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. 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). 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.
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.
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. 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. 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.
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. 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. In the early 1990s, Blomgren and colleagues first reported the use of an extracranial body frame to deliver high-dose radiotherapy to the liver. 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]
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. 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. 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 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.
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 although results appear dose-dependent, vary by extent of pretreatment and primary tumor site. 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%. 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.
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. 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.
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.
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.
The oligometastatic patient, as originally proposed by Hellman and Weichselbaum, describes a unique phenotype of detectable metastases limited in number and location, suggesting a different biology than the polymetastatic patient, who exhibits widespread metastases. 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). Likewise, aggressive surgical treatment of metastatic sites, including solitary brain metastases and malignant spinal cord compression, 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. Similarly, Uematsu et al reported local progression in only 2 of 66 lung tumors treated with SBRT, a majority of which were metastatic lesions. These early results were confirmed in multi-institutional studies of SBRT for liver and lung 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.
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. 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. For prostate cancer, SBRT for limited bone metastases is well tolerated with a > 90% local control rate, and in select cases of nodal relapse, SBRT may lead to prolonged PSA control without androgen suppression. 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 Trial||Median Metastases/Patient (Range)||Total Dose/No. of Fractions||Median Follow-Up, Months (range)||Metastasis Control||Overall Survival||Grade 3+ Toxicity|
|Mt. Sinai, USA (n = 21)||1 (1-5)||40-60 Gy/10 fx||10 (2-18)||1-year: 85%||1-year: 75%||NA|
|Univ. of Rochester, USA (n = 121)||2 (1-5)||50 Gy/10 fx||85 (55-125)b||2-year: 67%||4-year: 28%||1%a|
|Univ. of Chicago, USA (n = 61)||2 (1-5)||24-48 Gy/3 fx||21 (3-61)||2-year: 53%||2-year: 57%||10%a|
|Arhus Univ., Sweden (n = 64; m = 141)||2 (1-6)||45 Gy/3 fx||52 (2-76)||2-year: 86%||4-year: 13%||55%a|
|Erasmus Univ., Netherlands (n = 20)||1 (1-3)||37.5-45 Gy/3 fx||26 (6-57)||2-year: 74%||2-year: 83%||10%a|
|Stanford (pooled analysis), USA (n = 65)||1 (1-4)||22-60 Gy/1-6 fx||14 (4-62)||1-year: 67%||1-year: 72%||6%a|
|Korea Cancer Center Hospital (n = 13)||1 (1-3)||39-51 Gy/3 fx||28 (15-57)||3-year: 53%||3-year: 65%||0%|
|Non–Small Cell Lung Cancer|
|Univ. of Rochester, USA (n = 38)||(1-8)||50-60 Gy/5-10 fx||13.5 (1-87)||NR||5-year: 14%||NR|
|Univ. of Chicago, USA (n = 25)||2 (1-5)||24-50 Gy/3-10 fx||14||1.5-year: 71%||1.5-year: 53%||NR|
|Univ. of Rochester, USA (n = 40)||2 (1-4)||40-60 Gy/10 fx||NR||4-year: 89%||4-year: 59%||NR|
|Ludwig-Maximilians Univ., Germany (n = 44)||1 (1-2)||20 Gy/1 fx||14 (3-48)||1-year: 96%||1.5-year: 75%||0%|
|Milan, Italy (n = 19)||1 (1)||33-36 Gy/3 fx||17 (3-35)||100%||NR||8%|
|Univ. of Firenze, Italy (n = 25)||NR||30 Gy/3 fx||29 (14-48)||3-year: 90%||3-year: 92%||0%|
|Renal Cell Carcinoma|
|Univ. of Chicago, USA (n=18)||2 (1-7)||24-48 Gy/3 fx 50 Gy/10 fx||21||2-year: 91%||2-year: 85%||0%|
|Univ. of Colorado, USA (N = 13)||2 (1-3)||40-50 Gy/5 fx 42-60/3 fx||28 (4-68)||1.5-year: 88%c||1.5-year: 60%d||7%a|
|Methodist Hospital, USA (n = 14)||NR||24-40 Gy/3-6 fx||9||87%a||NR||0%|
|Karolinska Inst., Sweden (n = 50)||(1-4)||32-45 Gy/4-5 fx||37 (7-80)||90%a||2-year: 60%d||33%a d|
|Univ. of Colorado, USA (N = 17)||2 (1-3)||40-50 Gy/5 fx 42-60/3 fx||28 (4-68)||1.5-year: 88%c||1.5-year: 60%d||7%a|
|Univ. of Rochester, USA (n = 14)||4 (1-16)||50 Gy/10 fx||11 (4-88)||3-year: 82%||2-year 45%d||0%|
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.