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Keywords:

  • stereotactic body radiotherapy;
  • radiosurgery;
  • intensity-modulated radiotherapy;
  • lung cancer;
  • liver cancer;
  • spine metastases;
  • oligometastases;
  • normal tissue complications

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. TECHNIQUE AND TECHNOLOGY
  5. CLINICAL APPLICATIONS
  6. FUTURE EFFORTS
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Stereotactic body radiotherapy (SBRT) involves the treatment of extracranial primary tumors or metastases with a few, high doses of ionizing radiation. In SBRT, tumor kill is maximized and dose to surrounding tissue is minimized, by precise and accurate delivery of multiple radiation beams to the target. This is particularly challenging, because extracranial lesions often move with respiration and are irregular in shape, requiring careful treatment planning and continual management of this motion and patient position during irradiation. This review presents the rationale, process workflow, and technology for the safe and effective administration of SBRT, as well as the indications, outcome, and limitations for this technique in the treatment of lung cancer, liver cancer, and metastatic disease. Cancer 2014;120:942–954. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. TECHNIQUE AND TECHNOLOGY
  5. CLINICAL APPLICATIONS
  6. FUTURE EFFORTS
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

The first treatment of cancer with ionizing radiation dates to the late 1890s[1, 2] and within 10 years was recognized as a potentially effective treatment for several malignancies.[3, 4] By the 1930s, the use of protracted courses of ionizing radiation, delivered in multiple sessions (“fractions”) to a tumor and surrounding tissue at risk for harboring malignant cells, had emerged as a primary treatment modality for cancer.[5] The fundamental principle underlying fractionated radiotherapy is that normal and malignant tissues respond differently to the same dose of radiation and that breaking up the treatment course into many small fractions will permit repair of normal tissue while delivering a high cumulative dose of radiation to malignant cells.[6] In the developed world, more than half of all patients with cancer will receive radiation therapy at some point in their treatment and the dominant technique remains fractionated delivery of high-energy X-rays.[7]

For small intracranial lesions, the use of a few high-dose treatments to the target (“stereotactic radiosurgery”) has emerged as an alternative to conventional fractionated radiotherapy in selected situations.[8] These lesions are essentially fixed in position with respect to the skull and, with appropriate immobilization of the patient's head and the accurate delivery of multiple small radiation fields, radiation damage can be limited to the target lesion. Although the precise dose-response relationship at high doses per fraction is controversial,[9, 10] the proportion of cells killed appears to increase at least exponentially with dose and, above some dose threshold, may involve destruction of the vascular endothelium.[11] Thus, a few treatments delivered at a high dose per fraction may be far more effective at killing tumor cells than the equivalent total dose given in many small fractions.

Treatment of tumors in the body is complicated by the need to reduce and/or account for the motion of the target. Without such control, a large radiation field would be required, substantially limiting the dose that could safely be delivered in a few fractions. Over the past decade, stereotactic body radiotherapy[12] (SBRT) has been introduced to administer radiation therapy to extracranial targets that are mobile and/or difficult to visualize during treatment. This review describes the technology and technique for SBRT, along with the clinical applications, indications, and limitations for this treatment modality.

TECHNIQUE AND TECHNOLOGY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. TECHNIQUE AND TECHNOLOGY
  5. CLINICAL APPLICATIONS
  6. FUTURE EFFORTS
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

The guiding principle underlying SBRT is delivery of radiation to a target in the body, with sufficient intensity to kill, or at least control, the underlying malignancy, while minimizing the radiation dose to adjacent normal tissues. Effectively and safely accomplishing these conflicting goals requires quantitative visualization and localization of the target lesion, complex radiation plans, continual management of the target position throughout treatment, and robust quality assurance. A schematic of the process for planning and delivering SBRT is shown in Figure 1.

image

Figure 1. Schematic diagram shows the process flow for stereotactic body radiotherapy (SBRT). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Patient Evaluation

Selection of the appropriate treatment modality requires a thorough history, physical examination, and review of relevant imaging studies, pathology and laboratory results, preferably in a multidisciplinary setting. In obtaining informed consent for SBRT, it is important to emphasize that there is limited long-term data on the efficacy and normal tissue complications associated with SBRT. Developing such information will require results from prospective, large clinical trials and it is appropriate to offer enrollment in these trials to eligible patients.

Simulation

In this phase of the process, the patient is immobilized and imaged in the treatment position. The fundamental requirements for immobilization are that the device comfortably, reliably, and securely holds the patient in the treatment position over an entire session of SBRT (up to 1 hour.) Typically, an immobilization device consists of a custom molded “cradle” or extended head-and-neck mask. This device also provides a precise, accurate correlation between the treatment machine and patient/target geometry, facilitating treatment planning and patient setup during treatment.

After fashioning the immobilization device, a high-resolution computed tomography (CT) scan is typically performed to image the patient and treatment target, providing the precise, quantitative location of these structures in space. In the case of mobile targets, such as a lung or liver lesion, it is essential to image the target over the entire respiratory cycle. Target motion information acquired through this 4-dimensional CT (4D-CT) imaging requires time-based correlation of respiratory motion with the CT images. Respiratory signals are obtained from surface-mounted or internal markers associated with respiration. The surface marker is more popular because it is less invasive. However, internal surrogates for respiratory motion, either anatomical structures or implanted metal markers, will be better correlated with the actual target motion than the surface markers and can be used for image-guided target verification in the treatment room.

In addition, the simulation CT images are frequently combined with magnetic resonance, positron emission tomography, and single-photon emission computed tomography (SPECT) images, which can provide superior visualization of soft-tissue lesions, as well as biological/functional information. Rigid-body image registrations are used to fuse the diagnostic and planning images. Deformable image registration is also being explored. However, careful validation of such software and its clinical utility needs to be performed.

Treatment Planning

The first step in treatment planning is careful delineation of the target volume and normal tissue structures on the fused image set. Typically, this consists of the practitioner drawing the outline of the image on each slice of the image set (termed “contouring”), and these images are combined by the planning software to yield a 3-dimensional (3D) representation of the structure. These images can be subsequently manipulated to add a margin to be treated or avoided around a structure, depending on the accuracy of imaging, precision of the treatment machine, judgment of microscopic extension of malignant cells beyond the visualized tumor, the anticipated set-up error prior to treatment, and target motion during radiotherapy.

After contouring the structures and specifying the dose constraints, a treatment plan will be developed to effectively meet these constraints. Typically, a variety of treatment plans and techniques will be assessed, depending on the size and shape of the target, the prescription dose, the proximity and tolerance of the surrounding normal structures and the specific treatment machine available. Because most radiation treatment facilities use x-rays, the choice of treatment plan will revolve around the number of radiation beams, beam energy, and the use of 3D conformal radiotherapy (3D-CRT) versus intensity-modulated radiotherapy (IMRT). In 3D-CRT, radiation is delivered via several beams directed toward the center of the target (the isocenter) with the aperture of each beam shaped to fit the profile of that target, using multiple tungsten leaves (“multileaf collimators.”)

In IMRT, the beam aperture is continually adjusted (modulated) such that a differential radiation dose may be delivered to different portions of the target. This “dose painting” permits irregularly shaped targets in close proximity to critical normal tissues to be adequately covered by the desired dose of radiation while sparing the adjacent normal tissue. IMRT requires sophisticated computer-based optimization to achieve the desired dose distribution and specialized quality assurance to ensure that the plan is correct and executable.

3D-CRT plans can be generated quickly and can readily be delivered using straightforward quality assurance (QA) techniques. However, it is difficult to conform the dose to follow concave surfaces, e.g., a vertebral body wrapping around the spinal cord. In these situations, IMRT offers the advantages of superior dose distributions at the cost of much higher planning effort, more complex quality assurance and often lengthier treatment delivery times. Representative radiation dose distributions for 3D-CRT versus cord-sparing IMRT for a spinal lesion are shown in Figure 2.

image

Figure 2. Radiation dose distribution is shown for (A) a simple posterior-anterior field, (B) 3-dimensional conformal radiotherapy, and (C) intensity-modulated radiotherapy (IMRT) to the spine. The colored lines in each figure represent equal doses (“isodoses”) with the red, green, and magenta lines representing 100%, 95%, and 50% of the prescribed dose. Observe that whereas both the 3-dimensional conformal radiotherapy and IMRT plans provide a more conformal dose distribution about the vertebral body compared to the posterior-anterior field, the IMRT plan also substantially reduces the dose to the spinal cord. Typically, stereotactic body radiotherapy for spinal lesions requires IMRT planning in order to achieve adequate dose to the target lesion while sparing the spinal cord.

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Treatment planning for SBRT is an iterative, labor-intensive process in which a plan is generated, the dose distribution critically reviewed by the involved physicians, and the plan is discarded, optimized, or accepted. In some cases, it may be impossible to obtain an adequate dose distribution using the technology available at a treatment center. In these cases, it is necessary to consider alternate treatment modalities or referral to a radiation center with more sophisticated capabilities, e.g., protons for the case of a chordoma abutting the spinal cord.

Treatment Delivery

A variety of devices may be used to deliver SBRT, such as linear accelerators with multileaf collimators, rotational tomographic units and robotic-arm–based linear accelerators, each of which has specific advantages and limitations.

In all systems, the patient is securely positioned in the immobilization device on the treatment table and the position roughly adjusted using markings on the device or patient. In linear accelerators with multileaf collimators, orthogonal x-ray images and/or a cone-beam CT scans are taken prior to treatment. (A cone-beam CT mounted on the treatment machine offers particular advantages in that it provides rapid acquisition of high-resolution images in multiple planes, with minimal dose deposition.[13]) Comparing the images acquired at planning and on the treatment table, the patient position is adjusted in the translational planes and rotational axes until the image sets exactly overlay one another in the region of interest.

Management of organ/target motion is particularly critical for SBRT of lung and liver lesions. Throughout treatment, the position of external or internally implanted markers is constantly monitored and radiation will only be administered when the position of these markers falls within a limited range. In contrast the robotic-arm–mounted linear accelerator continuously adjusts the position of the radiation beam, depending on the position of markers on the patient's surface or implanted near the target.

Quality Assurance

SBRT is a complex and technically demanding process, requiring sophisticated equipment, attention to detail and well-trained, experienced staff. A robust QA program, integrated into every aspect of the process with the commitment of all personnel, is essential.[14] A number of standard QA protocols have been developed and established for SBRT systems.[15-17] However, an institution's QA system must be tailored to the specific treatment system workflow and organizational culture, with continual measurement of errors and the application of corrective action to prevent any deviation.

CLINICAL APPLICATIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. TECHNIQUE AND TECHNOLOGY
  5. CLINICAL APPLICATIONS
  6. FUTURE EFFORTS
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Lung

SBRT has been studied most extensively in patients with medically inoperable, stage I non–small cell lung cancer (NSCLC). Prior to the introduction of SBRT, such patients were generally treated with a 6- to 7-week course of conventional radiation therapy. Although no phase 3 trials have compared these 2 approaches, SBRT appears to be more effective, is certainly more convenient, and is currently considered the standard of care. Numerous prospective phase 2 studies have consistently demonstrated high rates of local control and relatively low rates of complications after SBRT.[18-23] For example, the Radiation Therapy Oncology Group (RTOG) performed a multicenter study to evaluate SBRT in a medically inoperable population.[24] Peripheral, stage I tumors (< 5 cm) were treated with 3 fractions of 20 Gy each without tissue density heterogeneity corrections (roughly equivalent to three 18-Gy fractions with corrections).[25] After a median follow-up of 34 months, the 3-year actuarial local tumor control was 98%. The most common site of failure was distant metastases, occurring in 22% of patients. Overall survival at 3 years was 56%. Grade 3-4 toxicity occurred in 15% of patients, primarily pulmonary toxicity including decreased pulmonary function, pneumonitis, and hypoxia.

Patients with lung cancer who undergo SBRT should be appropriately immobilized with their arms above their head. In particular, degenerative arthritis is common in older adults and many have difficulty holding their arms in this position for extended periods of time. Analgesics can be helpful to prevent unnecessary motion attributable to pain. Lung tumors inevitably move during the respiratory cycle. This needs to be assessed during simulation, most commonly with fluoroscopic imaging and a 4D-CT scan, and accounted for during treatment, as described above. Most lung cancer patients are adequately treated with SBRT using 3D-CRT (Fig. 3). IMRT can be helpful if tumors are in close proximity to critical structures, such as the esophagus, brachial plexus, or spinal cord, although this may not be practical if the tumor motion is large or irregular. A variety of fractionation schemes have been used successfully. It seems clear that the biological effective dose should be at least equivalent to 50 Gy administered in 5 fractions.[26, 27] Finally, image guidance at the time of radiation delivery, using cone beam CT or a similar technique, as described above, is critical to ensure that radiation is delivered correctly to lung lesions.

image

Figure 3. (A) Lung planning computed tomography (CT) scan (free-breathing) showing a tumor in right upper lobe. A 4-dimensional CT scan was also obtained for treatment planning (not shown). (B) A 3-dimensional plan was designed using 9 axial beams. The patient received 54 Gy in three 18-Gy fractions. (C) The 54-Gy isodose line is shown in yellow.

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One of the most challenging aspects of SBRT to lung lesions is the posttreatment radiographic evaluation. Essentially all patients develop CT changes in the lung 6 to 12 months after SBRT.[28, 29] These radiographic abnormalities can range from patchy ground-glass opacities to diffuse consolidation. With longer follow-up, the radiographic findings evolve. A mass-like pattern can develop that can be difficult to distinguish from persistent tumor. Although no single radiographic finding is specific for progressive disease, an enlarging area of consolidation or mass > 12 months after SBRT is cause for concern. PET is a useful tool in this setting to help discriminate tumor progression from fibrosis.[30]

Enthusiasm for SBRT of lung lesions remains high, but it is imperative that clinicians be aware of the potential complications of SBRT and the strategies available to mitigate risk. High-grade toxicity following SBRT in patients with central and large tumors, particularly with high-dose three fraction regimens, has been reported.[31] RTOG 0813 is a dose escalation study attempting to define the maximally tolerated dose for tumors that arise within 2 cm of the tracheobronchial tree. This study closed to accrual in September 2013, and results are pending. Many patients have peripheral tumors in close proximity to the chest wall. Rib fractures and chronic chest wall pain have also been observed after SBRT.[32-35] Dose to the chest wall clearly influences risk.[32, 33, 35] The dose to the chest wall should be assessed and planning reoptimized if necessary. Furthermore, radiation oncologists must be vigilant in evaluating the dose to the skin, especially in thin patients with posterior tumors near the chest wall, as skin toxicity has been reported after SBRT.[35, 36] Finally, in patients with apical lesions, the brachial plexus should be delineated on the treatment planning software and the dose administered to that structure assessed. The risk of brachial plexopathy is unacceptably high when the maximum dose exceeds 26 Gy.[37] IMRT can be helpful to spare the brachial plexus when tumors are in close proximity.

In summary, SBRT is an effective, well-tolerated, treatment for stage I lung cancer. Randomized trials comparing surgery with SBRT have been initiated but patient enrollment has been challenging. Long established standards of care, lack of equipoise among specialists, and in particular, patient randomization to a surgical versus nonsurgical treatment, have hindered enrollment. Given the high rates of local control after SBRT, and a shift in patterns of failure to primarily distant metastases, control of systemic disease is currently the most pressing concern.

Liver

Historically, radiation has not had an established role in the management of hepatic malignancies due to concerns of radiation-induced liver toxicity. Prior to the availability of 3D-CRT, dose escalation to enhance local tumor control was not feasible given high rates of radiation-induced liver disease (RILD) with whole-liver doses above 30 Gy.[38] In the era of CT-based treatment planning, Dawson et al reported on use of normal tissue complication probabilities to estimate risk of RILD based on dose and volume of liver irradiated.[39] In the early 1990s, Blomgren and colleagues first reported the use of an extracranial body frame to deliver high-dose radiotherapy to the liver.[40] Since then, several small prospective and retrospective series have been published on the use of SBRT for primary intrahepatic malignancies[41-50] and hepatic metastases.[40, 47, 51-61]

Hepatocellular Carcinoma

In operative candidates, surgery (hepatectomy or liver transplant) is considered the gold standard. Most patients are not candidates for surgery at presentation due to tumor size, multifocal disease, proximity to critical vascular structures and poor liver function. Radiofrequency ablation (RFA), ethanol injection, cryoablation, radioembolization, transarterial chemoembolization (TACE), bland embolization, and SBRT are alternative local therapies in the management of hepatocellular carcinoma (HCC). SBRT has not been routinely recommended in consensus or national treatment guidelines due to a lack of level I evidence, despite a growing body of early prospective and retrospective data.

The first prospective trial of SBRT from Mendez-Romero et al treated 25 patients with liver tumors (8 with HCC). The 1-year local control was 75% and 1 patient with Child-Pugh class B disease developed RILD.[47] Cardenes et al conducted a phase 1 prospective study demonstrating that SBRT toxicity among HCC patients is based largely on treatment volume and baseline liver dysfunction.[43] Four of 5 patients in this study with Child-Pugh score ≥ 8 developed grade 3+ toxicities or survived < 6 months after treatment. Dawson et al[42] reported the largest prospective phase 1/2 study of 102 Child-Pugh class A patients with HCC treated with SBRT (55% with tumor vascular thrombus, 60% with multiple lesions). Outcomes were excellent with 1-year local control of 87% using a median dose of 36 Gy in 6-Gy fractions. Median overall survival was 17 months. Despite available evidence for tolerability and apparent efficacy of SBRT in HCC, there is no data showing an overall survival benefit compared to other local therapies, systemic therapy or supportive care. We await results from the recently opened Radiation Therapy Oncology Group (RTOG 1112). This phase 3 randomized study of patients unsuitable for surgery, RFA, or TACE seeks to evaluate sorafenib alone versus sorafenib and SBRT. The primary study endpoint is overall survival with goal of establishing SBRT as part of standard therapy in this cohort. Other areas warranting further study are the role of SBRT as first-line therapy in nonsurgical patients and use of SBRT in conjunction with other local modalities, such as TACE or RFA, in an effort to further improve disease outcomes.

Hepatic Metastases

As with HCC, hepatic metastases can also be treated aggressively with surgical resection[62-64] or local therapies such as RFA[65, 66] or SBRT. Although level I evidence is lacking regarding use of SBRT in patients with liver metastases, there are increasing data from retrospective and prospective studies. Among patients who are not surgical candidates or refuse surgery, aggressive local therapy with SBRT is a reasonable consideration with the hypothesis that local disease control can influence progression-free survival and overall survival. Rates of local control using SBRT have been reported as high as 100% at 2 years[57] although results appear dose-dependent,[67] vary by extent of pretreatment[54] and primary tumor site.[54] A prospective, multicenter phase 1/2 study evaluated 63 lesions in 47 patients delivering a dose of 60 Gy in 3 fractions. At median follow-up of 16 months, 2-year local control was 92%. Among lesions ≤ 3 cm the 2-year local control was 100%.[58] Patients with liver metastases tend to have normal hepatic function and thus reported RILD is rare. Given evidence of better local control with dose escalation, a higher total dose and dose per fraction can be considered with careful attention not only to the volume of liver spared but also to maximum dose to the spinal cord, heart, esophagus, kidney, stomach, and bowel.[67]

Spine

Employing conventional techniques, various dose fractionation schemes have been used to palliate spinal metastases. These regimens (eg, 30 Gy in 10 daily treatments, 20 Gy in 5 treatments, or 8 Gy in a single treatment) achieve at least partial clinical response in approximately 65% to 75% of patients,[68, 69] and remain the mainstay of treatment for symptomatic metastases to the spine. However, challenges in treating these patients remain.

Retreatment rates for symptomatic local recurrence after conventional radiation therapy have been reported as high as 20%.[68, 69] Other patients develop recurrent or progressive tumor but never receive retreatment, as concern for radiation myelopathy has historically limited the feasibility of reirradiation. With ongoing advances in the management of advanced disease, the subset of patients who live long enough to become symptomatic from recurrent spinal metastases is growing (see the discussion of oligometastatic disease below), and recurrent disease can be quite morbid with respect to pain, radiculopathy and/or spinal cord compression. In addition, for particularly radioresistant histologies (eg, renal cell carcinoma, melanoma, sarcoma), conventional dose fractionation schemes may be suboptimal in providing tumor control.[70, 71]

SBRT is well-suited for re-irradiation of the spine and may provide superior tumor control compared to conventional techniques and dose fractionation schemes. SBRT maximizes the therapeutic index by achieving excellent dose coverage of a concave target (eg, a vertebral metastasis that wraps around the spinal cord), while obtaining rapid falloff of dose to spare the spinal cord.[72] This advantage in dose conformity allows significantly higher doses to be delivered to a tumor target with each of 1 to 5 treatments (eg, 16-24 Gy in a single treatment), resulting in a higher total biologically effective dose. Emerging data from multiple institutions have reported local control rates between 70% and 100% in the reirradiation setting.[73-75] Rates of symptom control, including pain and neurological deficits, are similar in magnitude across these studies, despite the inhomogeneity of reported outcome measures. Using a recursive partitioning analysis, one group has proposed a prognostic index for overall survival in spine SBRT, predicting that those with excellent performance status and greater than 30 months from initial diagnosis to time of treatment derive the greatest benefit from spine SBRT.[76]

Spine SBRT treatments are generally well-tolerated. The high treatment dose and the proximity of target to critical structures, however, could potentially result in significant complications, including radiation myelopathy, compression fracture, or radiculopathy. Published data reveal few myelopathic events attributed to SBRT (< 2% of treated tumors), but when it does occur, it can cause permanent and potentially catastrophic motor and sensory deficits.[75, 77-79] The radiobiology of hypofractionated spinal cord irradiation is being investigated, along with dosimetric and volumetric parameters that may be critical in determining the development of this serious complication.[77, 79, 80] The risk of vertebral body fracture after spine SBRT is less well established, with one report demonstrating an increased risk of fracture in lower thoracic and lumbar vertebral bodies, as well as those having an extensive amount of lytic disease prior to treatment.[81]

Given the inherent physical, logistical, and radiobiologic advantages of SBRT, there have been efforts to understand its potential in settings beyond reirradiation. First, its role in upfront treatment for spinal metastases is being investigated. Multiple retrospective studies have shown the feasibility of SBRT in treating spinal metastases upfront, demonstrating similar, if not superior, control of target lesions and toxicity compared to historical controls treated with conventional dose fractionation, particularly among radioresistant tumors.[74, 82-84] RTOG 0631 is an ongoing phase 2/3 study which addresses this question prospectively, randomizing patients with spinal metastases to either conventional fractionation or SBRT. Second, spine SBRT after surgical intervention (eg, kyphoplasty, decompression) has been examined, with promising results to date.[85, 86] Third, parameters for spine SBRT continue to be refined, including fractionation, dose escalation, and optimal target/normal tissue delineation.

SBRT offers excellent control of spinal metastases while minimizing acute and late toxicity. It may have particular utility in the setting of prior irradiation, radioresistant histologies, and geometrically challenging tumors. The proximity of tumor target to spinal cord, however, demands superior quality assurance and expertise in treatment planning to ensure safe and accurate radiation delivery. Ongoing studies should elucidate the optimal dosimetric parameters and further refine radiosurgical techniques.

Oligometastatic Disease

The oligometastatic patient, as originally proposed by Hellman and Weichselbaum,[87] describes a unique phenotype of detectable metastases limited in number and location, suggesting a different biology than the polymetastatic patient, who exhibits widespread metastases.[88] Although the oligometastatic phenotype may arise de novo, it may also be induced by tailored systemic therapies that effectively eradicate subclinical disease. In addition, advances in diagnostic imaging have led to greater sensitivity in detecting limited metastatic disease. Together, these factors predict a future increase in the incidence of oligometastatic disease. The limited number of detectable metastases in a particular patient, questions the common use of systemic agents based on an assumption of widespread undetected micrometastases. Indeed, many surgical series report promising long-term outcomes for selected patients undergoing resection of limited metastatic deposits from colorectal cancer (CRC),[89-92] sarcoma,[93, 94] non–small cell lung cancer (NSCLC),[95, 96] and renal cell carcinoma (RCC).[97] Likewise, aggressive surgical treatment of metastatic sites, including solitary brain metastases[98] and malignant spinal cord compression,[99] has resulted in improved survival in randomized clinical trials.

The rapid evolution of SBRT, as noted above, has established it as a noninvasive, effective and well-tolerated metastasis-directed therapy alternative to surgical resection or other invasive ablative techniques, such as RFA. SBRT may be particularly useful in patients who are not medically fit for surgery or who are not technically resectable, as well as those who are not candidates for systemic therapy. It is likely not useful in patients with widespread metastatic disease, those with very large metastases, or those with rapidly progressive disease.

Many of the early clinical experiences with SBRT included patients with oligometastatic disease. Blomgren et al described the results from SBRT including 31 patients with 42 metastatic lesions, demonstrating an 80% crude rate of local control following SBRT.[40] Similarly, Uematsu et al reported local progression in only 2 of 66 lung tumors treated with SBRT, a majority of which were metastatic lesions.[100] These early results were confirmed in multi-institutional studies of SBRT for liver[58] and lung[101] metastases showing 2-year local control rates of 92% and 96%, respectively. In addition, SBRT has been used to treat patients with limited multiorgan metastases.[102-104] Few reports have attempted to integrate SBRT and systemic therapies for oligometastatic patients, although a phase 1/2 study reported that 37.5 mg of sunitinib given concurrently with ten 5-Gy doses of SBRT was well tolerated.[102]

Typically, SBRT studies for oligometastases focus on delivering radiation to specific anatomic sites of metastasis (eg, lung or liver). These studies suggest that SBRT is efficacious and safe of with regard to physical treatment delivery, anatomic localization, and optimal dose, though interpretation is complicated by the diversity of histologies treated.[58, 101, 105-108] This knowledge is now being applied in an individualized approach to the interdisciplinary care of specific oligometastatic diseases, summarized in Table 1. For example, inoperable oligometastatic colorectal cancer patients have been treated with SBRT[54, 59, 109, 110] with promising metastasis control (53%-86%) and evidence of long-term survival. Several institutions have reported the use of SBRT to all known sites of disease in patients with oligometastatic non–small-cell lung cancer.[111-115] For example, one study reports that SBRT to up to 5 metastatic lesions resulted in a 53% 1.5-year overall survival.[113] Interestingly, patients with breast cancer oligometastases may have distinctly better outcomes as reported in a study of 40 patients with 5 or fewer metastases treated with SBRT achieving 59% overall survival and 89% local control at 4 years.[116] For prostate cancer, SBRT for limited bone metastases is well tolerated with a > 90% local control rate,[117] and in select cases of nodal relapse, SBRT may lead to prolonged PSA control without androgen suppression.[118] Furthermore, SBRT may provide local control in tumors considered to be relatively radioresistant. Patients with oligometastatic renal cell carcinoma, melanoma, and sarcoma treated with SBRT had local control ranging from 82% to 91%.[119-121] This disease-specific approach aims to translate the technical benefits of SBRT into meaningful improvements in outcomes for patients with a particular disease.

Table 1. Stereotactic Body Radiotherapy (SBRT) for Oligometastatic Disease
SBRT TrialMedian Metastases/Patient (Range)Total Dose/No. of FractionsMedian Follow-Up, Months (range)Metastasis ControlOverall SurvivalGrade 3+ Toxicity
  1. a

    Crude rate

  2. b

    surviving breast cancer patients

  3. c

    melanoma and renal cell

  4. d

    approximate.

  5. Abbreviations: fx, number of fractions of radiation; NA, not applicable; NR, not reported.

Multi-Histology
Mt. Sinai, USA[102] (n = 21)1 (1-5)40-60 Gy/10 fx10 (2-18)1-year: 85%1-year: 75%NA
Univ. of Rochester, USA[106] (n = 121)2 (1-5)50 Gy/10 fx85 (55-125)b2-year: 67%4-year: 28%1%a
Univ. of Chicago, USA[107] (n = 61)2 (1-5)24-48 Gy/3 fx21 (3-61)2-year: 53%2-year: 57%10%a
Colorectal Cancer
Arhus Univ., Sweden[54] (n = 64; m = 141)2 (1-6)45 Gy/3 fx52 (2-76)2-year: 86%4-year: 13%55%a
Erasmus Univ., Netherlands[59] (n = 20)1 (1-3)37.5-45 Gy/3 fx26 (6-57)2-year: 74%2-year: 83%10%a
Stanford (pooled analysis), USA[109] (n = 65)1 (1-4)22-60 Gy/1-6 fx14 (4-62)1-year: 67%1-year: 72%6%a
Korea Cancer Center Hospital[110] (n = 13)1 (1-3)39-51 Gy/3 fx28 (15-57)3-year: 53%3-year: 65%0%
Non–Small Cell Lung Cancer
Univ. of Rochester, USA[111] (n = 38)(1-8)50-60 Gy/5-10 fx13.5 (1-87)NR5-year: 14%NR
Univ. of Chicago, USA[113] (n = 25)2 (1-5)24-50 Gy/3-10 fx141.5-year: 71%1.5-year: 53%NR
Breast Cancer
Univ. of Rochester, USA[116] (n = 40)2 (1-4)40-60 Gy/10 fxNR4-year: 89%4-year: 59%NR
Prostate Cancer
Ludwig-Maximilians Univ., Germany[117] (n = 44)1 (1-2)20 Gy/1 fx14 (3-48)1-year: 96%1.5-year: 75%0%
Milan, Italy[136] (n = 19)1 (1)33-36 Gy/3 fx17 (3-35)100%NR8%
Univ. of Firenze, Italy[118] (n = 25)NR30 Gy/3 fx29 (14-48)3-year: 90%3-year: 92%0%
Renal Cell Carcinoma
Univ. of Chicago, USA[120] (n=18)2 (1-7)24-48 Gy/3 fx 50 Gy/10 fx212-year: 91%2-year: 85%0%
Univ. of Colorado, USA[121] (N = 13)2 (1-3)40-50 Gy/5 fx 42-60/3 fx28 (4-68)1.5-year: 88%c1.5-year: 60%d7%a
Methodist Hospital, USA[137] (n = 14)NR24-40 Gy/3-6 fx987%aNR0%
Karolinska Inst., Sweden[138] (n = 50)(1-4)32-45 Gy/4-5 fx37 (7-80)90%a2-year: 60%d33%a d
Melanoma
Univ. of Colorado, USA[121] (N = 17)2 (1-3)40-50 Gy/5 fx 42-60/3 fx28 (4-68)1.5-year: 88%c1.5-year: 60%d7%a
Sarcoma
Univ. of Rochester, USA[119] (n = 14)4 (1-16)50 Gy/10 fx11 (4-88)3-year: 82%2-year 45%d0%

Prospective studies are underway to define the role of SBRT in the overall treatment of patients with oligometastatic disease. The SABR-COMET study is randomizing patients with 1 to 5 metastatic lesions to standard-of-care therapy with or without SBRT to all metastases. The primary endpoint is overall survival; secondary endpoints include quality of life, toxicity, progression free survival, and the effect of SBRT on subsequent chemotherapy. Also in development is RTOG 1311, a phase 1 dose escalation study for breast, lung, or prostate oligometastases attempting to determine the optimal SBRT dose scheme for patients with 2 to 4 metastases and those with metastases in close proximity. In addition, RTOG 1312 will randomize patients with 1 to 2 breast cancer metastases to standard of care with or without metastasis-directed SBRT or surgery.

Other Clinical Applications

In addition to the above situations, SBRT is being evaluated for prostate,[122-124] breast,[125, 126] and other cancers. SBRT should not be employed for palliative treatment of bone metastases,[127, 128] except in the selective treatment of osseous spine lesions, described above.

FUTURE EFFORTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. TECHNIQUE AND TECHNOLOGY
  5. CLINICAL APPLICATIONS
  6. FUTURE EFFORTS
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Although SBRT appears to offer high rates of local control with minimal morbdity, it is essential to execute the multi-instutional clinical trials described above in order to establish the clinical efficacy and long-term morbidity of this technique. QUANTEC[129, 130] (quantitative analysis of normal tissue effects in the clinic), a joint task force of the American Association of Physicists in Medicine and the American Society of Radiation Oncology, attempted to establish the dose-volume-toxicity relationship for various organ systems in SBRT but was limited by the lack of long-term clinical data. Since the original articles were published in 2011, a great deal of additional data on SBRT has emerged, and the task force has been re-established to model and estimate both clinical tumor control probability and normal tissue complications specifically for intracranial radiosurgery and SBRT. The results from this effort are expected to be published in late 2014.

As experience with SBRT continues to grow, it will be beneficial to elucidate the radiobiology of SBRT and the effect of SBRT combined with other modalities, such as chemotherapy and biologics. In particular, the apparent effectiveness of SBRT in controlling radioresistant tumors leads to speculation that factors limiting the efficacy of conventionally fractionated radiotherapy (e.g., hypoxia and innate radiation resistance of tumor stem cells) may be overcome at high doses per fraction.[80] Exploiting this feature of SBRT would benefit from an understanding of the underlying molecular and microenvironmental mechanisms. As another example, the hypothesis-generating study by Formenti indicates that antigen presentation may be enhanced by SBRT and potentially synergize with immunotherapy.[131] This suggests a potential role for radiotherapy as a sensitizer for systemic therapy.

The relative cost-effectiveness of SBRT is an issue.[132-135] Clearly, the conclusion depends on the technique to which is SBRT is compared. For example, in spinal SBRT a single 8-Gy fraction delivered via 2 opposed fields will clearly have a lower treatment cost than SBRT. Conversely, a 3-fraction course of SBRT to a lung lesion may be less costly than surgical resction or a 6-week course of 3D-CRT. Any analysis must also consider the efficacy of treatment, therapy-related morbidities and the need for additional treament and surveillance of recurrent disease, as well as the impact on quality of life. The relative cost-effectiveness will also depend on the disease site, tumor type, and patient subpopulation. Because SBRT is a novel, technologically sophisticated, logistically favorable and conceptually attractive technique, quantitative economic analyses are essential to aid patients, practitioners and payors make appropriate and objective decisions regarding SBRT.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. TECHNIQUE AND TECHNOLOGY
  5. CLINICAL APPLICATIONS
  6. FUTURE EFFORTS
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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