Stereotactic Body Radiation Therapy (Stereotactic Ablative Radiotherapy) for Stage I Non-Small Cell Lung Cancer - Updates of Radiobiology, Techniques, and Clinical Outcomes
Abstract: Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), has emerged as one of the standard treatment options for stage I non-small cell lung cancer (NSCLC), mainly in medically inoperable patients. Its use has also been explored in operable patients. A large body of experience, either from retrospective studies or clinical trials, has been accumulated over the years and more is known about the radiobiology, cancer biology, technical aspects, clinical outcomes, and toxicities of SBRT. This article provides updates of these aspects of SBRT for stage I NSCLC.
Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), has emerged as an innovative therapy for various organ sites and there is a large body of data in the literature, including data from well-conducted clinical trials, on the use of SBRT in mainly medically inoperable stage I non-small cell lung cancer (NSCLC) from across the globe (Lo et al., 2010; Timmerman et al., 2007). SBRT has now become one of the standard treatment options for patients with stage I, mainly medically inoperable NSCLC. This article provides updates of the radiobiology, techniques, and clinical outcomes of SBRT for stage I NSCLC.
Radiation and Cancer Biology of SBRT
The biologically effective dose is a characteristic dose value that allows for comparisons between the effects of different dose-fractionation schemes and is based on the linear-quadratic (LQ) model. Complete repair of sublethal damage between fractions is assumed. While it accurately describes the effects of radiation for low dose per fraction in conventional fractionation, it is not intended for describing doses in the ablative range (i.e., ≥ 8-10 Gy per fraction) as used in SBRT. Recently, Park et al. (2008) from University of Texas Southwestern Medical Center described effects of radiation in ablative dose range using a universal survival curve (USC) model, which combined the LQ and multitarget models. Overall, the USC model was found to describe measured data better than the LQ model over a broad dose range. In turn, the LQ model was found to significantly overestimate the effects of radiation in the ablative dose range. Taking it into the clinical context, when the potency of the doses used in the Indiana University phase II trial of SBRT for medically inoperable NSCLC (20 Gy x 3) was compared to that of the Japanese trial (12 Gy x 4) using the LQ model, the potency of the Indiana University dose regimen would be 1.7 times as potent as the Japanese dose regimen (180 Gy vs. 106 Gy, assuming the alpha-beta ratio is 10). However, when the USC model is used, the potency of the Indiana University regimen is actually only 1.34 times more than the Japanese regimen (107 Gy vs. 80 Gy) (Park et al., 2008). Wang et al. (2007) from Ohio State University has proposed the use of a generalized LQ (gLQ) model to bridge the radiation therapy regimens from the conventional radiation therapy to hypofractionated or ablative regimens. In the gLQ model, the reduction of conversion of sublethal to lethal injury in hypofractionated ablative dose radiation is taken into account and the actual effect of the radiation is lower than what is being estimated by the LQ model.
Recent studies have suggested that the actual mechanism of tumor killing with SBRT may be different from that of conventionally fractionated RT. The acid sphingomyelinase (ASMase) pathway has been implicated in the rapid endothelial apoptosis that occurred 1-6 hours after irradiation of mouse fibrosarcoma and melanoma cells with 15-20 Gy, followed by death of cells that appeared to be intact for 2-3 days (Fuks, 2005; Garcia-Barros et al., 2003). This mechanism of tumor killing was not observed in mice treated with conventionally fractionated RT. In a recent study, Lee et al. (2009) has found that CD8+ T cells are responsible for the therapeutic effects of ablative radiation. The delivery of an ablative dose of radiation of 15-25 Gy was found to cause a significant increase in T cell priming in draining lymphoid tissue, leading to reduction or eradication of the primary tumor or distant metastasis in a CD8+ T cell dependent fashion in an animal model.
In previous studies and trials of SBRT for early stage NSCLC, heterogeneity correction has not been consistently used. Given the fact that the lung parenchyma has a much lower electronic density relative to soft tissue, there will be a significant discrepancy between the computer-formulated plan and the actual dose delivered if heterogeneity correction is not used. It is crucial that, when heterogeneity correction is used, a treatment planning system with algorithms that can accurately account for both the effects of attenuation and differential scattering is used. In a recent study from Vanderbilt University, the SBRT plans of 10 patients were generated using pencil beam convolution (PBC) without heterogeneity corrections and were then recalculated using PBC with modified Batho heterogeneity corrections and anisotropic analytical algorithm (AAA) using identical beams and monitor units. When compared to Monte Carlo dose calculations, AAA could predict the dose distribution in the lungs and at the lung-soft tissue interface for a 6 megavolt beam accurately (Ding et al., 2007). PBC without heterogeneity correction was closer to the prescribed dose compared to using PBC with modified Batho heterogeneity corrections for the actual planning treatment volume (PTV) coverage when AAA was used as a reference, although there were still significant discrepancies (≤ 10%) in PTV dose coverage between AAA and PBC without heterogeneity correction (Ding et al., 2007). In a study from Radiation Therapy and Oncology Group (RTOG), a subset of 20 patients from four institutions participating in the RTOG 0236 protocol who used superposition/convolution algorithms were compared. The prescribed dose was 20 Gy x 3 (60 Gy). According to the protocol, treatment planning was performed without using heterogeneity correction; and using the same beam orientation and monitor units, another plan was generated using heterogeneity correction. The dose differences between the two plans for each patient were then compared. With the heterogeneity correction applied, theportionof PTV receiving > 60 Gy decreased on average by 10.1% from 95%, the dose delivered to 95% of the PTV was 55.9 Gy (range 44.1-64.2), the maximal dose to any point ≥ 2 cm away from the planning target volume increased from 35.2 Gy to 38.5 Gy, and the minimal ratio of the volume of the prescription isodose to that of the PTV was 0.6 and the maximal ratio was 1.5 (mean, 1.0) (Xiao et al., 2009). In another dosimetric study from University of Toronto, 12 patients who were planned for SBRT for NSCLC were scanned using helical computed tomography (CT) and 4-dimensional (4D) CT. The prescribed dose was 60 Gy in 3 fractions (RTOG 0236 regimen). Treatment planning was done based on targets from the free-breathing helical CT without heterogeneity correction. Those plans were then recalculated using heterogeneity correction with convolution-superposition dose calculation algorithm based on targets from the free-breathing helical CT without heterogeneity correction and targets from 4D CT datasets. With heterogeneity correction, there was significant decrease in the percentage of PTV constructed either based on free-breathing helical CT or 4D CT receiving the prescribed dose. When PTV constructed based on 4D CT was used as a reference, low dose spillage increased for recalculated plans using heterogeneity corrections with or without re-optimization (Franks et al., 2009).
Based on these recent dosimetric studies, lower prescription doses may be necessary when treatment planning is done using heterogeneity correction in order to achieve a similar level of toxicity and high and low dose spillage compared to planning without heterogeneity corrections.
Recently, initial or updated results of several prospective trials have been reported. One of the first prospective trials in medically inoperable NSCLC patients, the updated results of the phase II study from Indiana University were recently reported. Seventy patients with medically inoperable stage I NSCLC (tumors < 7 cm) were treated with SBRT with a dose regimen of 60-66 Gy in 3 fractions to 80% isodose line. After a median follow-up of 4.2 years, 3-year local control was 88%, regional failure 9%, 3-year overall survival was 43%, and 3-year cause-specific survival was 82% (Fakiris et al., 2009). There was no difference in local control or survival between T1 and T2 tumors, by tumor volume, or by peripheral vs. central location. (A T1 tumor is defined as a tumor ≤ 3 cm, surrounded by lung and visceral pleura, and not in the main bronchus. A T2 tumor is defined as a tumor > 3 cm, involving mainstem bronchus but ≥ 2 cm from carina, invading visceral pleura, or with associated atelectasis or obstructive pneumonitis extending to the hilar region but not involving the entire lung.) Similarly, updated results from a phase II trial of SBRT for medically inoperable stage I NSCLC from Scandinavia utilizing 45 Gy in 3 fractions showed a 3-year overall survival rate of 60%, 3-year cause-specific survival rate of 88%, and a 3-year progression-free survival (PFS) rate of 52% in 57 patients at a median follow-up of 35 months (Baumann et al., 2009). Ricardi et al. (2010) from Italy recently reported the final results of a phase II trial of SBRT for stage I NSCLC in 62 patients — 43 with T1 and 19 with T2 tumors. The radiation dose was 15 Gy x 3 (45 Gy). At a median follow-up of 28 months, the 3-year local control, cause-specific survival, and overall survival rates were 87.8%, 72.5%, and 57.1%, respectively. Out of the 20 deaths that occurred, eight were non-cancer related. In a recently reported phase II study of SBRT for stage I NSCLC from Japan, Koto et al. (2007) enrolled 31 patients (19 with T1 and 12 with T2 tumors), of which 20 were medically inoperable. The radiation doses used was 15 Gy x 3 (45 Gy) or 7.5 Gy x 8 (60 Gy). At a median follow-up time of 32 months, the 3-year local control rates were 77.9% and 40% for T1 and T2 tumors, respectively. The 3-year overall survival and cause-specific survival rates were 71.7% and 83.5%, respectively.
Most recently, mature results of the Radiation Therapy and Oncology Group (RTOG) 0236 trial were presented in a research publication. A total of 59 patients with peripherally located medically inoperable stage I NSCLC were accrued and 55 (44 with T1 and 11 with T2 disease) were evaluable. The prescribed dose was 54 Gy in 3 fractions. The 3-year primary tumor control was 97.6% (and only one patient had primary tumor recurrence) at a median follow-up of 34.4 months (Timmerman et al., 2010). Three patients had recurrence in the involved lobe, which was included in their definition of local control. The 3-year local control rate for the involved lung lobe was 90.6%. Two patients developed regional recurrence such that the locoregional control rate was 87.2%. The 3-year distant metastasis rate was 22.1% and the 3-year disease-free survival and overall survival rates were 48.3% and 55.8%, respectively (Timmerman et al., 2010). The most common severe adverse event categories were pulmonary/upper respiratory and musculoskeletal, with grade 3 and 4 adverse events occurring in 13 (24%) and 2 (4%) patients, respectively.
Evaluation of Treatment Response
With the accumulation of experience with the use of SBRT for the treatment of stage I NSCLC, the post-SBRT radiographic changes are better understood. Multiple non-opposing and non-coplanar beams converging at the center of the lung tumor are used in SBRT to create a very conformal isodose distribution and a very steep fall-off of the radiation dose outside of the planning treatment volume (PTV). As a result of this type of isodose distribution, predominant radiographic changes typically originate from both the region of the lung tumor and the rim of normal lung parenchyma surrounding the tumor as well as consolidation/collapse of lung parenchyma downstream from airways and vessels near the targeted tumor. In addition, radiographic changes can occasionally result from intermediate dose associated with the entrance and exit of beams. Five patterns of early radiographic changes, including diffuse consolidation, diffuse ground-glass opacity, patchy consolidation and ground-glass opacity, patchy ground-glass opacity, and no change, were described (Linda et al., 2009; Trovo et al., 2009). For late changes, four patterns, including modified conventional pattern, mass-like pattern, scar-like pattern, and no changes, were described (Linda et al., 2009; Trovo et al., 2009). It may be difficult to distinguish between post-SBRT fibrosis and tumor recurrence just based on CT findings at one single time point, and serial studies are needed to monitor the changes. Typically, fibrosis may initially progress and will then become stable radiographically. In contrast, the opacity (indicating the presence of a nodule) would generally continuously enlarge if there is tumor progression.
In an attempt to better evaluate treatment response, fluorodeoxyglucose-positron emission tomography (FDG-PET), which has superior sensitivity and specificity, has been used. Hoopes et al. (2007) from Indiana University evaluated the treatment response using FDG-PET in 58 patients enrolled in their phase I/II study of SBRT for medically inoperable stage I NSCLC. SBRT dose was 24-72 Gy in 3 fractions, and pre-SBRT functional imaging was performed in 57 of the 58 patients, while post-SBRT PET was performed in 28 of the 58 patients, typically upon concern for recurrence (Hoopes et al., 2007). The 3-year overall survival and local control rates were 49% and 75%, respectively. Pre-SBRT PET scan did not predict for overall survival or local control, and it was determined that moderate PET activity may persist for 2 years after treatment without definitive evidence of recurrence, as occurred in 4 patients in the study (Hoopes et al., 2007). In a pilot trial from Indiana University, 14 patients with medically inoperable stage I NSCLC treated with SBRT in the phase II trial were followed prospectively with FDG-PET at 2 weeks, 6 months, and 12 months after treatment. At a median follow-up time of 30.2 months, none of the patients experienced local failure. The median tumor maximum standardized uptake values [SUV(max)] before SBRT, at 2 weeks, 6 months, and 12 months were 8.70, 6.04, 2.80, and 3.58, respectively. Patients with low pre-SBRT SUV were more likely to develop initial 2-week increase in SUV while patients with high pre-SBRT SUV frequently had decrease in SUV 2 weeks after treatment (Henderson et al., 2010). Six (43%) of 13 patients with primary tumor SUV(max) > 3.5 at 12 months after SBRT remained free of local disease failure on further follow-up. These studies show that post-SBRT PET studies cannot independently predict tumor persistence or progression. For medically inoperable patients, tissue confirmation verifying tumor status is difficult due to poor patient tolerance. Currently, RTOG protocols predominantly follow CT scans looking for treated tumor enlargement. With enlargement present, PET scans are then obtained looking for FDG avidity similar to the initial tumor presentation.
With the accumulation of experience in the use of SBRT for the treatment of stage I NSCLC, more is known in terms of normal tissue constraints. Although various radiobiologic models could provide radiation oncologists with some guidance, the effects of radiation cannot be fully accounted for based on mathematical formulae. The safest approach is to refer to dose constraints determined from well-conducted studies, preferably prospective phase I clinical trials studying dose/response relationships.
Tumor location is a well known factor predicting severe toxicities when a 3-fraction regimen is used (Timmerman et al., 2006). Recently, various toxicities associated with SBRT for stage I NSCLC have been reported in the literature. Hoppe et al. (2008) from Memorial Sloan-Kettering Cancer Center examined the risk factors associated with severe skin toxicities in 50 patients with Stage I NSCLC treated with 60 Gy in three fractions or 44-48 Gy in four fractions. Factors predicting grade 2 or higher acute skin toxicity included using only 3 beams, distance from the tumor to the posterior chest wall skin of less than 5 cm, and a maximum skin dose of 50% or higher of the prescribed dose. RTOG trials for stage I NSCLC require that the skin, defined as a concentric ring starting 5 mm from the body surface, be contoured as an organ-at-risk, so that hotspots in the skin can be detected and treatment plan can then be modified (Lo et al., 2009).
Chest wall pain and rib fractures have been observed in patients who receive SBRT for peripheral NSCLC close to the chest wall. In a study by Voroney et al. (2009), pain and rib fracture after SBRT for peripheral NSCLC was observed in a significant portion of patients with tumors close to the chest wall, even in areas that received less than the prescription dose. The Kaplan-Meier estimate of rib fracture at 2 years was 48%. Dunlap et al. (2009) demonstrated that the chest wall volume receiving more than 30 Gy predicts risk of severe pain and/or rib fracture following lung SBRT, and they recommend that the volume of chest wall receiving 30 Gy should be limited to no more than 10 cm3 if possible.
In patients with stage I NSCLC at apical locations, the brachial plexus is at risk. Data regarding brachial plexus tolerance to hypofractionated radiation therapy is limited. In a recent analysis by Forquer et al. (2009) from Indiana University, 36 patients with apical lesions, defined as epicenter of the lesion being superior to aortic arch, were treated with SBRT (27 patients were treated in 3 fractions and 9 patients in 4 fractions). Grade 2-4 brachial plexopathy developed in 7 out of 36 patients after a median of 7 months (range 6-23 months). The 2-year risk of brachial plexopathy for maximum brachial plexus dose > 26 Gy was 46% vs. 8% for doses ≤ 26 Gy. The authors concluded that the maximum dose to the brachial plexus should be kept < 26 Gy in 3 to 4 fractions.
Ongoing Clinical Trials
Although dose schedules have not yet been established, it appears that local control is excellent with the different dose regimens used in studies from centers with a large body of experience and a number of prospective clinical trials. The current RTOG standard dose for peripheral tumors, 54 Gy in 3 fractions, showed 3-year primary tumor control of 98%. While alternate fractionation regimens might have less toxicity, it is unlikely that any alternate regimen would demonstrate improved tumor control. Currently under accrual, the RTOG 0915 Phase II randomized study will compare two different SBRT fractionation schedules (34 Gy in 1 fraction vs. 48 Gy in 4 daily consecutive fractions) for patients with stage I peripheral NSCLC. The latter fractionation is most frequently used in Japanese regimens. The fractionation that proves to be less toxic, a feature that may be particularly important in frail patients, will serve as an arm in a future phase III trial compared to the current RTOG standard fractionation schedule (54 Gy in 3 fractions) for medically inoperable patients. Similarly, RTOG 0813 is a phase I/II study, with seamless transition from phase I to phase II, of SBRT dose-escalation fractionation schedules (from 50 Gy up to 60 Gy in 5 fractions) in medically-inoperable patients with early-stage centrally-located NSCLC. The Trans Tasman Radiation Oncology Group (TROG) in Australia is conducting a phase III trial (TROG 09.02) comparing 3D-CRT (60 to 66 Gy in 30-33 fractions) and SBRT (54 Gy in 3 fractions) to determine if hypofractionation is more effective, results in longer life expectancy, and is just as safe as standard fractionation. Similarly, Scandinavian Stereotactic Precision And Conventional Radiotherapy Evaluation (SPACE) trial is a phase II randomized study comparing 3D-CRT (70 Gy in 35 fractions) with SBRT (45 Gy in 3 fractions).
Given that the effectiveness of SBRT in inoperable patients is comparable to that historically achieved using surgery, there are now studies assessing its effectiveness in operable patients with early-stage disease, as well as studies comparing SBRT and surgery in early-stage operable patients. The Japan Clinical Oncology Group (JCOG) completed a phase II trial (JCOG 0403) of SBRT of 48 Gy in 4 fractions for patients with stage IA NSCLC, including a treatment arm for operable patients, with mature 3-year overall survival outcomes to be reported this year (2010). RTOG 0618, a phase II trial of SBRT in the treatment of patients with operable stage I disease, will determine effectiveness of 54 Gy in 3 fractions. In the Dutch ROSEL (Radiosurgery Or Surgery for Early Lung cancer) study, patients with stage IA NSCLC will be randomized to either surgery or SBRT in order to study the local and regional tumor control, quality of life, and treatment costs at 2- and 5-years. The M.D. Anderson Cancer Center is coordinating the Lung Cancer STARS (STereotActic Radiotherapy vs. Surgery) international randomized study, sponsored by Accuray, comparing CyberKnife-based SBRT with surgical resection in stage I NSCLC, with the primary endpoint of overall survival at 3 years. Hopefully, the results of these trials will help better define the role of SBRT in the management of stage I NSCLC.
Robert D. Timmerman, M.D., has research grants with Varian Medical Systems and Accuray, Inc. His grant from Elekta Oncology has expired. Billy W. Loo, M.D., Ph.D., had speaking honorarium from Accuray, Inc. More than a year ago, he had honoraria from Varian, GE Medical systems, and superDimension.
(Corresponding author: Simon S. Lo, M.D., Associate Professor of Radiation Oncology and Neurosurgery, Department of Radiation Oncology, Arthur G. James Cancer Hospital, Ohio State University Medical Center, 300 West 10th Ave., Ste. 088A, Columbus, Ohio 43210, USA.)
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[Discovery Medicine, 9(48):411-417, May 2010.]