Abstract
Background. To analyze the treatment outcomes of a potentially curative therapy, stereotactic body radiation therapy (SBRT), for patients with single or oligometastasis to the lungs. Material and methods. Sixty-seven metastatic lung lesions in 57 patients were treated with SBRT between September 2001 and November 2010. All patients had single or oligo-metastasis to the lungs following a meticulous clinical work-up, including PET-CT scans. The lungs were the most common primary organ (33 lesions, 49.3%), followed by the head and neck (11 lesions, 16.4%), the liver (nine lesions, 13.5%), the colorectum (seven lesions, 10.4%), and other organs (seven lesions, 10.4%). Three different fractionation schedules were used: 50 Gy/5 fractions to four lesions (6.0%); 60 Gy/5 fractions to 44 lesions (65.7%); and 60 Gy/4 fractions to 19 lesions (28.3%). Results. Local tumor progression occurred in three lesions (4.5%). The three-year actuarial local control rate was 94.5%. Tumors larger than or equal to 2.5 cm showed poorer local control (98.3% vs. 77.8%, p <0.01). Metastatic tumors from the liver and colorectum showed lower local control rates than those from other organs (77.8%, 85.7%, and 100%, p =0.04). The two-year overall survival rate was 57.2%. Patients with tumors smaller than 2.5 cm had more favorable survival rates (64.0% vs. 38.9% at two-year, p =0.032). Patients with extrathoracic disease had poorer survival rates (66.1% vs. 0% at two-year, p =0.003). Patients with disease-free intervals longer than two years showed a trend toward good prognosis (71.1% vs. 51.1% at two-year, p =0.106). Grade 2 lung toxicity occurred in four patients (6.0%). One patient experienced Grade 5 lung toxicity following SBRT. Conclusion. SBRT for single or oligo-metastasis to the lung seems quite effective and safe. Tumor size, disease-free interval, and presence of extrathoracic disease are prognosticators for survival.
Hematogenous metastasis to the lung from various malignancies is regarded as an incurable condition and symptom-based supportive management, with or without palliative systemic chemotherapy, is the mainstay of treatment. Local therapies, however, are often conducted with a potentially curative aim in the clinical setting of single or oligometastasis to the lungs. Oligometastasis indicates that the numbers and sites of metastatic tumors are limited, whereas distant metastasis is generally considered to be extensive in numbers and organ sites [Citation1]. The clinical implications are that a proportion of patients with oligometastasis could be cured by effective local therapies and expected to have a long-term survival [Citation2].
The International Registry of Lung Metastases (IRLM) reported the results of pulmonary resection in 5206 patients with lung metastases [Citation3]. Patients who underwent complete surgical resection had five- and 10-year survival rates of 36% and 26%, whereas the patients who received incomplete resection had five- and 10-year survival rates of 13% and 7%, respectively. This finding suggests that adequate local treatment for metastatic tumors is an important factor for improving survival.
Stereotactic body radiation therapy (SBRT) is a local ablative radiation modality that is very effective for treating small tumors outside the cranium. SBRT for early-stage non-small cell lung cancer (NSCLC) has promising outcomes in medically inoperable patients, with a local control rate of about 90% and very low complication rates [Citation4–7]. However, few results have been reported for SBRT for metastatic tumors. In the current study, we analyzed clinical outcomes following SBRT for single or oligometastasis to the lung.
Material and methods
Patients
After clinical evaluations including complete history and physical examination, baseline assessment of respiratory and cardiac function, and chest radiograph and computed tomography (CT) scans of chest, and 18F-deoxy-glucose positron emission tomography (FGD-PET) or PET/CT, SBRT was considered if: (1) the patient had a controlled primary tumor; (2) the size of the tumor was less than 5 cm in maximum dimension; and (3) the number of lung metastases was less than five. Patients with extrathoracic disease were included if the disease was potentially controllable by surgery or radiation therapy, such as solitary lymph node or adrenal metastasis. Informed consent was obtained from all patients. 18F-deoxy-glucose positron emission tomography (FDG-PET) or PET/CT were performed in 40 patients (70%) at the time of diagnosis of metastasis to the lung. Between September 2001 and November 2010, a total of 57 patients with 67 lesions were treated with SBRT and enrolled in the retrospective analysis
SBRT procedures
All the patients were immobilized individually in either the supine or prone positions depending on the location of the tumor. The patients were supine if the target lesion was located anteriorly. Until February 2008, helical CT images (Hi-speed Advantage, GE Medical System, Milwaukee, WI, USA) were obtained during free breathing. A set of transverse images were collected at 3 mm thick intervals and transferred to a Pinnacle treatment planning station (ADAC Laboratories, Milpitas, CA, USA). The clinical target volume (CTV) was determined with 3 to 4 mm margins around the gross tumor volume (GTV). The CTV was expanded by 5 to 10 mm margin to create the planning target volume (PTV) while considering respiratory movement. Since March 2008, four-dimensional CT (4D-CT) has been available at our institution. Before CT simulation, all patients underwent respiratory training aided by a goggle display, which showed a prerecorded respiratory curve for each patient. An image set with a 2.5 mm thick interval was acquired during quiet breathing. The 10 phases of the 4D-CT datasets were acquired using a Real-time Position Management (RPM) system. With all of the CT datasets, the internal target volume (ITV) was determined from the sum total of the GTV on each phase. A 5 mm margin was added to the ITV to create the PTV. The treatment plan was based on the quiet breathing image set.
The RT was administered using multiple non-coplanar beams (median 5 beams, range 4 to 8) by a linear accelerator with 4, 6 or 10 MV photons. The dose was prescribed at the calculation point set within the GTV, with the 80% to 90% isodose line encompassing the PTV. The SBRT dose was escalated sequentially from the biologically effective dose (BED) of 100 Gy10 to 150 Gy10, assuming the alpha-beta ratio of the tumor to be 10:50 Gy in 5 fractions (BED10 =100 Gy10) from September of 2001 till May of 2002; 60 Gy in 5 fractions (BED10 =132 Gy10) from June of 2002 till December of 2009; and 60 Gy in 4 fractions (BED10 =150 Gy10) from January of 2010 till November of 2010.
Follow-up
The clinical response was evaluated by chest CT taken at one to three months according to World Health Organization criteria [Citation8], and patients were followed up with either a chest CT or PET-CT at three to four month intervals thereafter. Tumor progression was determined when the tumor size was increased on two consecutive CT scans. Because it was often difficult to distinguish between tumor recurrence and radiation fibrosis, any undetermined densities on CT scans were considered to be stable disease until apparent tumor re-growth developed on follow-up CT scans and/or was evident by increase in glucose uptake on FDG-PET scan. The grade of treatment-related toxicity was determined by the Common Terminology Criteria for Adverse Events, version 3.0.
Statistics
The survival rate was determined by the Kaplan-Meier method. The duration of survival was calculated from the date of start of SBRT to the date of the last follow-up or death. The differences between groups were compared by the log-rank test, and the Cox proportional hazards regression model was used for multivariate analysis. The distribution of categorical variables was analyzed by the χ2 test. P-values less than 0.05 were considered to be statistically significant. SPSS 19.0 was used for analyses.
Results
Patients
The characteristics of the patients are summarized in . The numbers of target lesions were one in 50 patients (87%), two in five (9%), three in one (2%), and four in one (2%). The lung was the most common primary organ (33 lesions, 50%), followed by the liver (nine, 14%), the head and neck (11, 16%), the colorectum (seven, 10%), and others (seven, 10%). SBRT was performed with 50 Gy/5 fractions (BED10 =100 Gy10), 60 Gy/5 fractions (BED10 =132 Gy10) and 60 Gy/4 fractions (BED10 =150 Gy10) to four lesions (6.0%), 44 (66%) and 19 (28%). 4D-CT simulation was performed in 30 patients (53%). The median follow-up period of the surviving patients was 21 (3–107) months.
Table I. Patient characteristics.
Local control rate and response
Local tumor progression occurred in three patients (three lesions, 5%). The three-year actuarial local control rate was 94.5% (). Local control rates by 100 Gy10, 132 Gy10 and 150 Gy10 were 100%, 93.2% and 100%, respectively. Tumors larger than or equal to 2.5 cm showed lower local control (98.3% vs. 77.8%, p <0.01). Metastatic tumors from the liver and the colorectum showed lower local control rates than those from other organs (81.8%, 80.0%, and 100%, respectively, p =0.04). The actuarial local control rate according to tumor size and primary histology is shown in .
Figure 1. Actuarial local control rates (A) and overall survival rates (B) for all patients.
Figure 2. Actuarial local control rates according to (A) tumor size and (B) primary tumor.
Complete response was noted in 17 lesions (25%), partial response in 40 (60%) and stable disease in 10 (15%). There was no correlation between radiologic response and local control ().
Table II. Analysis of factors affecting local control rate.
Survival
The two- and five-year overall survival rates were 59.7% and 56.2% in all patients (). Univariate analysis showed that tumor size and the presence of extrathoracic disease were significant factors for overall survival. Patients with tumors smaller than 2.5 cm had more favorable survival (64.0% vs. 38.9% at two-year, p = 0.032) (). Patients with extrathoracic disease had lower survival (66.1% vs. 0% at two-year, p = 0.003) (). Other factors including age, sex, performance score, primary site, histology, length of disease-free interval, and target number did not show any significant difference statistically. Multivariate analysis showed that the presence of extrathoracic disease was the only statistically significant factor (p = 0.049).
Figure 3. Factors affecting overall survival (OS).
Toxicities
Grade 2 pneumonitis occurred in four patients (6.0%). The median V10 and V20 (Vdose:% volume of total lung receiving indicated dose or more) were 15.2% (range, 14.3–33.7%) and 8.2% (range, 7.3–25.2%), respectively. One patient died of Grade 5 pneumonitis following SBRT. The patient had a long history of COPD. One year before the SBRT for metastatic lung lesion, the patient received left pneumonectomy and postoperative RT for NSCLC. SBRT was performed for metastatic lumg tumor of 2.8 cm in diameter with 60 Gy in 5 fractions. Four months after SBRT, he complained of severe dyspnea with pulmonary infiltration within the radiation field and then he died of respiratory failure five months after SBRT. V10 and V20 were 61.0% and 37.1%. In the other 42 patients whose dosimetric parameters were evaluable, the median V10 and V20 were 10.8% (range, 2.7–26.1%) and 5.4% (range, 1.0–11.9%), respectively.
Rib fractures inside or adjacent to the SBRT volume occurred in nine lesions (13%), most of which resulted in minimal or mild pain. The median V30 and V60 of nine lesions were 38.3 cm3 (range, 19.4 to 117.1 cm3) and 0.7 cm3 (range, 0 to 6.6 cm3), respectively.
Discussion
There is no standard treatment regimen of SBRT for primary or metastatic lung tumors. The dose-fractionation of SBRT varied from 48 to 60 Gy in 4–8 fractions in Japan [Citation9] to 54 to 66 Gy in 3 fractions in published trials from the Radiation Therapy Oncology Group (RTOG) [Citation4,Citation7]. Our institution escalates from 50 Gy in 5 fractions to 60 Gy in 4 fractions, sequentially. Herein, we reported an excellent local control (LC) rate of 94.5% and a low incidence of radiation-related toxicity after treatment for single or oligometastasis to the lung by SBRT.
Several studies have analyzed outcomes of SBRT for metastatic lung tumors (). Hamamoto et al. [Citation10] performed SBRT using 48 Gy in 4 fractions (105.6 Gy10) for 12 metastatic lung tumors and reported a poor LC rate of 25% at two years, although they commented that the most common primary site was colorectal cancer. Norihisa et al. [Citation11] found that the LC rate of 43 metastatic lung tumors was 90.0% at two years and showed that 60 Gy in 5 fractions (132 Gy10) was superior to 48 Gy in 4 fractions (105.6 Gy10) for LC (100.0% vs. 83.3%). Recently, Rusthoven et al. [Citation12] reported the final results of a prospective, multi-institutional phase I/II trial of SBRT for oligometastasis to the lung. A two-year LC rate of 96% was achieved by 48 to 60 Gy in 3 fractions (124 Gy10 to 180 Gy10) for 63 metastatic lesions. McCammon et al. [Citation13] showed the dose-LC relationship of SBRT for 246 lesions including primary or metastatic lung tumors (67% of all lesions). A SBRT regimen of 54 to 60 Gy in 3 fractions (151 Gy10 to 180 Gy10) achieved 89.3% of LC rate at three years. In the present study, RT was delivered with 50 to 60 Gy in 4 or 5 fractions (100 Gy10 to 150 Gy10). Local progression occurred in only three lesions (4.5%) and we could not find any statistical difference of LC rate according to RT dose. Most published data, however, suggest that it seems to be associated with high LC rate around 90% to deliver RT dose higher than 120 Gy10. It should be clarified with the multi-institutional prospective studies.
Table III. Treatment outcomes of SBRT for metastatic lung tumors in recently published study.
The primary site of metastatic lung tumors may influence the LC by SBRT. Milano et al. [Citation14] reported the results for 293 metastatic lesions treated by SBRT with the preferred regimen of 50 Gy in 10 fractions. The two-year LC rate of all lesions was 77% and metastatic tumors originating from pancreatic, biliary, liver, or colorectal cancer were associated with significantly poorer LC. Kim et al. [Citation15] performed SBRT with 39 to 51 Gy in 3 fractions for 13 metastatic lung tumors from colorectal cancer and reported a three-year LC rate of 52.7%. Hamamoto et al. [Citation10] explained that a large proportion of metastatic tumors from colorectal cancer (67%) might be the reason for poor LC (25% at two years). Takeda et al. [Citation16] analyzed LC of metastatic lung tumors compared with primary lung cancer after SBRT. The LC rate in tumors from colorectal origin was significantly worse than that in tumors of other origins (72% vs. 94% at two years, p <0.05). The present study also detected poorer LC rates in metastatic tumors from liver or colorectal cancers (p = 0.04). However, the crude LC rate of 81.3% (13/16) is still high. Hamamoto et al. [Citation10] found that the primary site of metastatic lung tumors becomes less important when higher and more intense doses of SBRT are delivered.
Tumor size is also a significant predictor of LC. Kim et al. [Citation15] reported a three-year local progression-free survival rate of 52.7% for all patients and of 83% when the ITV was less than 17 ml (approximately 3 cm in diameter). McCammon et al. [Citation13] demonstrated that the LC rate was better in small tumors with GTV less than 8.9 ml (p = 0.003) using univariate analysis. We previously reported that tumors less than 2.5 cm were associated with higher LC rates than tumors more than or equal to 2.5 cm (100% vs. 82.3%, p = 0.05) in patients with primary or metastatic lung cancer treated by SBRT [Citation17]. In the present study, we found that tumors less than 2.5 cm have better LC rates (98.3% vs. 77.8%, p <0.01). The cut-off point was set up at 2.5 cm because the value embraced a statistical difference of local control between the each group of tumor sizes. If more patients were enrolled in the study, the cut-off tumor size would have been different from the current value.
The large surgical series of the IRLM [Citation3] demonstrated a two-year survival rate of 70% and a five-year survival rate of 36% in patients who underwent complete resection. The four largest published series of SBRT showed that the two-year overall survival rate was 54.5% in a total of 175 patients with 311 lesions [Citation18]. The current study showed excellent two-year and five-year overall survival rates of 60.2% and 57.2%, respectively. Although comparisons of overall survival between studies are limited by patient selection criteria, these data indicate that SBRT, like surgical resection, may be performed with curative aims in patients with single or oligometastasis to the lung. The IRLM study demonstrated that a disease-free interval longer than 36 months and single metastasis were good prognosticators. Norihisa et al. [Citation11] also found that disease-free intervals are good prognosticators in patients treated by SBRT. In the current study, we showed that tumor size smaller than 2.5 cm, disease-free interval longer than two years, and the absence of extrathoracic disease were the prognosticators for overall survival. Larger tumors and the presence of extrathoracic disease indicate larger tumor burden for metastatic disease in the setting of oligometastasis, which may result in poorer survival.
Many series studying SBRT showed minimal toxicity. Grade 3 or higher radiation toxicities were observed in about 4% of patients [Citation18]. We observed grade 5 lung toxicity in one patient and rib fractures in nine patients (13.4%). The details of the case of grade 5 lung toxicity are described in ‘Results’ section. Special attention should be paid when considering SBRT for patients with compromised lung function. The incidence of rib facture was reported to range from less than 5% to as high as 25% in a series of SBRT for primary NSCLC [Citation19]. Chest wall pain could affect quality of life, so the risk of rib fractures should be minimized. To restrict volumes of the chest wall receiving moderate to high doses of radiation should be considered when SBRT is planned [Citation19,Citation20].
Our study has some limitations of retrospective analysis. The time period of the study was relatively long, so patient materials are inhomogeneous. The metastatic lesions are from several different primary tumors and three different fractionation schedules are used. The multi-institutional prospective trial is required to clarify the role of SBRT for single or oligometastasis to the lung.
In conclusion, potentially curative SBRT with 50 to 60 Gy in 4–5 fractions for single or oligometastasis to the lung is both effective and safe. Tumor size, disease-free interval, and the presence of extrathoracic disease are the prognostic factors for survival.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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