Stage I Nonsmall Cell Lung Cancer and Oligometastatic Disease

SABR Protocol Development, Implementation, and Quality Assurance

A dedicated SABR team should consist of radiation oncologists, medical physicists, and technicians (e.g., radiographers, radiation therapists), all of whom should have attended appropriate training courses organized by professional bodies and/or industry in accordance with the above-mentioned guidelines. Written treatment protocols that are consistent with national regulations, institution-specific equipment, and training and education of the individual radiotherapy team members should be available. SABR requires additional and more frequent physical quality assurance: verification and quality assurance of the entire SABR treatment chain is mandatory, and end-to-end tests for overall uncertainty estimation are recommended. It is paramount to verify that the radiation isocenter coincides with the mechanical isocenter, including couch rotation, room lasers, and, especially, the imaging isocenter.

Diagnosis and Staging Before SABR

Diagnosis and confirmation of NSCLC based on tissue biopsy is recommended before starting any local treatment for early-stage NSCLC. However, obtaining a histologic diagnosis may not be possible for peripheral lung lesions or may pose a high risk of toxicity in a patient group with considerable medical and/or pulmonary comorbidities. In the latter case, radiographic criteria of malignancy are used to establish a diagnosis. Models that predict the probability of malignancy in solitary pulmonary nodules based on both clinical and radiographic characteristics have been described and validated. It is important to note that these criteria may not hold true in geographic regions with a high incidence of infectious and/or granulomatous lung diseases. Therefore, current guidelines state that any treatment for a possible early-stage NSCLC without a pathologic diagnosis should proceed only after assessment by an experienced multidisciplinary tumor board. If the clinical and radiographic findings are inconclusive, repeated imaging to evaluate the growth pattern is an option for some patients, but careful follow-up is required because patients with malignancy are at risk for early disease progression.

Guideline-specified nodal staging should be performed before SABR, as nodal regions are not radiated. Staging with ¹⁸ F-2-deoxy- d -glucose-positron emission tomography (FDG-PET) is essential because of its higher diagnostic accuracy for the detection of node metastases (negative predictive value, 90%) and also because unsuspected distant metastases and second primary tumors can be excluded. In the event of pathologic FDG uptake in regional lymph nodes, further evaluation by endobronchial ultrasound or endoscopic ultrasound is recommended and, if the findings are inconclusive, a mediastinoscopy may be necessary. Staging with PET–computed tomography (CT) should ideally be performed within 6 to 8 weeks before SABR is given because of the risk of disease progression in the interim.

Target Volume Definition and Treatment Planning

All imaging should be acquired in the treatment position, with standard practice dictating that planning CT images encompass the entire lung volume, and a slice thickness of 2 mm to 3 mm is used. Using intravenous contrast medium may improve the delineation of centrally located primary tumors. As conventional three-dimensional (3-D) CT risk introduces artifacts and systematic errors, four-dimensional (4-D) CT, also known as respiration-correlated CT, is the recommended technique for SABR planning. Although a single 4-D CT planning image provides only a snapshot of a patient’s breathing pattern, several studies have demonstrated that the motion pattern and amplitude are stable over time, making routine repeated 4-D CT imaging unnecessary. The use of FDG-PET alone is not appropriate for a reliable assessment of target motion in SABR planning.

Target Volume Concept and Motion Management Strategy

Gross tumor volume is determined on the basis of CT findings in the lung and soft-tissue window. Current guidelines do not recommend the use of clinical target volume margins when SABR is delivered, as the high radiation doses combined with rather flat dose profiles in pulmonary tissue of low electron density result in sufficient coverage of potential microscopic disease extension. Integration of breathing-induced target motion into the target volume concept will ensure patient-tailored tumor targeting, with clinical implementation dependent on the chosen motion management strategy. Several different approaches are used in routine clinical practice. Continuous radiation in free breathing is performed using the internal target volume concept, the mean target position concept, or real-time tumor tracking. Tumor tracking is possible using dedicated robotic delivery machines, by dynamic multileaf tracking, a gimbaled multileaf collimator, or a dynamic treatment couch. Noncontinuous radiation of the tumor in a reproducible position is performed using gated beam delivery in predefined phases of the breathing cycle, in voluntary breath-hold, or in breath-hold using the active breathing coordinator.

It is important to emphasize that active motion management strategies, such as gating and tracking, require continuous intrafractional monitoring; however, continuous intrafractional monitoring is less critical for passive strategies, such as the internal target volume or mean tumor position concept. Although patient-specific motion management is strongly recommended, data from the available prospective trials did not involve the use of advanced motion management strategies. Of the individualized 4-D motion management strategies used, resulting field sizes are largest for the internal target volume concept; however, this motion management strategy is straightforward to implement and ensures adequate target coverage. Even if all uncertainties in treatment planning and delivery are minimized by currently available technologies, residual errors still remain and require minimum planning target volume (PTV) margins of about 5 mm.

Dose Fractionation and Prescription

Dose prescription and reporting should comply with the International Committee on Radiation Units and Measurements Report on Prescribing, Recording, and Reporting Intensity-Modulated Photon-Beam Therapy as closely as possible, but historical practice and experiences need to be considered as well. Most prospective and retrospective studies used inhomogeneous dose distributions within the PTV, with maximum doses ranging between 105% and 150% of the prescribed dose. Inhomogeneous dose distributions offer the opportunity to deliver an extra dose to the center of the PTV, where the (potentially hypoxic) macroscopic tumor is located, without increased doses to the peripheral normal tissue.

As a result of large differences in single-fraction and total doses between SABR studies, a comparison of physical doses is less meaningful. The linear quadratic model has been widely used for modeling of SABR outcomes data, but it has not been validated for very high single doses. Despite uncertainty surrounding the linear quadratic model, several groups have independently demonstrated a clear dose-effect relationship for local tumor control using biologic effective doses (BEDs), with a minimum PTV dose of more than 100 Gy BED (α/β ratio, 10 Gy) required for local tumor control rates of higher than 90%. The current recommended tumor dose for SABR of lung tumors is a minimum of 100 Gy BED, prescribed to the target volume encompassing isodose. A meta-analysis demonstrated a potential detrimental effect of SABR doses exceeding more than 146 Gy BED.

Total doses are typically delivered in one to eight fractions, but insurance reimbursement rules have resulted in a widespread use of five or fewer fractions in the United States. However, use of very high single-fraction doses and total doses (e.g., delivery of three fractions of 20 Gy) can damage normal tissues in or adjacent to the target volume. Consequently, treatment of tumors in proximity to critical normal organs has led to the use of so-called risk-adapted fractionation schemes that deliver the required dose of 100 Gy BED in a larger number of treatment fractions with lower single-fraction doses. Fractionation appears to spare some critical normal organs while ensuring sufficiently high doses to achieve local tumor control.

Fractionation appears to be especially valuable in SABR for centrally located tumors, as it allows for radiobiologic sparing of critical organs such as large bronchi, vessels, heart, and esophagus. High-quality prospective data on the safety and efficacy of SABR for centrally located lesions are limited, but a systematic review of the literature demonstrated local control rates of 85% or greater when the prescribed BED to the tumor was 100 Gy or higher. The overall treatment-related mortality was 2.7%, and when the BED to normal tissue was 210 Gy or lower (α/β ratio, 3 Gy), the rate was 1.0%. Until mature prospective multicenter data become available, a recommended fractionation scheme for experienced centers is 8 × 7.5 Gy, with D _max (PTV) of 125%.