Clinical outcomes of patients with malignant lung lesions treated with stereotactic body radiation therapy (SBRT) in five fractions

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1 J Radiat Oncol (2012) 1:57 63 DOI /s ORIGINAL RESEARCH Clinical outcomes of patients with malignant lung lesions treated with stereotactic body radiation therapy (SBRT) in five fractions Hua Ren & Angel I. Blanco & Shanda Blackmon & Arnold C. Paulino & Stephen B. Chiang & E. Brian Butler & Bin S. Teh Received: 13 December 2011 / Accepted: 25 January 2012 / Published online: 15 February 2012 # Springer-Verlag 2012 Abstract Purpose This study aims to investigate factors associated with local control and survival benefit of five-fraction stereotactic body radiation therapy (SBRT) for patients with lung malignancies. Methods and materials Patients with pathologically proven malignant lung lesions were treated using SBRT with prescribed dose of 40, 50, and 60 Gy in five fractions. The biologically effective dose assuming α/β ratios of 10 Gy (biologically equivalent doses (BED)10) was 72, 100, and 132 Gy. GTVall and lesion average BED(10), instead of gross tumor volume (GTV) and BED(10), were used in patients with multiple lesions in the overall survival-related factors analysis. GTVall was defined as the sum of all target GTV in treatment, and lesion average BED(10) was defined as the sum of all target BED(10) in treatment divided by number of targets. H. Ren : A. I. Blanco : A. C. Paulino : E. B. Butler : B. S. Teh (*) Department of Radiation Oncology, The Methodist Hospital, Cancer Center and Research Institute, 6565 Fannin, DB1-077, Houston, TX 77030, USA bteh@tmhs.org S. Blackmon Department of Surgery, The Methodist Hospital, Houston, TX, USA S. B. Chiang Department of Radiology, The Methodist Hospital, Houston, TX, USA H. Ren Department of Radiation Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People s Republic of China Results One hundred and three lesions were treated in 84 patients between June 2004 and June 2008, 69 lesions in 56 patients were eligible in this analysis. No severe (grade >2) toxicities were noted. Two-year local control rates were 92.6%, 100% for primary and recurrent/metastatic groups, respectively. There was no significant factor for local control in univariate and multivariate analyses. One- and 2-year overall survival rates were 96.2%, 45.5%, and 80.0%, 45.6% for the primary and recurrent/metastatic groups, respectively. Multivariate analysis showed that lesion average BED(10) 100 and GTVall <20 ml were favorable factors associated with overall survival (P and P00.029, respectively). Conclusions SBRT in five fractions is safe and provides excellent local control for both primary and recurrent/metastatic lung malignancies. BED(10) and tumor volume were shown to be important for overall survival. Additional studies are needed to test the values of lesion average BED(10) and GTVall. Keyword Stereotactic body radiation therapy (SBRT). Lung cancer. Biologically effective dose (BED) Introduction Stereotactic body radiation therapy (SBRT) is now being investigated in several prospective studies for patients with early-stage nonsmall cell lung cancer (NSCLC) patients [1 5]. Furthermore, a recent phase I/II trial of SBRT for lung metastases demonstrates that high-dose SBRT is also safe and effective for the treatment of patients with one to three lung metastases [6]. SBRT is a feasible treatment option for patients with malignant lung lesions.

2 58 J Radiat Oncol (2012) 1:57 63 SBRT has been carried out in the Methodist Hospital, Houston, TX, USA for patients with malignant lung lesions since In this report, we retrospectively analyzed the outcome data of patients with malignant pulmonary lesions, treated with SBRT in five fractions using 4-dimensional (4D) computed tomography (CT), internal target volume (ITV) approach and image-guided SBRT. Methods and materials Patients One hundred and three malignant pulmonary lesions in 84 patients were treated with SBRT between June 2004 and June 2008, 69 lesions in 56 patients treated with SBRT in five fractions were eligible in this analysis. All patients had a pathologically proven malignant neoplasm. All cases were discussed at a multidisciplinary thoracic tumor board. Image-guided SBRT was offered as the sole modality of treatment to a select group of patients after careful consideration when other treatment options, including surgery, standard fractionated radiotherapy, or chemotherapy, were not deemed to be good options. Treatment The patients were treated using Novalis stereotactic system (BrainLAB, Feldkirchen, Germany). During simulation, the patients were immobilized in the supine position, in the Body Fix Immobilization Device (Medical Intelligence, USA). BrainLAB infrared sensitive body markers were placed on the chest as part of the ExacTRAC imageguided system (BrainLAB, Feldkirchen, Germany) for daily target localization. All patients underwent CT simulation using 3-mm cuts, with axial images obtained. 4D CT was also performed and used to create a maximum intensity projection or MIP dataset. From this CT dataset, we can observe the extent of the target motion and create internal target volume or ITVs that encompass the entire trajectory of the target. Gross tumor volume (GTV) was delineated on axial CT images in the mediastinal setting and then expanded the target volume to include the spiculated margin in the lung window setting. The patients also have PET/CT images in the treatment position which were coregistered to aid the GTV target delineation. Utilizing 4D CT images, we typically delineate the GTV on MIP images. Clinical target volume (CTV) was identical to GTV because the latter encompassed enough microscopic tumors in the lung window setting and PET-avid target. Planning target volume (PTV) was determined by adding a 3 5 mm margin to the axial plane and a 7 10 mm margin to the superior inferior direction of the GTV to account for daily setup variations. The critical structures including ipsilateral and contralateral lungs, spinal cord, esophagus, trachea bronchial trees, heart, aorta, and pulmonary arteries were outlined. Treatment planning was formulated on the Novalis planning system. The normal tissues dose constraints were adapted from data given in the Radiation Therapy Oncology Group (RTOG) 0236 protocol [5]. Treatment dose was prescribed to the PTV margin such that 85% of the isodose curve of the isocenter dose volume would cover 95% of the PTV volume. Dose was delivered using intensity modulated radiotherapy or conformal arcs. The choice of fractionation was based mostly on size, volume, and location of the tumor. In general, central lesions in close proximity to adjacent critical structures especially esophagus and mainstem trachea/bronchus were prescribed 40 Gy in five fractions. Peripheral lesions usually received Gy in five fractions after fulfilling the lung dose volume histogram constraint of V 20 <10%. Other factors, such as prior treatment, other adjacent normal tissue, e.g., spinal cord, brachial plexus, heart, and major blood vessels, the patient s general condition and tolerability/comorbidity, were also considered. A pair of kilovoltage X-ray images was acquired, and automatic 2D to 3D image fusion comparing the simulation CT was performed to further improve localization accuracy. Before delivery of radiation, an individual patient treatment quality assurance check was performed, including stereoscopic X-rays obtained for verification and to determine the precision and accuracy of localization. ExacTrac image guidance allows patient motion as internal organ changes to be verified and compensated. When all quality assurances were met, SBRT was delivered. Evaluation All patients were followed up on an outpatient basis with CT or PET/CT. Follow-up CT or PET/CT scans were performed at 1 and 3 months after SBRT, thereafter at 3-month intervals during the first 1 year, even in the absence of clinical symptoms. Subsequently, follow-up visits and CT or PET/CT scans were obtained at 6-month intervals. If there was a possibility that local treatment or systemic therapy would be required for suspected tumor recurrence, PET/CT was performed to assess the extent of locally recurrent lesions and detect distant metastases. Toxicity was graded using the National Cancer Institute-Common Toxicity Criteria for Adverse Events v3.0 (CTCAE). Statistical analysis The date of the first SBRT was used as the starting point of follow-up to determine median follow-up time and time-toevent estimates as outcome data. Control and survival rates

3 J Radiat Oncol (2012) 1: were calculated by using Kaplan Meier analysis, multivariate analysis using Cox-regression model with SPSS 13.0 (SPSS Inc., Chicago, IL, USA). Log-rank test was used to compare control or survival between the subsets of patients analyzed. All tests were two-tailed with p values <0.05 considered significant. Results Patients Sixty-nine malignant pulmonary lesions were treated with SBRT in 56 patients were eligible in this analysis. All of these patients had histopathologic or cytologic confirmation of lung malignancy. Median follow-up was 17.5 months (range, 2 49 months). Twenty-eight patients with primary lung cancer were not appropriate candidates for surgery because of chronic pulmonary disease, poor lung function, advanced age, or other chronic illnesses. Patient, lesions, and treatment characteristics are shown in Table 1. Toxicity Despite their medical comorbidities and advanced age, SBRT was well tolerated. Thirty-six patients (64.3%) reported no toxicities. Grade 1 toxicities included asymptomatic radiation pneumonitis in 13 patients (23.2%), fatigue in one patient (1.8%) and dysphagia in one patient (1.8%). Grade 2 toxicities included radiation pneumonitis in four patients (7.1%), fatigue in one patient (1.8%), and chest pain in one patient (1.8%). There was no grade 3 or higher toxicity. Local control The 1- and 2-year local control rates for primary and recurrent/metastatic lesions were 92.6%, 92.6% and 100%, 100% (p00.075), respectively. Univariate analysis and multivariate analysis were performed on tumor type (primary vs. recurrence/metastases), GTV, tumor location and biologically equivalent doses (BED)(10) 100. There was no significant favorable factor for local control (Table 2). Table 1 Baseline characteristics NSCLC non small cell lung carcinoma; SCLC small cell lung carcinoma; CRC colorectal carcinoma; RCC renal cell carcinoma Characteristic Primary Recurrent/Metastic Total N (%) Age Median Range No. of patients Male (39.3) Female (60.7) No. of lesions Primary tumor Lung (NSCLC/SCLC) 27 (26/1) 26 (24/2) 53 CRC RCC other Malignancy (unknown primary) Location Peripheral (84.1) Central (15.9) Lesion volume (ml) Median Range SBRT BED(10) (Gy) SBRT duration (days) Median Range

4 60 J Radiat Oncol (2012) 1:57 63 Table 2 Univariate and multivariate analysis for factors associated with local control Factors N Local control rate (%) Univariate P value Multivariate P value 1 Year 2 Years Type of tumor Primary Recurrent/Metastases Gross tumor volume (GTV) <14 ml ml Location Central Peripheral BED(10) BED < BED Survival The 1- and 2-year overall survival in patients with primary and recurrence/metastases were 96.2%, 45.5% and 80.0%, 45.6% (p00.193; Fig. 1), respectively. When analyzing factors associated with overall survival in patients with multiple lesions, GTVall, and lesion average BED(10) were used instead of GTV and BED(10), respectively. GTVall was defined as the sum of all target GTV in treatment, and lesion average BED(10) was defined as the sum of all target BED(10) in treatment divided by number of targets. Univariate analysis showed that lesion average BED(10) 100 is prognostic factor and small GTVall (<20 ml) is marginally significant (Table 3). The estimated median survival time in patients receiving lesion average BED(10) 100 and BED(10) <100 were 25.1 and 19.5 months (p , Table 3), respectively. The estimated median survival Fig. 1 The 1- and 2-year overall survival in patients with primary and recurrence/metastases time in patients with GTVall <20 ml and GTVall 20 ml were 24.8 and 20.2 months (p00.059, Table 4), respectively. Multivariate analysis results showed that lesion average BED(10) and GTVall were significant factors associated with overall survival (p and p00.029, respectively, Table 3). Discussion SBRT, also known as stereotactic ablative body radiotherapy, can provide good long-term local control and possibly improve quality of life with minimal side effects of treatment. Survival results of SBRT for stage I primary lung cancer in several studies are promising [3, 7, 8]. Chi et al. [9] published a systematic review on SBRT for early stage NSCLC in 2010, the 2-year median local control and overall survival (OS) rates in 21 studies with available data were 88% (range, 68 96) and 65.4% (range, 32 91). The 2-year local control and OS rates in our primary tumor group of 93.5% and 43.0% were comparable to Timmerman s and Hoyer s phase I/II studies [2, 4] of 2-year local control and OS rates of 96%, 92% and 55%, 47%, respectively. SBRT can play a role in treatment of metastatic lung lesion and achieve equivalent survival as surgery in lung oligometastases. Recently, Siva et al. [10] published a systematic review reporting 334 patients with 564 lung metastatic lesions treated with SBRT in 13 institutions. The 2- year local control was 77.9%, 2-year overall survival was 53.7%, with a 4% rate of grade 3 or higher radiation toxicities in SBRT series. In 2009, Rusthoven et al., [6] published a phase I/II trial of high-dose SBRT for the treatment of patients with one to three lung metastases. Patients with one to three lung metastases received SBRT delivered in three fractions. In phase I, the total dose was safely escalated from 48 to 60 Gy. The phase II dose was 60 Gy. Thirty-eight

5 J Radiat Oncol (2012) 1: Table 3 Univariate and multivariate analysis factors associate with OS Factors N Estimate survival (month) Overall survival rate (%) Univariate P value Multivariate P value 1 Year 2 Years Type of tumor Primary Recurrent/Metastases GTV all <20 ML ML Location Central Peripheral Lesion average BED(10) BED < BED patients with 63 lesions were enrolled and treated at three participating institutions. There was no grade 4 toxicity. The incidence of any grade 3 toxicity was 8% (3 of 38). Symptomatic pneumonitis occurred in one patient (2.6%). In the current study, the 2-year local control, median survival time, and OS rates of recurrent/metastatic tumor group, were 91.3%, 16 months and 33.6%. These are comparable to Rusthoven s phase I/II clinical trial [6] of SBRT to lung metastases results of 2-year local control and OS rates being 96%, 19 months and 39%. The choice of fractionation and total dose is an unresolved issue, with the most popular fractionation schedules being Gy in 3 5 fractions (See Table 4). These results suggest that there is no apparent difference in LC and OS for patients treated with SBRT of BED(10) >100 Gy to PTV in 3 5 fractions. In a phase I/II clinical trial using three fractions [2, 11], tumor location was a strong predictor of toxicity, with hilar or pericentral tumors showing an 11- fold increased risk in grades 3 5 adverse events when compared to more peripheral tumors (p00.004). The 2- year freedom from severe adverse events was 54% for these central tumors, as compared to 83% for the peripheral tumors. As a result, RTOG 0236 [5] excluded patients with centrally located early stage inoperable NSCLC, and RTOG Table 4 Selected SBRT clinical studies in 3 5 fractions Study Primary/ metastasis N Prescription dose BED (10) Overall survival (%) Local control (%) Years Current Primary 26 50/5 median (2 Years) Takeda Primary 69 50/ (T1) 93 (3 Years; T1) 60 (T2) 96 (3 Years; T2) Baumann Primary 57 45/ (3 Years) Onimaru Primary 28 48/ (T1) 48 Gy better than 40 Gy 32 (T2) (T2) 13 40/ (T1) 0 (T2) Chang Primary/recurrent 27 50/4 112 N/A 100 (1.7 Year) 40/ (1.7 Year) Hoyers Primary 40 45/ (2 Years) Timmerman Primary / (2 Years) Current Metastasis/ 30 50/5 median (2 Years) recurrent Zhang Metastasis 71 48/4 median (3 Years) 84.1 (5 Years) Rusthoven Metastasis 38 60/ (2 Years)

6 62 J Radiat Oncol (2012) 1: was conducted to evaluate the efficacy of patients with centrally located early stage inoperable NSCLC with SBRT of Gy total in five fractions. In our study, SBRT of Gy total in five fractions provide comparable local control and OS rate without > grade 3 CTCAE 3.0 toxicity for lung malignancies in central and peripheral location. Five fractions may be a more optimal choice for SBRT because of its lower toxicities and equivalent efficacy. Prospective clinical trial using five fractions should be conducted for lung malignancy not only in central location but also in peripheral location. There have been several studies [12, 13] focusingon dose local control relationship. In our study, the analysis was focused on the factors related to both local control and OS. When analyzing factors associated with OS in patients with multiple targets, GTVall and lesion average BED(10) were used instead of GTV and BED(10), respectively. GTVall was defined as the sum of all target s GTVin treatment and lesion-average BED(10) was defined as the sum of all target s BED(10) in treatment divided by number of target. The rationale of using GTV all in patients with multiple targets is GTV signifies tumor burden and the tumor burden for these patients should encompass all tumor volumes combined. The use of lesions average BED(10) is derived from the concept of PTV mean dose. PTV mean dose was used to describe radiation dose intensity of one tumor target. The dose intensity for patients with multiple lesions should be lesions average dose, thus leading to the use of lesions average BED(10) in our study. The revised parameters are not perfect, but they allowed direct comparison and endpoint assessment in terms of OS with dose and tumor volume in the population of patients with multiple lesions in the lung possible. These revised parameters and their applicability will need to be tested in future trials. The physical advantage of stereotactic radiation arises from the ability to achieve a highly conformal dose distribution and deliver that treatment with high accuracy. With this accuracy, we were able to minimize radiation dose to normal tissues. In terms of hypofractionating the dose, we calculated the BEDs for the SBRT doses used in our study. For tumors, the BED10 (α/β010) values for 40, 50, and 60 Gy in five fractions are equivalent to 72, 100, and 132 Gy, respectively. In comparison, a fractionation scheme of 48 Gy in four fractions also has a BED(10) of 106 Gy similar to 50 Gy in five fractions but lower than 60 Gy in five fractions. Results of our series suggest a high rate of local control achieved with BED(10) of at least 72 Gy, aggressive regimens in that dose range resulted in local control rates of over 90%. Our observations are concordant with the recent SBRT work of Chang et al. [13], who observed local control of 100% in patients with centrally located lung cancer with the use of 50 Gy in four fractions of SBRT compared with three of seven recurrent patients with 40 Gy in four fractions of SBRT. Onimaru et al. [12] also observed greater local control for 41 patients with stage I primary lung cancer with the use of 48 Gy in four fractions of SBRT compared with 40 Gy in four fractions of SBRT, a difference in favor of 48 Gy group was especially pronounced for the stage IB subgroup. Furthermore, we analyzed relationship of dose with OS. Lesion average BED(10) 100 Gy was significant favorable factor for OS in univariate analysis. One- and 2-year OS of patients received BED(10) 100 Gy were 88.6% and 60.5%. Lesion average BED(10) was also proven to be the only significant factor in multivariate analysis. A Japanese multi-institutional retrospective survey [14] proved that at almost same dose level, a BED10 greater than 100 Gy resulted in significantly better survival and local control than a BED10 less than 100 Gy when SBRT was used to control Stage I NSCLC. Some reports [12, 15, 16] on SBRT for early-stage NSCLC have shown that the local control rate of T1 tumors to be significantly higher than that of T2 tumors with SBRT. Baumann et al. [15] treated 141 patients with Gy/2 4 fractions. They found local failure to be more frequent for T2 (13%) than T1 tumors (3%). Koto et al. [16] treated patients with 45 Gy/3 fractions or 60 Gy/8 fractions. The 3- year local control rates were 77.9% (T1) and 40.0% (T2). T2 lesions were also found to have poorer OS (p ) and CSS (p ) by Onimaru et al. [12]. In our study, patient groups with GTV 14 ml and GTVall 20 ml were defined according to the criteria of highest 1/3 volume group of GTV and GTVall, respectively. The result showed that although statistical significance was not observed on local control, larger GTVall were significantly associated with poorer OS on univariate analysis (p<0.026) and multivariate analysis(p ). A recent study [17] reported a 3-year local control rate was as high as 96% for both T1 and T2 tumors, while the overall survival rates in patients with stages 1A and 1B were 90% and 63% (p00.09), respectively. In conclusion, SBRT in five fractions to PTV is feasible, safe, and effective. SBRT provides excellent local control for both primary and recurrent/metastatic lung malignancies. Tumor volume and BED(10) of SBRT were proven to be important factors for overall survival rates. Additional studies are needed to better test the value of GTVall and lesion average BED(10) in patients with multiple malignant lung lesions treated using SBRT. Acknowledgment This study was supported in part by a Grant-in-Aid for Cancer Research from Cancer Fighters of Houston, Inc. References 1. Timmerman R, Papiez L, McGarry R et al (2003) Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 124:

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