development. The numbers of patients treated with SBRT have been limited, and the follow-up periods for the treated patients have been relatively shorter than for those with conventional radiotherapy. Even the clinical or dosimetric risk factors for RP after conventional radiotherapy have not been consistent across different studies (11). The risk factors related to Grade ≥3 RP after SBRT are also thought to be inconstant, which is similar to the situation with conventional radiotherapy. Therefore, we should pay careful attention not only to the early graphical appearance of RP but also to the potential risk factors proposed in other studies of SBRT and conventional radiotherapy.
Timing of graphical RP appearance in conventional radiotherapy and SBRT
Sekine et al. (17) retrospectively analyzed 385 lung cancer patients who developed radiation-induced lung injury after 50–70 Gy of conventional radiotherapy and were treated with or without corticosteroid therapy. They divided their cases into three groups. Group 1 included 307 patients who were stable without corticosteroids, Group 2 included 64 patients who were stable with corticosteroids, and Group 3 included 14 patients who died despite corticosteroid administration. The median for the number of weeks between the end of radiotherapy and the first graphical changes was 9.9, 6.7, and 2.4 for Groups 1, 2, and 3, respectively (p <0.001). Taking into consideration that the treatment time for 60 Gy/30 fractions takes approximately 6 weeks, the median for the number of weeks between the start of radiotherapy and the first graphical changes might be 15.9, 12.7, and 8.4 for Groups 1, 2, and 3, respectively.
Wang et al. (18) studied 31 NSCLC patients with severe RP to identify the prognostic factors involved. After multivariate analysis, they reported that the extent of RP (out of field or in field) was independently associated with survival and that, although not statistically significant, patients with out-of-field RP tended to have a shorter latent period than those with in-field disease (53 ± 26 days vs. 70 ± 32 days). These findings imply a more rapid onset and more severe pulmonary injury for out-of-field RP.
Out-of-field RP is considered to arise from a disease process that is pathophysiologically different from classic RP 19, 20, 21. In such cases, lymphocytosis is often found in bilateral bronchoalveolar lavage fluid, suggesting a hypersensitivity immune response to the damaged lung tissue (19). The resulting inflammatory reaction spreads out from the radiation field and causes a severe impairment of gas exchange.
With regard to SBRT, graphical changes around the PTV were usually observed within 2–6 months of the treatment 22, 23. Although most reports describe symptomatic RP as rare 1, 2, 3, an exceptionally high incidence of symptomatic Grades 2–5 RP has been reported (9). In our study, the graphical changes occurred within 2 months after the start of SBRT in all but one patient with Grade ≥3 RP. The proportions of Grade ≥3 RP were high when they occurred within 2 months. The median interval from the start of treatment to the appearance of graphical RP was 1.9 months, which is as short as the interval for fatal RP after conventional radiotherapy reported by Sekine et al. (17).
Comorbidities
Although comorbidities, including IPF, COPD, and other lung diseases, were not significant factors that influenced Grade ≥3 RP in this study, we should carefully observe patients with severe pulmonary comorbidities. In our series, two patients with severe COPD were included among the seven patients with Grade ≥3 RP. They were given home oxygen therapy when RP occurred, and steroids were not administered because their graphical RP regions were limited in and adjacent to the PTV. In such cases, it is difficult to distinguish clearly between Grade ≥3 RP and the natural progression of COPD. Therefore, we must carefully check the pretreatment pulmonary function and then decide on an indication for SBRT with informed consent.
Two patients with IPF were also included among the seven patients with Grade ≥3 RP. These two, as well as two other patients, showed Grade ≥3 RP with large extents of graphical RP. In patients with IPF, the frequency of acute exacerbation following conventional radiotherapy is reported to be approximately 25% 24, 25. Therefore, IPF is often considered a contraindication for conventional radiotherapy. SBRT is occasionally indicated for patients with IPF. However, this therapy remains controversial, and in a prospective study with the Japan Clinical Oncology Group 0403 protocol, SBRT was contraindicated for patients with radiography demonstrating any kind of change consistent with IPF (5).
Limitations
Our patients with Grade ≥3 RP were only 7/133 (5.3%), which might be too small to detect slight statistical differences. If we were to make the cutoff at Grade 2, we might more clearly show the significance of other clinical or dosimetric factors. However, Grade ≥3 RP was a critical condition; we should use steroids or administer oxygen therapy in the hospital for the patients. In contrast, for patients with Grade 2 RP, we simply followed them carefully without administering medication at the outpatient stage. In this context, we focused on RP of Grade ≥3 in this study.
Conclusion
Only the latent period after SBRT until the graphical appearance of Grade ≥3 RP was a significant factor in our study. During follow-up after SBRT, we should be vigilant with regard to the early graphical appearance of RP. We found no pretreatment clinical or dosimetric factors that were significantly associated with a risk for Grade ≥3 RP. Patients, especially with severe pulmonary comorbidities, should be carefully observed in terms of the graphical appearance of RP within a few months during the follow-up period after SBRT.
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Conflict of interest: none.
PII: S0360-3016(09)00836-0
doi:10.1016/j.ijrobp.2009.06.001
© 2010 Elsevier Inc. All rights reserved.
Volume 77, Issue 3 , Pages 685-690, 1 July 2010
