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 moderated sized tumors in extracranial sites in either a single or limited number of dose fractions.

Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) have been successfully used for intracranial, orbital, and base of skull tumors, as well as benign conditions that can use the skull as a reference system. Extension of these approaches to extracranial sites has required significant technical advances in the use of tumor imaging to guide radiation administration, patient immobilization, and conformal radiation delivery techniques.

The term stereotactic body radiotherapy has been adopted by the Centers of Medicare and Medicaid Services. Although the term stereotactic implies the use of an external frame of reference, not all of the approaches require an external stereotactic localization method. Other names that have been applied to this approach include extracranial radiosurgery and extracranial radiotherapy.

The rationale for SBRT, its techniques, and early results in selected tumors will be reviewed here.

RATIONALE — Radiation therapy (RT) requires a balance between cytotoxicity to a tumor and the adjacent normal tissue. Conventional external beam RT encompasses the tumor as well as a significant margin of normal tissue to avoid missing any part of the tumor and to maximize the likelihood of a favorable therapeutic outcome. Technical factors that necessitate irradiation of a margin of normal tissue include limited accuracy in delineating the tumor target, organ movement due to respiration, and variation in patient positioning from one treatment to the next.

There is a strong biologic rationale for dose fractionation if normal tissue is irradiated along with tumor. Radiation-induced damage is repaired more rapidly in normal tissues compared to tumor. Thus, dose fractionation increases the differential cell killing between tumor and normal tissue. In addition, multiple small fractions permits reoxygenation of the tumor between treatments, thereby helping to overcome radiation resistance due to hypoxia.

Early radiobiologic and clinical studies confirmed that dividing the total radiation dose into multiple relatively small fractions, rather than using one or a limited number of larger doses, provided better tumor control for a given level of acute and delayed toxicity. For most clinical situations, the total radiation dose is divided into daily fractions of 1.5 to 3 Gy, given over a course of several weeks.

SRS and SRT utilized multiple technical advances to deliver a single or limited number of high dose radiation fractions to an intracranial target. The decreased volume of irradiated normal tissue permits the delivery of high dose fractions. The success with SRS and SRT for intracranial indications has led to the development of new techniques to extend this approach to extracranial targets.

TECHNOLOGICAL ADVANCES — SBRT requires a high degree of precision in defining the target and administering the radiation. Technical advances have been required to minimize alterations in patient position between the initial CT simulation and treatment ("setup error"), to avoid organ motion due to respiration, and to immobilize the patient while treatment is being administered.

Examples of the approaches that are under development include the following:

• Immobilization — A custom body cast with radiopaque markers to establish a coordinate system in the three-dimensional space has been used to treat thoracic and abdominal tumors. Subsequent variations have included alternative systems for immobilization and/or positioning, the implantation of markers ("fiducials") on the skin or internally to facilitate tumor targeting, and combinations of these approaches.

• Imaging — Incorporation of a computed tomography (CT) imaging system into the linear accelerator is feasible and commercially available, and allows imaging and target position verification in the treatment position. These image-guided methods should offer better accuracy and are likely to supplant body frame based techniques in the future. Such techniques may be particularly important given the known variability of internal organ position in relation to external anatomy.

• Compensating for respiratory movement — Organ movement with respiration may be compensated for by incorporating tumor positional variation into the target volume, reducing tidal volume with abdominal compression, turning the beam on and off ("gating") in conjunction with the normal respiratory cycle, and utilizing a breath hold apparatus during beam on time.

Application of these techniques for irradiating specific body sites include the following:

• A rigid fixation technique has been used in patients receiving spinal irradiation. The patient lies prone in a rigid box and a clamp is fixed on the surgically exposed spinous processes above and below the target areas. Coordinates of the target relative to the clamps are acquired by CT and the box is transferred to the treatment table and aligned using lasers.

• A lung SBRT system takes advantage of a gold marker placed in the airway as a reference marker. This marker is continuously imaged with fluoroscopy during treatment, and the delivery of radiation is limited (gated) to the intervals when the marker falls into a predetermined spatial range.

• A frameless technique to treat metastatic lesions in the liver incorporates a CT scanner, an x-ray simulator, and a linear accelerator. Lipiodol is injected via transcatheter arterial chemoembolization and serves as a radio opaque marker. Supplemental oxygen and a constricting belt around the abdomen are used to limit respiratory movement. This allows both imaging and treatment without moving the patient off the treatment couch, thus minimizing any setup error.

CLINICAL EXPERIENCE — Early results suggest that SBRT offers important advantages in a number of settings. The technology is evolving rapidly, and the optimal dose, schedule and technique remain to be determined.

Lung tumors

NSCLC — Although surgical resection is the preferred approach for patients with early stage primary non-small cell lung cancer (NSCLC), RT is used in patients who are not candidates for surgery. Previous experience with conventional external beam RT showed that control of the primary lesion is directly related to the dose of radiation, suggesting that higher doses might offer better local control.

SBRT has been extensively evaluated in patients with early stage primary non-small cell lung cancer (NSCLC). SBRT dosing is influenced by a number of parameters, including the size of the tumor and the number of fractions, and the optimal dose and fractionation schedule is not yet known.

In the largest reported experience, 300 patients with stage I NSCLC were treated at multiple institutions with varying doses and schedules, ranging from 18 to 75 Gy in 1 to 22 fractions. The rate of local recurrence was 15 percent, and a dose response relationship was found for a biological equivalent dose (BED) 100 Gy versus <100 Gy (recurrence rate, 14 versus 33 percent). Among medically operable patients, five-year survival was significantly higher in those treated with BED 100 Gy (74 versus 37 percent, compared to a BED <100 Gy).

Lung metastases — Carefully selected patients with lung metastases may benefit from treatment with SBRT. The rationale for this approach comes from surgical observations that complete resection, if achievable, can prolong survival. In a series of over 5200 patients with pulmonary metastases, complete surgical resection was successful in 88 percent; these patients had a 36 percent survival at five years and 26 percent at ten years

Several of the SBRT studies for early stage primary NSCLC included patients with lung metastases . Dose fractionation schemes and techniques employed were similar to those for primary lung tumors, and control rates range from 66 to 100 percent with acceptable toxicity.

Toxicity — Although direct comparisons are not possible, use of detailed modeling suggests that the doses used with SBRT are biologically equal to or greater than those with conventional fractionated RT, and SBRT has generally been associated with an acceptable toxicity profile.

The lung parenchyma generally tolerates the high fractional and total doses used in SBRT. Although radiographic evidence of asymptomatic radiation pneumonitis and radiation fibrosis have been identified in more than 60 percent of cases in most series, symptomatic or disabling pneumonitis is rare. Despite this, pulmonary function studies have not found a decline in FEV1 or DLCO values following therapy. Total lung capacity, vital capacity, and forced expiratory volume were unchanged one year after SBRT, while carbon monoxide diffusion capacity improved in patients who had been heavy smokers prior to treatment.

Other thoracic tissues may be more sensitive than lung parenchyma. Reported complications have included bronchial stenosis, rib fracture or chest wall pain, esophageal ulceration or perforation, and pulmonary artery bleeding

Treatment of lesions in the perihilar and mediastinal region has been associated with an increased risk of serious toxicity compared to peripheral lesions. In a series of 70 patients with stage I NSCLC treated with a total of 60 to 66 Gy in three fractions, the two-year incidence of severe toxicity was higher in patients with central lesions (46 versus 17 percent in those with peripheral lesions.

Liver metastases and primary hepatocellular cancer — Most patients with hepatic metastases have a substantial disease burden in the liver and at other sites. However, in those with a limited number of isolated hepatic metastases, surgery can be associated with long-term benefit.

This approach is most often considered for patients with isolated liver metastases from colorectal cancer or gastroenteropancreatic neuroendocrine tumors (eg, carcinoid tumors). For patients with a limited number of isolated liver metastases from colorectal cancer, the five-year relapse-free survival rates following hepatic resection average 30 percent.

Patients undergoing hepatic metastasectomy must be medically fit, have disease limited to the liver, and adequate reserve of normal liver parenchyma. As a result, only a small fraction of patients are eligible for hepatic resection although, at least in the case of colorectal cancer liver metastases, the use of neoadjuvant or downstaging chemotherapy may increase the number of eligible candidates.

Some patients with liver metastases who are poor candidates for surgery may benefit from nonsurgical alternatives such as SBRT. SBRT offers an ideal approach to minimize radiation to normal liver, while increasing the dose to the tumor. Normal liver function can be maintained as long as there is a sufficient volume of normal tissue remaining. The risk of hepatic injury due to radiation is a function of both the volume of liver irradiated and the dose of radiation administered. Techniques such as three dimensional conformal RT have been used to limit the volume of liver irradiated, thereby permitting dose escalation.

Several studies have evaluated the feasibility of treating liver metastases. Two studies, using different treatment approaches, illustrate the potential value of SBRT in this setting:

• A prospective, multicenter phase I/II study involving 36 patients, found that 60 Gy in three fractions over 3 to 14 days was well tolerated. For the 28 lesions treated at this dose level, the actuarial local control rate was 93 percent.

• In another series, 174 metastases were treated in 69 patients. The preferred schedule was 50 Gy in five fractions over two weeks, but was varied if necessary based upon normal tissue radiation exposure. The most common primary tumors in these patients were colorectal (20), breast (16), pancreas (9), and lung (5). Liver metastases were either the only site of metastatic disease or were thought to be life-limiting. Local disease control with SBRT at 10 and 20 months was 76 and 57 percent, respectively, and the median overall survival was 14.5 months.

The role of SBRT in patients with potentially resectable colorectal cancer liver metastases compared to surgical resection remains to be determined.

Experience with SBRT for primary liver tumors is limited but increasing. Hepatocellular carcinoma (HCC) is frequently multifocal and often develops in a cirrhotic liver, which may be more sensitive to radiation injury. However, the limited experience to date with SBRT for HCC suggests that it is safe and associated with favorable short-term results.

The approach seems most applicable to patients with relatively small HCCs who are either inoperable or who refuse operation. Whether SBRT is a more effective or less toxic approach than radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI) in these patients will require a randomized trial.

Distinguishing reactive changes in normal hepatic parenchyma from recurrent or residual tumor can be difficult following SBRT. Serial evaluation by CT and the use of positron emission tomography (PET) may help determine whether residual tumor is present.

Pancreatic tumors — Conventional RT plus concomitant chemotherapy with infusional 5-fluorouracil provides a modest survival benefit compared to supportive care alone. Other techniques, such as intraoperative radiotherapy or radioactive seed implantation, have been used to increase the dose to the tumor. Although local control appears to be enhanced with these approaches, survival is limited by the development of distant metastases.

SBRT has been explored as an alternative approach to managing locally advanced disease, but possible benefit from SBRT remains uncertain:

• After a phase I study demonstrated that a single treatment with 25 Gy could be safely administered, 16 patients received a boost with SBRT following concurrent 5 fluorouracil and conventionally fractionated intensity modulated RT to 45 Gy. All but one patient were free of local progression until death, and the median survival was 33 weeks. Toxicity included grade 3 gastroparesis requiring parenteral support and the delayed development of symptomatic duodenal ulcers.

• Less promising results were seen in a report in which 22 patients with locally advanced, unresectable pancreatic cancer were treated with SBRT (45 Gy divided into three doses of 15 Gy over five to ten days). Acute toxicity was pronounced, with deterioration of performance status, nausea, and increased pain seen at 14 days. Four patients developed severe gastric mucositis or ulceration and one patient had a nonfatal stomach perforation. Six patients developed local tumor progression, and median survival was six months .

Other abdominal tumors — SBRT has been used in a variety of other abdominal and pelvic tumors, generally as a boost following conventional RT . Additional experience is required to determine its utility in different indications, the optimal dose and schedule, and toxicity.

Examples of potential applications include the following:

• Nine patients with nonmetastatic renal cell carcinoma were treated with SBRT using a body frame to doses of 40 Gy in 5 fractions . At a median follow-up of 27 months, four patients remain alive. There was one local failure in a patient with bilateral disease who developed a new primary in an unirradiated portion of the kidney four years after the initial treatment.

• A boost with SBRT was evaluated in 14 patients with endometrial or cervical cancer, either as an alternative to brachytherapy or to treat a local relapse. At a median follow-up of 12 months, only one patient with cervical cancer had developed a pelvic recurrence, which was salvaged surgically. Late rectal bleeding was seen in one patient 18 months after reirradiation for a vaginal vault relapse; the patient had received 55 Gy of fractionated RT prior to SBRT.

Spinal and paraspinal tumors — RT for spinal and paraspinal tumors is limited by the sensitivity of spinal cord to radiation injury and the seriousness of radiation myelopathy. The precision with which SBRT delivers radiation to tumors while sparing normal tissues, the availability of readily visualizable bony structures as landmarks, and the lack of respiratory motion make SBRT an attractive approach for these tumors.

The accuracy of positioning the lesion in the radiation beam has been addressed with multiple techniques, including the use of a body frame with daily CT imaging, fiducial markers implanted into spinous processes, combining CT imaging into the linear accelerator units, and orthogonal x-ray imagers combined with a stereotactic infrared marker array.

A variety of fractionation schemes have been used with doses ranging from 6 to 30 Gy in 1 to 5 fractions. Using these techniques and prior knowledge of the radiation tolerance of the spinal cord, early experience with spinal SBRT has avoided significant radiation toxicity.

The results with this approach are illustrated by a prospective cohort of 393 patients with 500 histologically verified spinal metastases. Using a tumor dose of 12.5 to 25 Gy, pain management and tumor control were successfully achieved in 86 and 90 percent of cases, respectively. Of those with progressive neurologic deficit prior to treatment, 27 of 32 (84 percent) had clinical improvement. SBRT may have a particularly important role in patients who require retreatment for previously irradiated malignant spinal cord compression.

CONCLUSIONS — High dose fractions of radiation precisely administered using a stereotactic frame of reference have been used successfully for multiple cranial indications. With further technical advances, this approach is now being evaluated in the management of tumors at a variety of extracranial sites.

The technology to precisely define radiation fields, accommodate organ movement, and avoid irradiation of normal tissues is rapidly evolving and clinical results should improve over time. Although the optimal technique, dose, and fractionation schemes are not yet defined, initial results suggest that SBRT will be useful in selected situations, including patients with spinal lesions and early stage non-small cell lung cancer who are not surgical candidates. Long term follow-up is needed to confirm the preliminary positive results, since there may be an increased risk of late toxicity risk with the use of large dose fractions.