Stereotactic body radiation therapy for lung tumors

INTRODUCTION — Stereotactic body radiation therapy (SBRT) is a technique that utilizes precisely targeted radiation to a tumor while minimizing radiation to adjacent normal tissue. This targeting allows treatment of small- or moderate-sized tumors in either a single or limited number of dose fractions. (See "Radiation therapy techniques in cancer treatment".)

Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) initially were used successfully for intracranial, orbital, and base of skull tumors, as well as benign conditions in which the skull could be used as a reference system. (See "Stereotactic cranial radiosurgery".)

The success of SRS for intracranial indications led to the development of techniques to extend this approach to extracranial targets. Stereotactic radiation therapy for extracranial sites has required significant technical advances including tumor imaging to guide radiation administration, patient immobilization, and conformal radiation delivery techniques.

SBRT has been defined by the American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) as the use of very large doses of radiation, defined as >6 Gy/fraction given over few (five or fewer) fractions [1]. SBRT has unique radiobiologic characteristics, which can cause dramatic tumor response, leading to the associated term "ablative" radiotherapy.

The rationale for SBRT in treating both primary non-small cell lung cancer (NSCLC) and metastatic lung tumors, specific techniques, and early results with this technique will be reviewed here.

TECHNIQUES FOR LUNG TUMORS — The proximity of lung tumors to critical thoracic structures requires that the high doses of oligofractionated radiation therapy used in SBRT be delivered accurately and precisely to minimize normal tissue exposure to radiation. SBRT thus requires reliable and reproducible patient immobilization, daily imaging for accurate repositioning from simulation to treatment, use of multiple treatment fields, and a method of accounting for tumor and organ motion during treatment.

Patient positioning and immobilization — Consistent, reproducible, and comfortable patient immobilization is essential for ensuring treatment accuracy.

There are several commercially available systems designed for stereotactic patient positioning and immobilization, including body frames, vacuum cushions, and thermal plastic restraints. These devices typically feature a stereotactic fiducial system that is rigidly attached and registered to the target. Other, so called "frameless" systems rely on methods to effectively relocate a reference position within the patient. As an example, implanted fiducial seeds within the tumor can be accurately relocated on a daily basis using imaging techniques. Newer technologies under development include magnetic resonance imaging (MRI) or positron emission tomography (PET) imaging that can identify targets that can be tracked in real time to ensure accurate positioning during the entire treatment course.

Image-guided treatment — Sophisticated image guidance, typically with computed tomography (CT) and more recently with MRI or PET, is incorporated into the treatment unit and allows validation of patient positioning prior to each treatment. Image-guided radiation therapy minimizes the uncertainty associated with external reference points and allows accurate tumor localization in near real time. Because lung tumors are very distinct on CT scan, pretreatment reference volumes can be linked to the image and appropriate adjustments can be reliably made on the day of treatment.

Tumor motion control — Lung tumors often move relative to other thoracic structures particularly during the respiratory cycle. This motion can vary significantly depending upon the location of the tumor and patient characteristics [2,3].

Several methods exist to reduce or compensate for tumor motion [4-10]:

●Abdominal compression places a pressure device on the abdomen to reduce motion related to the diaphragm.

●Deep inspiration and breath holding attempts to arrest the tumor in a reproducible position within the respiratory cycle.

●Respiratory gating combines these approaches to trigger delivery of radiation during a specific segment of the respiratory cycle.

●Tumor tracking systems actually move the radiation beam to follow the motion of the tumor.

Regardless of the method used, careful assurance of accuracy, reproducibility, as well as implementation of motion data into treatment planning, is essential for precise treatment delivery with SBRT.

Treatment planning — SBRT utilizes advanced treatment planning approaches to minimize radiation exposure outside the planned tumor volume. This is accomplished by using multiple beams (typically 10 to 12) or large angle arc rotations. Use of nonopposing beams is encouraged to avoid overlap of dose at points of entrance and exit. In most circumstances, noncoplanar beams are preferred to further spread out the entrance and exit dose within normal tissues. Alternatively, volumetric modulated arc therapy is often used today and is an intensity modulated radiation therapy-based treatment targeting system.

Target volumes are determined using mechanisms to predict and quantify tumor motion such as four-dimensional CT and fluoroscopy. Intravenous contrast is potentially useful, even for small tumors, to differentiate tumor (intermediate density) from atelectasis (low density) and adjacent vessels (high density). When tumor is hard to differentiate from normal tissue, advanced imaging techniques such as positron emission tomography (PET) or magnetic resonance imaging (MRI) can be combined with CT to accurately determine tumor volume. As an example, in lung tumors adjacent to the chest wall or associated with lung atelectasis or consolidation, PET/CT can help delineate targets more precisely than CT images alone.

Reducing high doses of incidental radiation outside the intended treatment volume is critical to preventing normal tissue toxicity with the high-dose fractions used in SBRT. Protocols commonly define criteria related to the conformality of target dose and compactness of intermediate dose. In addition, normal tissue dose constraints are being developed and modified based on existing data from patients treated with SBRT to help predict toxicity based on dose-volume relationships.

PRIMARY NSCLC — Surgical resection remains the standard therapy for patients with stage I non-small cell lung cancer (NSCLC) who are surgical candidates. Five-year survival rates range from approximately 60 to 70 percent. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Surgical candidates'.)

However, SBRT is an alternative as primary treatment for patients who are not candidates for or who refuse surgery (image 1). In a phase III randomized trial comparing SBRT with conventionally fractionated radiotherapy in patients who are not candidates for surgery, SBRT was associated with both improved local control for peripherally situated tumors as well overall survival at three years post-therapy [11]. The data supporting the use of SBRT in patients with stage I or II NSCLC and the data comparing SBRT with surgery are discussed separately. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Stereotactic body radiation therapy'.)

For those who will be receiving SBRT for primary NSCLC, we typically administer three fractions over 1.5 to 2 weeks, using fractions of 18 Gy for peripherally situated tumors based on Radiation Therapy Oncology Group (RTOG) 0236 [12,13]. Alternatively, a single fraction of 34 Gy or four fractions of 12 Gy has been evaluated with acceptable five-year outcomes, although larger studies are needed [14].

For central tumors, 5 fractions over 2.0 to 2.5 weeks is better tolerated than a 3 fraction regimen, using fractions of 10 to 12 Gy. In a phase I/II study of patients with T1 to 2, node-negative, centrally located NSCLC, the maximum tolerated dose was 12 Gy/fraction, which was associated with dose-limiting toxicity in 7.2 percent [15]. Two-year rates of local control in the 11.5- and 12.0-Gy/fraction cohorts were 89 and 88 percent, respectively. Most United States centers continue to use 5 fractions of 10 Gy for central tumors to avoid high grade toxicity in a frail population. More protracted treatments or treatments with longer intervals between fractions are being studied to avoid toxicity for central tumors [16].

An early phase II randomized trial comparing SBRT alone with combining SBRT and immunotherapy suggests improved event-free survival at four years with the addition of immunotherapy in the treatment of stages IA to IB patients with who were unable or unwilling to undergo surgical resection [17]. Further data are needed prior to routine use of this strategy. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Stereotactic body radiation therapy'.)

LUNG METASTASES — The lungs are one of the most common sites of spread of disease for patients with a wide variety of primary tumors. Although this usually is a manifestation of widespread disease, carefully selected patients benefit from surgical resection of one or a limited number of lung metastases when this is the sole site of recurrence. (See "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

SBRT appears to be an effective and well tolerated local therapy for patients with limited metastatic disease within the lung. Local control rates in patients with lung metastases have ranged from 67 to 92 percent using various dose fractionation schemes [18-23]. These results suggest that SBRT provides equivalent local control to surgical resection; thus, SBRT may be an alternative to surgery in patients with oligometastatic disease.

The potential role of SBRT in patients with lung metastases is illustrated in the trials below:

●In a single-institution series of 121 patients with five or fewer lung metastases, the two-year and four-year local control rates following SBRT were 77 and 73 percent, respectively [19]. A subsequent report based upon the same series observed that SBRT was used to retreat nine recurrent and 29 new lung lesions, which developed after the initial SBRT treatment [20].

●In a multicenter phase I/II study of 38 patients, each with one to three enlarging pulmonary metastases, the SBRT dose was escalated from 48 to 60 Gy given divided into three fractions [18]. None of the 12 patients in the phase I portion of the study experienced a dose-limiting toxicity. In an analysis of the assessable 50 lesions, actuarial local control rates at one and two years were 100 and 96 percent, respectively.

●Subsequent trials including patients receiving SBRT to various sites including the lung have also shown conflicting results. One trial in 99 patients demonstrated improvements in median overall survival with SBRT to metastatic sites (HR 0.47, 95% CI 0.27-0.81) [24]. Approximately half of the metastatic lesions were in the lungs, and the majority of patients had one to three metastases. By contrast, a separate randomized phase II trial failed to demonstrate benefit from adding stereotactic radiotherapy to a limited number of metastatic lesions in patients receiving immune checkpoint inhibitors as monotherapy [25]. Approximately one-third of patients in this trial were treated for lesions in the lungs.

REIRRADIATION — Because of the conformal high doses given with SBRT, its use has extended to patients previously treated with thoracic radiation.

Multiple series and one small prospective trial have looked at using SBRT in the setting of local failure after prior fractionated radiation for early-stage or locally advanced non-small cell lung cancer. Doses used have included 48 Gy in four fractions [26] as well as dose ranges over 5 to 10 fractions [26-32]. Reported local control rates have been encouraging, ranging from 60 to 95 percent, but levels of toxicity have also been higher than SBRT in previously untreated tumors, including higher percentage of fatal radiation-induced toxicities [30]. The increased risk of toxicity suggests that caution should be taken in selection and therapy of these patients to avoid significant late toxicity.

FOLLOW-UP — Typically, follow-up computed tomography (CT) scans of the chest with contrast are the preferred method of following both primary and metastatic lesions treated with SBRT. Follow-up CT scans are generally performed at intervals of three to six months, as was suggested in the clinical trial setting. Because of the inflammation and fibrosis caused by hypofractionated radiation, changes seen on CT can often mimic disease progression and can be difficult to distinguish from radiation injury.

Careful communication with thoracic radiologists including knowledge of the dosimetry and potential effects of high-dose radiation is essential. Certain patterns of response to SBRT and subsequent CT changes correlating with radiation fibrosis are well described in the literature and can be used as guides when interpreting follow-up scans [33,34].

When there is a suggestion of progressive disease after SBRT, correlation with other imaging modalities, such as positron emission tomography (PET)/CT, is warranted and biopsy confirmation of relapse is recommended if feasible [35,36]. Because moderate residual metabolic uptake can often be seen up to 12 months after SBRT [37], PET/CT in the absence of suspicious CT changes is not routinely recommended.

TOXICITY — Because of the high doses per fraction used during SBRT, there is an increased risk of normal tissue toxicity compared with conventionally fractionated radiation therapy unless care is taken to minimize radiation exposure to normal structures. The numbers of patients and length of follow-up are limited in the studies described above. However, prospective assessment of dosimetric endpoints such as dose volume information has been used to modify SBRT dose constraints in normal tissues, and SBRT for thoracic lesions appears to have a reasonable safety profile.

The Radiation Therapy Oncology Group (RTOG) has observed reasonable rates of toxicity for treatment of medically inoperable patients when the SBRT dose is divided into three fractions for peripheral tumors [12]. Grade 3 to 4 toxicity was seen in 17 patients (31 percent) treated on RTOG 0236, and no treatment-related deaths were seen with five years of follow-up [13]. Additionally, in a meta-analysis evaluating 21 prospective studies of patients receiving SBRT to various sites (29 percent of whom received SBRT to the lung), the estimated rates of acute and late grade ≥3 effects were 1.2 and 1.7 percent, respectively [38]. Other studies have also observed that SBRT was well tolerated, and that changes in pulmonary function tests were minimal [39].

Peripheral and apical lesions — For lesions near the lung periphery, chest wall toxicity may be manifested by rib fractures or pain [40-42]. The incidence of chest wall toxicity was illustrated by a series of 347 treated lesions, which included 203 on the chest wall. Both chest wall pain and rib fractures were more frequent when chest wall lesions were irradiated compared with nonchest wall lesions (16 versus 3 percent and 8 versus 1 percent, respectively) [42].

When SBRT is used to treat primary lung cancers in apical sites, there may be an increased risk of injury to the brachial plexus. In a series of 36 patients with apical lesions treated with SBRT to a median dose of 57 Gy in three fractions, seven patients developed grade 2, 3, or 4 brachial plexopathy [43]. These authors felt that the tolerance of the major trunks of the brachial plexus was around 26 Gy for a three-fraction regimen. (See "Brachial plexus syndromes", section on 'Neoplastic and radiation-induced brachial plexopathy'.)

Proximal lesions — SBRT appears to offer a reasonable alternative for patients with proximal lesions, although its safety may require some modification of the SBRT fractionation schedule.

The phase II study, which included 70 patients with medically inoperable central lung cancers, found that central and perihilar structures within the lung are very sensitive to the high doses of radiation delivered during SBRT [44]. Low-grade toxicities included fatigue, musculoskeletal pain, and radiation pneumonitis. Fourteen patients had severe toxicity, including decline in pulmonary function tests, pleural effusions, and pneumonias. There were six deaths that may have been treatment-related, the majority of which were from pneumonia. Four of the six deaths were in patients with central tumors within 2 cm from the proximal bronchial tree, and these patients had an 11-fold increased risk of having a severe toxicity compared with patients with peripheral lesions.

A systematic review of the literature, based primarily upon retrospective case series, included data from 315 patients with central early-stage non-small cell lung cancer in 20 studies [45]. This review concluded that local control could be achieved as effectively as with peripheral lesions, with an acceptable level of toxicity, provided that an adequate dose of radiation to the periphery of the tumor was maintained. However, a Scandinavian study including "ultra" central tumors only 1 cm from the central bronchial tree demonstrated high grade toxicity in 22 of 65 patients including 10 toxic deaths after 8 fractions of 7 Gy [46]. While this experience shows higher toxicity than most reports, care must be taken in treating proximal lesions.

Lung metastases — When SBRT is used to treat patients with lung metastases, toxicity is typically less severe than that for those with primary lung cancer. These patients tend to present with better overall lung function and are more likely to have peripherally located tumors. In the multicenter dose-escalation study, no grade 4 to 5 toxicity was seen, and there were no treatment-related deaths [18]. Although multiple patients had more than one lesion treated with SBRT, only three had grade 3 toxicity. However, in the randomized trial described above, two treatment-related deaths were observed among patients receiving SBRT to lung metastases [47]. (See 'Lung metastases' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

SUMMARY AND RECOMMENDATIONS — Stereotactic body radiation therapy (SBRT) is a radiation therapy technique that utilizes precisely targeted radiation to a tumor while minimizing radiation to adjacent normal tissue. This targeting allows treatment of small- or moderate-sized tumors in either a single or limited number of dose fractions. (See 'Techniques for lung tumors' above.)

Application of SBRT techniques in patients with small primary non-small cell lung cancers (NSCLCs) or lung metastases has given results similar to surgical resection, although long-term follow-up data are not available. There are no results from randomized clinical trials comparing SBRT with surgery or other ablative techniques such as radiofrequency ablation. (See "Image-guided ablation of lung tumors".)

Primary NSCLC

●For patients with adequate pulmonary function and without serious medical comorbidity, we recommend surgical resection as the initial treatment for patients with stage I or II non-small cell lung cancer (NSCLC) rather than radiation therapy (Grade 1B). (See "Management of stage I and stage II non-small cell lung cancer", section on 'Surgical candidates' and 'Primary NSCLC' above and "Image-guided ablation of lung tumors".)

●For patients with primary tumors smaller than 7 cm and impaired pulmonary function or medical comorbidity that precludes surgical resection, we suggest SBRT rather than conventionally fractionated radiation therapy, if appropriate technical expertise is available (Grade 2B). (See 'Primary NSCLC' above and "Image-guided ablation of lung tumors".)

●For patients with larger primary tumors and impaired pulmonary function or medical comorbidity that precludes surgical resection, we recommend definitive standard-fractionation radiation therapy (Grade 1B) (see "Management of stage I and stage II non-small cell lung cancer", section on 'Nonsurgical candidates'). To date, there are no randomized studies that compare SBRT versus radiofrequency ablation in these patients. (See "Image-guided ablation of lung tumors".)

Lung metastases

●For patients with a limited number of lung metastases who meet the criteria for resection, SBRT may be an appropriate alternative to surgery, particularly in those with significant medical comorbidity. SBRT offers a survival benefit relative to surgery. (See "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques", section on 'Criteria for considering a resection' and 'Lung metastases' above and "Image-guided ablation of lung tumors".)