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Stereotactic Ablative Radiotherapy (SABR) for Non–Small Cell Lung Cancer Puneeth Iyengar, MD, PhD1,


Kenneth Westover, MD, PhD1,


1 Department of Radiation Oncology, University of Texas

Southwestern Medical Center, Dallas, Texas 2 Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, Texas

Robert D. Timmerman, MD1,2

Address for correspondence Robert Timmerman, MD, 5801 Forest Park Road, Dallas, TX 75235 (e-mail: [email protected]).

Abstract

Keywords

► ► ► ► ►

stereotactic ablative radiation lung cancer therapy

Stereotactic ablative radiotherapy (SABR), otherwise known as stereotactic body radiation therapy (SBRT), is an external beam treatment modality that offers the ability to deliver with high precision large doses of radiation over a limited number of fractions. SABR is currently a standard of care in the treatment of early-stage primary non–small cell lung cancers (NSCLCs) that are medically inoperable and for metastases in many anatomical locations. To date, local control and toxicity parameters with SABR for earlystage NSCLCs are comparable to those found in reports of experiences with surgical resection. It is increasingly apparent that some patients with borderline resectable lung primaries are also looking to SABR as a noninvasive means of therapy. However, randomized comparisons have not been completed to assess survival in operable patients. This review summarizes the advanced technology and radiation concepts that have helped clinicians optimize the use of stereotactic ablative therapies for lung cancer, with an emphasis on the rationale for future continued use of this advanced treatment modality.

Traditionally, clean distinctions in staging have guided management of non–small cell lung cancer (NSCLC) therapies. Patients with metastatic disease up front are treated with systemic therapy. Patients with stage III disease receive combined modality therapy, usually in the form of chemoradiation. We know from analyses of large retrospective databases that patients with early-stage NSCLCs who receive no treatment rarely survive longer than 5 years. Early-stage NSCLCs, primarily T1N0 and T2N0 lesions, have historically been treated with lobectomy and, less optimally, sublobar resections when surgery is medically feasible. In the setting of medical inoperability, lung cancers have been treated with fractionated radiation therapy. Compared with lobectomy, survival outcomes with fractionated radiation therapy are substantially worse with higher rates of local tumor recurrence. Hence it became apparent that changes in radiation regimens were required to achieve better results for lung cancer patients who were not candidates for even suboptimal surgeries.

Issue Theme Lung Cancer; Guest Editor, M. Patricia Rivera, MD

Higher dose per treatment radiation strategies originated with the use of single fraction/treatment of brain malignancies as part of a “stereotactic radiosurgery” approach. This technique involved noninvasive radiation delivery to small lesions in a concisely targeted fashion. The lesions had to be discrete, allowing coverage of the cancer using external beam radiation sources, including cobalt-60, with avoidance of critical uninvolved structures in the brain. Neoplasms were most accurately targetable when the patient’s skull was immobilized with a removable frame. The frame incorporated a coordinate system that ensured accurate delivery of the single high dose of radiation to a target volume anywhere within the coordinate boundaries. These advances were developed over several decades, starting in the 1940s. It was fundamentally important to master delivery of high dose per fraction radiation, heretofore referred to as stereotactic ablative radiotherapy (SABR), in a site such as the brain

Copyright © 2013 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0033-1358554. ISSN 1069-3424.

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Semin Respir Crit Care Med 2013;34:845–854.

SABR for NSCLC

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where tumors do not move, targets are easily delineated, and many parameters for radiation delivery are constrained because the anatomy of the skull is relatively similar from one patient to the next. This experience created an opportunity and rationale for radiation oncologists to attempt SABR in extracranial locations such as lung, where controlling earlystage unresectable NSCLCs with prolonged fractionated treatments was not optimal. The advent of linear accelerators, device-connected imaging technologies, and better tools for evaluation of lung tumor motion allowed radiation oncologists to use SABR in the treatment of pulmonary malignancies. It should be noted that the term SABR does not necessarily imply necrosis or innate damage to tissue architecture as is typical with thermal ablative procedures. In contrast to cranial tumors, extracranial tumors are often mobile relative to bony structures, giving rise to two challenges for SABR: the boundaries of a moving target are difficult to precisely visualize radiographically, and a moving target is difficult to hit. To circumvent these complexities, additional tools and efforts have been employed with SABR to deliver high doses to tumor while limiting adjacent normal tissue toxicity. One of these primary resources has been the introduction of image guidance to radiation therapy treatment delivery optimization. Image-guided radiation therapy (IGRT) often uses cone beam computed tomography (CT) in addition to kilovoltage (kV) or megavoltage (MV) imaging to distinguish disease and ensure that targeting of tumor and not normal tissues is being implemented before actual radiation beams are initiated. Four-dimensional CT (4-DCT) images are obtained at the time of SABR radiation treatment planning, along with fluoroscopy, to measure the extent of tumor motion with the respiratory cycle so that disease is not missed by the treatments and to ensure a minimal dose delivered to normal tissues. Both IGRT and motion evaluations are integral parts of SABR planning and accurate treatment execution. SABR has been defined to include all radiation therapy completing a course in few treatments (e.g., five or fewer) by giving very large doses per treatment (called oligofractionation) as per the American Society of Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR).1 These organizations have established guidelines for promoting quality control for SABR usage, consisting of adequate technology, experience on the part of the treating radiation oncologist, and support from radiation dosimetrists, therapists, and physicists. Ultimately, SABR has, to date, exceeded our expectations in the treatment of early-stage, medically inoperable NSCLCs. Our review will provide a discussion of the indications, rationale, and methods of treating NSCLCs with SABR. In this effort, we will present information that can be appreciated by members of the pulmonary medicine community.

SABR Becomes Possible for Early-Stage Lung Cancer with Improved Technology Given the extremely high fractional doses that are used in SABR, it becomes imperative to limit normal tissue toxicity as a means of optimizing the therapeutic ratio. Normal tissue Seminars in Respiratory and Critical Care Medicine

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injury can have more profound consequences in the setting of SABR than fractionated radiation based on radiobiological principles. Hence technology needed to catch up with theory for SABR to be a rational and safe treatment for lung tumors. Several technological advances over the past 20 years have facilitated the acceptance of SABR treatments in the thorax. Among them are tumor motion assessment and control, patient immobilization and positioning, target delineation and image guidance for precise radiation targeting, and class solutions in radiation treatment planning. Diaphragmatic excursion with respiration can cause motion of lung tumors, especially those in the inferior portion of the lung,2,3 although not all lung tumors move with respiration.3 The goal of radiation treatment can be summarized as follows: to target only disease while limiting normal tissue parenchyma or critical structures from receiving any significant dose. In the early days of SABR, motion was accommodated by increasing the superior and inferior treatment margins.4 With new technology tumor motion tracking has become an intrinsic aspect of SABR treatment planning. Fluoroscopy and 4-DCT are used to assess the extent of tumor motion in various phases of the respiratory cycle. This information then allows the radiation team to better account for the motion and location of malignancy at all times when planning the volumes of disease needing treatment and fields of treatment. To minimize the dose to normal lung tissue, which is an unavoidable result of adding margins to the tumor volume motion control, abdominal compression, deep inspiration breath hold/respiratory gating, and tumor tracking with fiducials have been employed with varying degrees of success. For the latter technique, radiopaque seeds can be placed in the tumor by pulmonologists, interventional radiologists, or radiation oncologists to facilitate our assessment of tumor motion, although many medically inoperable patients cannot tolerate fiducial placement, with roughly 30% of all patients developing pneumothorax after fiducial placement.5,6 More recent tracking techniques use noninvasive imaging in lieu of fiducials such as two-dimensional (2-D) soft tissue image capture, cone beam CT (CBCT) and positronemission tomography (PET).7,8 However, the impact of frameless techniques on dosimetry has not been well studied. Adequate patient immobilization and positioning are also fundamental requirements of SABR treatment planning and delivery. Limiting NSCLC patient movement with immobilization during radiation planning sessions and all treatments allows for reproducibility and consistency in precise radiation delivery to target over the one to five fractions normally given for SABR. Multiple immobilization systems are being used nationally and internationally for lung SABR treatments, including vacuum cushions and thermal plastic restraints. From a practical standpoint, patient comfort is important because SABR treatments require that the patient remain immobilized for 30 to 60 minutes. Many immobilization products contain stereotactic fiducial systems that allow placement of the isocenter at the time of planning, instead of at the time of simulation, which can be advantageous for dosimetry in treatment planning. These fiducial systems also once played a critical role in accurately positioning the

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Fig. 1 Typical patient setup with abdominal compression for lung stereotactic ablative radiotherapy (SABR). The patient is immobilized using a body frame fitted with a custom mold (blue color). The arms are placed above the head to keep them out of the radiation beam paths. Abdominal compression is applied using a plastic paddle, which is mounted on the stereotactic frame in patients where tumors move with respiration.

patient at the time of treatment, but this function has been largely supplanted in many practices by on-board imaging such as CBCT immediately prior to SABR delivery. However, as a target positioning method independent from the treatment couch, frame-based fiducial systems constitute welcome redundancy for quality assurance. Traditionally, our group has been using both an evacuated vacuum-molded cushion and a stereotactic body frame in the immobilization and positioning of lung cancer patients as pictured in ►Fig. 1. Early-stage lung cancers exhibit good tissue density contrast compared with normal lung. However, occasionally normal vascular or pulmonary structures can appear to be involved, creating uncertainty in tumor boundaries. With the introduction of computed tomography (CT), then 4-DCT, magnetic resonance imaging (MRI), and PET combined with CT, radiation oncologists can more accurately define the site and volumetric extent of lung cancers as part of target delineation, in the process sparing excessive normal tissue irradiation. Intravenous contrast emphasizes the differences between disease tissue and normal tissues9 and is recommended in all cases to aid segmentation. In general, targets are contoured in pulmonary windows. Careful examination of targets in axial, coronal, and sagittal planes is essential. It should be mentioned that evaluating dosimetric parameters requires consistency in anatomical segmentation. Contouring inconsistency by practitioners, despite clinical experience, has been documented.10 Atlases were recently published to standardize contouring practices, and these appear to be effective.11–13 Daily CBCTs prior to each SABR treatment allow real-time evaluation and adjustment at the time of treatment that support precise and near real-time targeting of and radiation delivery to tumor as part of image-guided radiation therapy (IGRT) principles. The margins we place around the tumors to ensure coverage and adequate treatment of malignancy have

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become more controlled as the field has incorporated daily image guidance prior to every SABR delivery. Finally, with continued treatment of patients with SABR, radiation dosimetrists, physicists, and oncologists have become adept at determining which forward-planned optimal beam arrangements are necessary to treat NSCLC while minimizing normal tissue toxicities. It has become apparent that the use of more beams (11–13) on average as shown in ►Fig. 2a is able to achieve objectives set on covering tumor and limiting dose to the heart, remainder of the lung, spinal cord, esophagus, brachial plexus, chest wall, and other areas. Noncoplanar beams are recommended to provide the most conformal treatment of tumor with high dose, as are the occasional beam across the contralateral lung. Daily imaging, motion determination, and pretreatment PET/CT evaluation have helped to delineate disease and make our SABR treatment planning more accurate. Conformal dose distributions with rapid fall-off to normal tissues, as shown in ►Fig. 2b, allow large ablative dose effects to be localized to within and near the tumor without significant loss of pulmonary function in most patients treated.

Clinical Basis for SABR Use in Early-Stage NSCLC To gain an appreciation for how SABR has become the standard of care in the treatment of medically inoperable early-stage NSCLC (stage I and II), it is important to evaluate the efficacy of previous treatment schemas for this group of patients. Fundamentally, medically inoperable lung tumor patients included those with very poor pulmonary function (chronic obstructive pulmonary disease, emphysema), and those with potentially other medical comorbidities (significant cardiovascular disease, renal and/or hepatic disease, otherwise poor performance status individuals). As this cohort of patients became more apparent to oncologic, surgical, and pulmonary specialists, one thought was to observe these individuals since they had significant competing interests with respect to mortality. However, even in this group of sick patients with early-stage NSCLC, the lung cancer–specific mortality was high with a short overall survival (OS) interval. Specifically, disease-specific survival from these medically inoperable stage I and II patients is 10 to 25%.14–16 Without any medical intervention, surgery, chemotherapy, or radiation, median OS is approximately 1 year, and these patients have only a 10% chance of being alive at 5 years.15,17 Several meta-analyses and retrospective/registry evaluations have validated these findings. In comparison, similar-staged NSCLC patients with early-stage disease eligible for surgery have 60 to 70% 5-year OS in several series.18,19 Knowing that some treatment was probably better than no treatment, specialists referred these medically inoperable patients to radiation oncologists for fractionated radiation (for instance 25–37 treatments). Outcomes from these fractionated radiation interventions were found wanting, with a 5-year OS of around 20% and median survival of 1.5 years. These results were not much better than no treatment and certainly nowhere near the surgical findings. Studies using Seminars in Respiratory and Critical Care Medicine

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SABR for NSCLC

SABR for NSCLC

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Fig. 2 (a) Common beam arrangements for lung stereotactic ablative radiotherapy (SABR). Common radiation beam arrangements are shown for right- and left-sided tumors. Typically 10 to 13 noncoplanar beam angles are used. (b) Typical dose distribution for SABR treatment. Plans are evaluated for “compactness” of the high-dose region and for dose to normal structures for which constraints have been established (►Table 1).

SEER registries suggested that external beam radiation offered only 5 to 7 months of OS when compared with no treatment. The radiation doses typically ranged from 45 to 66 Gy at 1.8 to 2 Gy per fraction. By 2005, several groups reported similar poor outcomes from conventional radiotherapy approaches. As a first step toward improving radiation alone outcomes for these medically inoperable early-stage NSCLC patients, groups at multiple institutions began to increase the total radiation dose as well as the dose per fraction delivered to the lesions. A classic dose escalation study conducted at Memorial Sloan Kettering demonstrated that with standard 2-Gy fractional doses, raising the total final doses to above 80 Gy resulted in increases in OS to around 36% at 5 years. The limitation of these results, however, was that the maximum tolerated dose (MTD) and potential concomitant increases in toxicity were not identified. Currently, in an attempt to continue to improve OS for fractionated radiation and to reach the MTD, ongoing trials compare dose escalation with standard dose per fraction treatments that also include concurrent chemotherapy. It became apparent from the findings with conventional radiation therapies that 2 Gy per fraction is not sufficient to adequately control early-stage NSCLCs, even when higher Seminars in Respiratory and Critical Care Medicine

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total doses were reached. With high enough total doses normal tissue toxicity prevents these treatments from sufficiently controlling these malignancies. Around the time of these conventional dose escalation studies, SABR use for extracranial malignancies was being evaluated. It was feasible to contemplate using SABR for thoracic lesions with improvements in technology and treatment planning already delineated in the foregoing sections—improved patient immobilization, better on board image guidance that could demonstrate accurate targeting of tumor, better tumor motion evaluation and accounting, and evolving SABR class solutions for forward radiation treatment planning. In retrospect, SABR and its ability to deliver high doses of radiation in limited treatments offered an opportunity to control disease locally while potentially avoiding significant normal tissue toxicity and was a natural evolution of radiation-only treatments for early-stage, medically inoperable NSCLCs. Over the last 10 years or so, several national and international groups have provided the clinical impetus that resulted in SABR’s general acceptance as standard of care for earlystage unresectable NSCLCs. Radiation oncologists from Indiana University completed a series of studies that helped standardize SABR use. They performed a phase 1 study accruing T1–T2 N0 NSCLC patients for treatment as part of

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Radiation Therapy Oncology Group (RTOG). This study offered the highest levels of SABR quality assurance centrally in an effort to standardize treatments. Fifty-five patients were accrued with medically unresectable T1–T2N0 NSCLC who had peripheral lesions (2 cm beyond the bronchial tree). Lesions were < 5 cm and all tumors were treated to 60 Gy in three fractions (without heterogeneity corrections). Fortyfour of fifty-five patients had T1 lesions. In 2010, the findings of the study were published in JAMA and heralded a new standard of care. With a median follow-up of almost 3 years, tumor control was at 98%. Three-year local (tumor plus lobe) control was 91%, 3-year locoregional control was 87%, and distant metastasis rate was 22%. Median OS was 4 years. Toxicity was limited in these patients from therapy, including no deaths from SABR. Distant failures (11/55) may have been secondary to understaging upfront. Nonetheless, disease-free survival at 3 years was 48% with OS at 56%.23 This study set the standard for radiation treatment for medically inoperable early NSCLCs and suggested that SABR is a treatment comparable to surgical resection. Fig. 3 High-risk central zone. Stereotactic ablative radiotherapy (SABR) within 2 cm of the central bronchial tree is higher risk for treatment-related toxicity. Clinical trials are under way to establish safe dosing schemes.

a stereotactic dose escalation from 24 Gy in three fractions to 72 Gy in three fractions in pursuit of dose-limiting toxicities. For T2 lesions > 5 cm, an MTD of 66 Gy was established. An MTD was not identified for T1 primaries up to 60 Gy in three fractions or T2 primaries < 5 cm up to 66 Gy in three fractions. These findings demonstrated safe delivery of high dose per fraction treatments for T1 and smaller T2 lesions. With respect to local control, there was only one failure in a patient whose lesion received doses of radiation at > 16 Gy per fraction. There were nine local failures when the lesions received < 16 Gy per fraction. In light of the phase 1 findings, Indiana University conducted a phase 2 trial that enrolled 70 medically inoperable, clinical T1N0 NSCLC patients who received SABR at 60 Gy in three fractions and T2N0 NSCLC patients (up to 7 cm) treated to 66 Gy in three fractions. Two-year local control was 95%, with a median follow-up of 17 months. Median OS was 2.7 years, and 2-year OS was 55%, all approaching surgical outcomes for this group of patients. Of significant importance was an evaluation of toxicity from this phase 2 study. Patients considered to have centrally located tumors with respect to the bronchial tree (►Fig. 3) had significantly more grade 3 toxicity (46% vs 17%) when compared with peripheral lesions, with six treatment-ascribed deaths. Four of the six deaths were secondary to pneumonias, potentially as a consequence of reduced pulmonary clearance after SABR. At 50 months follow-up, 88% control was still established locally, and OS was still at 42%. In parallel, later studies from other groups in Japan, the United States, and Europe established similar benefits with the use of SABR for this patient population.20–22 With mounting evidence of SABR’s potential benefit, a phase 2 study of multiple institutions was performed by the

Toxicity from SABR SABR, from all clinical trials, appears well tolerated in NSCLC patients who have peripheral lesions. Centrally located NSCLC lesions are still being evaluated for MTD delivered with SABR in ongoing RTOG studies. There are known toxicities associated with SABR for lung cancer. Increasingly well-understood dose constraints on normal tissue structures are being employed by radiation oncologists as a means of limiting this toxicity. There are currently no definitive guidelines for using pulmonary function cutoffs to exclude patients from treatment as a means of limiting toxicity. In the future, when reviewing findings from all the current SABR trials we may find forced expiratory volume in 1 second (FEV1) and diffusing capacity for carbon monoxide (DLCO) values that predict for significantly higher SABR-related pulmonary toxicity. However, the original critical role for SABR was in the treatment of NSCLC patients with terrible lung function. Hence SABR may always be a treatment option for early-stage NSCLC in patients who cannot tolerate surgery no matter the pulmonary values. Remarkably, multi-institutional studies on SABR for peripheral lung tumors have proceeded with limited toxicity. Because oligofractionation had not been well studied previously the dose constraints used in these trials were not based on strong data but instead relied on investigator experience. Toxicity data are now becoming more available. The constraints used in the prospective studies are considered reasonable guidelines until more data are available (see ►Table 1). Serious treatment-related toxicities after SABR are infrequent but generally manifest 6 to 24 months after therapy, although radiographic changes may precede this by months.24 The most clinically troublesome toxicities from SABR result from overdosing critical structures that run in series, such as central airways, neural structures, and the esophagus. Studies at Indiana University showed that, in tumors near the lung apex treated with radiation, cumulative Seminars in Respiratory and Critical Care Medicine

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SABR for NSCLC

SABR for NSCLC

Iyengar et al.

Table 1 Dose constraints from prospective stereotactic ablative radiotherapy trials RTOG 0236 OAR

ROSEL

RTOG 0813

RTOG 0915

60 Gy, 3 fx

60 Gy, 3 fx

60 Gy, 5 fx

50–60 Gy, 5 fx

34 Gy, 1 fx

48 Gy, 4 fx

max

18 Gy

18 Gy

25 Gy

30 Gy

14 Gy

26 Gy

Volume max

–

–

–

–

< 1.2 cc, 7 Gy

< 1.2 cc, 13.6 Gy

max

24 Gy

24 Gy

27 Gy

32 Gy

17.5 Gy

27.2 Gy

Volume max

–

–

–

< 3 cc, 30 Gy

< 3 cc, 14 Gy

< 3 cc, 23.6 Gy

max

30 Gy

30 Gy

32 Gy

105% of PTV

20.2

34.8

Volume max

–

–

–

< 4 cc, 18 Gy

< 4 cc, 10.5 Gy

< 4 cc, 15.6 Gy

max

27 Gy

24 Gy

27 Gy

105% of PTV

15.4 Gy

30 Gy

Volume max

–

–

–

< 5 cc, 27.5 Gy

< 5 cc, 11.9 Gy

< 5 cc, 18.8 Gy

Max

30 Gy

24 Gy

27 Gy

105% of PTV

22 Gy

34 Gy

volume max

–

–

–

< 15 cc, 32 Gy

< 15 cc, 16 Gy

< 15 cc, 28 Gy

max

–

–

–

–

30 Gy

40 Gy

Volume max

–

–

–

–

< 1 cc, 22 Gy

< 1 cc, 32 Gy

max

24 Gy

–

–

32 Gy

26 Gy

36 Gy

Volume max

–

–

–

< 10 cc, 32 Gy

< 10 cc, 11.2 Gy

< 10 cc, 17.6 Gy

V20  10%

V20 < 5–10%

V20 < 5–10%

1.5L  12.5 Gy

1.5L  7 Gy

1.5L  11.6 Gy

Spinal cord

Brachial plexus

Trachea, bronchus

Esophagus

Heart

Ribs

Skin

Lung Volume max

OAR, organs at risk; RTOG, Radiation Therapy Oncology Group.

doses to the brachial plexus above 26 Gy given over three fractions were associated with brachial plexopathy in 46% of patients.25 Esophageal doses in the context of SABR are less thoroughly studied, but generally it is recommended to limit doses below a maximum of 27 Gy given over three fractions and no more than 17.7 Gy to 5 mL of esophagus.26 Spinal cord myelopathy from SABR has been observed, but retrospective analyses suggest that a maximum cord dose of 14 Gy in a single fraction or 20 to 30 Gy in multiple fractions limit myelopathy risk to less than 1%. There are some indications that the cervical spinal cord is more sensitive than the thoracic spinal cord.14,27 Chest wall (defined as tissue 2 to 3 cm radial to the lung) toxicity has also been studied in some detail and can occur 6 to 9 months after treatment. The volume of chest wall receiving 30 Gy (V30) is one of the best predictors of chest wall pain; exposure of between 30 and 70 mL of chest wall to 30 Gy or more has been associated with development of grade 2 or more chest wall pain, although there are also reports that the percentage of chest wall receiving 30 Gy may also be important.28–30 Understandably radiation oncologists often include chest wall V30 as a normal tissue constraint Seminars in Respiratory and Critical Care Medicine

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when planning, but it should be noted that attempts to move dose from the chest wall result in additional dose to pulmonary structures. It is unknown whether or not this practice subjects patients to additional risk for pulmonary toxicity, and several multi-institutional trials do not include chest wall constraints (see ►Table 1). Obesity has also been associated with higher risk of developing chest wall pain.31 Pathological vertebral fracture is a risk in patients with low bone density such as the elderly. Interestingly spine SBRT is associated with a high risk of treatment-related compression fracture with  20% of patients developing fractures, although this number is confounded by involvement of the vertebrae by tumor.32 Nevertheless caution against excessive dose to the axial skeleton in patients with low bone density is warranted.33 Radiation pneumonitis (RP) has been observed after SABR, although not as commonly as with conventional treatment for more locally advanced disease. Definitions and identification of radiation pneumonitis in a population of patients prone to chronic obstructive pulmonary disease exacerbations make reporting unreliable. Several centers have attempted to predict radiation pneumonitis using dosimetry metrics, similar

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to with conventional radiotherapy, but results have been irregular.34–36 Despite the documented risk of subacute radiation pneumonitis there is evidence that SABR does not cause significant long-term losses in pulmonary function for most patients.21,37 From the early Indiana University studies on poor performance status, medically inoperable patients, 10% had a 10% decline in at least one measured value of pulmonary function (FEV1, forced vital capacity [FVC], DLCO, arterial oxygen concentration (pO2)). A majority of these patient’s values eventually returned to baseline, however. DLCO and PO2 were most commonly affected. One of two patients had dose-limiting grade 3 pneumonitis and one had grade 3 hypoxemia. Otherwise, this population of patients with poor lung function tolerated SABR very well. Dose-limiting toxicities, including death, were reported in the phase 2 study from Indiana University for patients with centrally located lesions (see ►Fig. 3), leading to the current RTOG dose assessment study.32 With peripheral lesions in RTOG 0236, 28% of patients had grade 3 to 4 toxicity, primarily pulmonary or musculoskeletal (pain) in nature, with no deaths.38 Overall, however, SABR appears very well tolerated for a majority of NSCLC patients.

SABR Delivery Modalities Photon-based SABR is the most thoroughly studied and was the modality used in most prospective studies. Delivery technologies have included linear accelerator (linac)-based, robotic (CyberKnife, Accuray, Sunnyvale, CA), and gamma knife technology. All of these employ multiple noncoplanar beams to optimize dose distributions and make them highly conformal. One unavoidable consequence of high conformality is that maximum point doses for photon SABR plans are often as much as 150% of the prescription dose. Some have proposed that hot spots may contribute to the effectiveness of SABR, although the experience with particle therapy is inconsistent with this idea (yet to be discussed).39 As mentioned steep dose gradients and conformality can be achieved with numerous (e.g., 10–13 per isocenter), noncoplanar, nonopposing photon beams converging on the target.38 Target apertures are small, indeed, using “negative” margins from the edge of the field around the target to improve dose gradients.40 In general, both high (prescriptionlevel) and intermediate dose are kept to the smallest reasonable volume around the target as possible, but the result is fairly large low dose volumes. This is the trade-off of all typical stereotactic radiation treatments where numerous relatively weak beams (minimizing entry damage) traverse tissue without overlap until they reach the target where they collectively deposit tumorcidal dose.41 Particle therapy SABR has also been studied, although on a smaller scale and primarily motivated by an interest in treating a subset of patients with exceptionally poor lung function or central tumors. The physics of particle therapy brings about energy deposition at a specified tissue depth with virtually no exit dose. This allows tissue sparing within the beam path before and after the target. It is therefore possible to achieve a steep dose gradient using only two or

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three beams, resulting in a smaller integral dose to normal tissues. Using a limited number of beams also allows avoidance of central airways and medical devices, such as pacemakers, that may be affected by ionizing radiation.42 However, range uncertainty in the depth of the Bragg peak results in less conformal treatment plans and consequently larger high-dose regions as compared with photon plans. Proton plans are also more homogeneous and do not generate large hot spots within the target field.43 It was unclear initially if these dosimetric differences would result in lower cancer control rates or higher toxicity rates, but despite these concerns proton-based therapy has, so far, given clinical results comparable to photons.42,44 It should be emphasized that proton SABR was never expected to be more biologically effective than photon SABR, and investigators have not argued that protons, which are far more costly to deliver, should replace photon SABR. Instead, proton SABR is proposed as an alternative for a subset of patients where photon-based delivery is considered high risk. Carbon ion SABR therapy has also been studied motivated by the hypothesis that hypoxia may promote treatment failure, which could be overcome by high linear energy transfer (LET) radiation due to a small oxygen enhancement ratio. These studies have shown disease control analogous to that attainable by photon- or proton-based approaches and similar acute toxicity profiles.45,46 The impact on long-term toxicity is still unknown, but carbon ion technology is scarce and expensive, making it difficult to implement or study broadly.

The Future of SABR for NSCLC There are many questions to be answered now that thoracic SABR treatment has been established. Future studies will seek to crystallize patient selection criteria for SABR, personalize treatment regimens, and improve overall outcomes. As data emerge comparing surgery and SABR in operable patients these questions may take on added dimensions and significance. Clinical, basic biological, and health policy questions will all be important. How much should treatment cost be weighted in treatment decision making for early-stage lung cancer? Several cost-effectiveness analyses have suggested an advantage to SABR over other treatments. In one study surgery was presumed to yield a better survival rate so that the costs of surgery still met the criterion of cost-effectiveness. If head to head randomized trials show SABR to be comparable to resection with regard to survival, it is likely that the conclusions of studies like these would change.47,48 Are there medically operable patients who may be better served by SABR? Recent population based studies argue that SABR is a superior treatment for elderly patients.49 In a large Surveillance, Epidemiology and End Results (SEER) study Shirvani and colleagues found that SABR gave the lowest risk of death within 6 months of diagnosis compared with lobectomy, conventional radiation, and observation, although the proportion of SABR cases within the study cohort was small (1.1%).50 One hypothesis for the differences in outcomes Seminars in Respiratory and Critical Care Medicine

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between surgery and SABR comes from data suggesting that the elderly do not tolerate thoracic surgery: older age is associated with a higher likelihood of residing in a nursing home or other facility after surgery in some studies.51 However, reports from the surgical literature suggest that outcomes are not statistically worse.52 Can we predict who will fail SABR treatment? How should failures be managed? Some proportion of patients will recur as much as 5 years after SABR.53 Other than the association between tumor size and cancer control probability mentioned earlier, no other factors are routinely used to identify patients with a high likelihood of local SABR failure, although some evidence supports that PET might be used as a prognostic marker for recurrence after stereotactic radiation therapy.54 For those who fail locally, what are the best salvage options? Can SABR be repeated or is surgery better?55 An even more important question asks what measures should be taken to prevent distant failure given that this is more common and more devastating. Should adjuvant chemotherapy be given after SABR in select patients? Additional markers for high-risk early-stage disease may be helpful. Is it possible to further improve the therapeutic ratio of SABR? There are no well-established preclinical models commonly used to evaluate potential radiosensitizers or radioprotectors, which may improve the therapeutic ratio of SABR. As clinicians further consider using oligofractionated radiation therapy in targets near susceptible normal tissues, safety should be a primary concern. Establishment of preclinical models would also help to guide to clinical trial dose constraints for both radiation and therapeutic compounds. Despite the wealth of clinical data related to SABR, basic scientific knowledge regarding the biology underlying these observations is lacking. The therapeutic effects of radiation therapy are generally rationalized in terms of DNA damage, and the linear quadratic (LQ) model56,57 is commonly applied to predict cell survival as a function of radiation dose over the 2- to 8-Gy range. However, the LQ model has proven unreliable in the ablative range (8–30 Gy).56,58 The basis for these differences and the outstanding clinical outcomes attributable to SABR are unclear, but involvement of tumor microvasculature59 and T-cell-dependent immune responses60 have been suggested. Despite this, many believe that we lack a complete fundamental understanding of the underlying basis for cell death from SABR.61,62 To fundamentally improve outcomes for SABR, basic questions will probably need to be answered: Does innate immunity contribute to SABR responses? Do ablative doses of radiation kill tumor cells through direct cellular effects or by secondary effects such as death of vascular endothelium? It remains unclear what mechanisms and pathways are involved in cell death from SABR. There are still several questions relevant to optimal SABR use in NSCLC that are being evaluated by institutions and national/international cooperative groups. Despite limitations on centrally located tumor treatments, several studies are attempting to determine a true MTD for these lesions with normal tissue anatomical limitations. RTOG 0813 is a phase 1/2 study that has accrued T1–T2 (< 5 cm) N0 lesions to escalating doses of SABR. Currently, the study has just comSeminars in Respiratory and Critical Care Medicine

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pleted accrual up to a dose of 60 Gy in five fractions of 12 Gy. Initially, patients’ tumors were treated at 50 Gy in 10-Gy fractions. RTOG 0915 compared two competing total doses and dose per fraction—34 Gy in one fraction and 48 Gy in four fractions. Preliminary data suggest that 34 Gy is more efficacious with respect to local control and equivalent in toxicity profile. The next trial in this series will compare 34 Gy in one fraction with 54 Gy in three fractions (with heterogeneity correction) to determine a final standard dosing for SABR use in peripheral unresectable early stage NSCLCs. It is now very critical for oncologists, pulmonologists, and surgeons to look to SABR as the definitive treatment for NSCLC patients with early-stage disease who cannot tolerate resection. Aside from cooperative group and randomized studies, other population-based efforts have continued to legitimize SABR’s prominent role in elderly/poor performance status patient populations. A study out of the Netherlands compared radiation practice patterns in three eras using national records: a period before SABR implementation for lung cancer, a second period during which time SABR was starting to be used, and a final period when SABR was standard for select groups of NSCLC. Overall, survival improved from the first to the third periods, with increasing likelihood of SABR use for medically inoperable patients being the main difference between eras compared with no treatment or conventional radiation therapy. Patients who were treated with surgery or conventional radiation fractionation for early-stage lesions had no better survival in the third versus first eras. This begs the question of whether or not there is a patient selection difference between SABR and surgery for early-stage NSCLC who may not be candidates for lobectomy. A study out of William Beaumont Hospital demonstrated that there was improved local control with SBRT but worse overall survival compared with wedge resection likely due to patient selection biases.43,63 This selection bias should not be an issue in future proposed studies described next. There are four cooperative group studies trying to determine whether or not SABR may be considered equivalent to surgeries less than lobectomy for stage I, T1N0 or also T2N0 NSCLCs. RTOG 0618 is a phase 2, multi-institutional study that has completed accrual after treating patients with SABR to a dose of 54 Gy in three fractions with heterogeneity correction for NSCLC, early-stage operable lesions for which the patients prefer radiation. A national ACOSOG/RTOG phase 3 study (Z4099/1021) was initially opened for accrual randomizing high-risk early-stage T1–T2 N0 (tumors  3 cm) NSCLC patients to either SABR (54 Gy in three fractions) or sublobar resections. Patients had to be high-risk surgery candidates and therefore more apt to receive sublobar resections traditionally. Due to poor accrual, the study was closed by ACOSOG/RTOG but may be resurrected in another form.

Conclusion The literature provides mounting evidence that SABR should be the primary modality in the treatment of medically inoperable lung cancer patients with higher rates of survival,

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tumor control, and a better toxicity profile when compared with historical reports of conventional radiation or no treatment. As a consequence, the natural extension of these findings is to compare lung SABR outcomes with surgery outcomes in patients with high operative risk (i.e., high-risk operable patients). Such a study is in the early stages of patient accrual. Though a discussion of the application of SABR to metastatic disease is beyond the scope of this review, it is worth noting that SABR can be used to treat limited numbers of lung metastases from multiple pathologies and also to treat isolated nodal or other metastases at distant subdiaphragmatic or intracranial sites as well. A future potential indication will be to use SABR with systemic agents in the treatment of limited-volume metastatic disease. These early-stage trials are also ongoing. From primary therapy to coverage of oligometastatic disease, SABR is being used for a variety of disease states in oncology. The roles for SABR continue to increase and should be maintained as an integral aspect of any academic or private practice treatment repertoire. To this point, peripheral T1 or T2 lesions up to 5 cm can be treated with three- or fivefraction SABR regimens, depending on proximity to the chest wall. For lesions centrally located, treatment with SBRT on trial is most acceptable. If not, 10 Gy times five is gaining favor as a safe standard of care. For lesions larger than 5 cm, fractionated radiation to 60 to 70 Gy at 2 Gy per fraction is considered appropriate.

Conflicts of Interest The authors declare no conflicts of interest.

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