The success of brain radiosurgery pioneered by Swedish neurosurgeon Lars Leksell 1 forms the basis of SBRT. Leksell not only developed what would become the modern day Gamma Knife, he departed from the current practice of the time to deliver radiation in a protracted fractionation schedule. With the newly developed technology, large dose-per-fraction treatments given in a single treatment at dose levels that would have historically resulted in considerable calamity were able to be routinely
delivered in the dose intolerant brain. The new treatment conduct went to great lengths to avoid prescription level dose to normal tissues. Whatever normal tissue was included, either by being adjacent to the target or by inferior dosimetry, was likely damaged. However, if this damaged tissue was small in volume or noneloquent, the patient did not suffer clinically apparent toxicity, even as a late event. On the other hand, it is undeniable that the large dose-per-fraction treatments are biologically extremely potent by overwhelming repair mechanisms.¹⁹ Targeted tumors are disabled and toxicity is avoided by simply missing most normal tissue.

Hamilton et al.²⁰ performed the earliest examples of treatments mimicking the stereotactic radiosurgery (SRS) treatments outside of the brain. These treatments employed the same rigid immobilization principles of SRS in the spine by screwing a frame to the spinous processes. Although reports were encouraging, the conduct of the treatment was not as gratifying as natural and inherent motion confounded accuracy. The brain can be practically immobilized by immobilizing the skull. Once the skull is immobilized, targets within the brain have very little additional movement. Such is not the case outside of the skull. Tumors in the body may be displaced as a function of time by forces exerted by muscle contraction, breathing, gastrointestinal peristalsis, cardiac activity, and many other important physiological processes. It is not possible to eliminate or account for all of these forces. As a result, SBRT is inherently less accurate than SRS.

As with the Gamma Knife, researchers again from Sweden, Ingmar Lax and Henric Blomgren, set out to overcome these problems by constructing a body frame that would both comfortably immobilize the patients torso as well as dampen the internal motion relating to respiration.²¹,²² Subsequently, they treated patients with localized tumors using dosimetry plans that mimicked SRS.²³ The dosimetry was constructed using multiple noncoplanar beams with aperture dimensions on the order of the target dimensions. Each of the many beams carried relatively lower weight than with CFRT such that the target dose at the convergence could be dramatically escalated. Blomgren and Lax treated patients with mostly metastases initially. Local tumor control was better than expected, leading them to treat more limited stage cancer patients. Blomgren et al.²⁴ shared their results via publications and eventually trained others in this new technique.

Meanwhile, investigators from Japan were exploring radiosurgery-like treatments in the chest. Shirato et al.²⁵ pioneered investigation into characterization and accounting of respiratory motion. Initially, they used CFRT dose schedules, but the understanding of target motion control was very important for the ultimate feasibility of SBRT, as it currently exists. Uematsu et al.²⁶,²⁷,²⁸ again from Japan worked in the early 1990s on developing technologies for delivering multiple focused beams of radiation for extracranial targets. In addition, Uematsu’s group treated patients with lung tumors primarily from primary non—small cell cancer.

Prospective testing of SBRT began with acquisition of the technology by the groups from the University of Heidelberg, University of Wurzburg, Kyoto University, and Indiana University.¹¹,¹⁴,²⁹,³⁰ Initially, dose-escalation toxicity studies were carried out in the liver and lung trying to find the most potent dose schedules for typically radioresistant primary and metastatic tumors. These prospective trials have been reported but are still maturing and will add a wealth of understanding for the use of SBRT. It is already clear that local tumor control will be higher with SBRT than has been observed with CFRT. SBRT is now a standard treatment for patients with peripheral tumors from early stage lung cancer with simultaneous medical problems precluding surgery. However, toxicity from large dose-per-fraction radiation schedules often appears quite “late” from time of treatment. Therefore, the total impact of treatment, good and bad, will require many years of follow-up to fully appreciate.

SBRT is best defined by its conduct. The proper performance of SBRT requires a team approach to carry out the following tasks³¹:

A working group from the American College of Radiology and American Society for Therapeutic Radiology and Oncology had formulated guidelines for the conduct of SBRT.⁸ In general, SBRT is used to treat well-demarcated visible gross disease up to 5 to 7 cm in dimension. It is not used for prophylactic (adjuvant) treatment, as the intent is to totally disrupt clonogenicity and likely disrupt all cellular functioning of the target tissues (i.e., the definition of an ablative therapy).³²,³³,³⁴,³⁵,³⁶

Tissues exposed to the prescription dose level or nearby are likely to be ablated. Such a treatment, properly directed would constitute a most potent form of cancer therapy. In turn, if misdirected or used too liberally, SBRT could lead to debilitating toxicity. At any rate, SBRT is very different from conventionally fractionated radiation therapy (CFRT) in its conduct, toxicity, and ability to control cancer. To this end, it is clear that all forms of radiotherapy do not constitute a black box.

Treatment plans are generally static with no specific accounting of motion that is typical in the treated patients. Still, the geometry and dose distribution from the radiation therapy treatment plan should be a reasonably true characterization of what is actually delivered to the patient. With the typical large volume of treatment and homogeneous dose-distributions characteristic of CFRT, such an emphasis on the proper correlation of the treatment plan and actual treatment is probably not so critical. However, for SBRT, claims regarding accuracy of equipment, quality of dose distributions, and dose tolerance should not be made based on the virtual computer simulation of the treatment plan; rather, on actual delivery of dose to treated patients. This is particularly true for predicting normal-tissue toxicity from SBRT where both heterogeneous dose and differential volume effects may equally affect outcome.

Although there is a general fascination within the radiotherapy community for electronic or sophisticated mechanical solutions to motion, passive immobilization can be extremely effective. Body frames, vacuum pillows, thermal plastic restraints, and other equipment have been used to try to achieve relocalization similar to the position of simulation,²²,³⁷,³⁸,³⁹,⁴⁰,⁴¹,⁴²,⁴³,⁴⁴,⁴⁵,⁴⁶,⁴⁷,⁴⁸,⁴⁹ Other systems will effectively relocate a reference position within the patient prior to each treatment, without the aid of frames or other immobilization devices (i.e., “frameless” systems).²⁷,⁵⁰,⁵¹,⁵² Both approaches have advantages and disadvantages, and no clearly superior method has been identified in clinical practice. In the end, it is most critical to be practical. SBRT treatment sessions are longer than CFRT sessions. Hence, it is important that the positioning system be comfortable and avoids awkward positions or positions fighting against gravity. In addition, the system employed must be properly utilized. As such, staff training and properly administered quality assurance programs are more essential than using a particular brand of equipment.

To minimize treatment margins for coverage, tumor (and normal tissue) motion must be characterized, controlled, or compensated. Motion control accounting approaches fall into three general categories: (a) dampening, (b) gating, and (c) chasing. Within the category of dampening includes the systems of abdominal compression aimed at decreasing one of the largest contributors to respiratory motion related to the diaphragm.²²,⁴¹,⁴⁴,⁴⁵,⁴⁶,⁴⁹ Also included in this category are the systems employing breath-hold maneuvers to “freeze” the tumor in a reproducible stage of the respiratory cycle (e.g., deep inspiration).⁵³,⁵⁴,⁵⁵,⁵⁶ Gating systems follow the respiratory cycle using a surrogate and employ an electronic beam activation trigger, allowing irradiation to only occur during a specific segment (e.g., end expiration).⁵⁰,⁵⁷,⁵⁸,⁵⁹ Tracking systems literally move the radiation beam along the same path as the tumor from the beam’s eye view.²⁵,⁶⁰,⁶¹,⁶²,⁶³ Tracking may be accomplished by moving the entire accelerator, the aperture (e.g., with the multileaf collimator), or moving the patient on the couch counter to the motion of the tumor. In the case of gating and breath hold, the beam is triggered on and off, constituting a duty cycle avoided by the other systems. In any case, the acquisition of planning information must include the same consideration for motion accounting as the treatment to achieve accuracy. Despite available motion control equipment, some uncertainty continues to require that planning treatment volume (PTV) is larger than gross tumor volume (GTV). In general, for typical dose prescriptions, this enlargement should not be greater than 1.0 cm in the cranial caudal plane and 0.5 cm in the axial plane.

Tumor Biology The cell survival curve (logarithm of surviving fraction vs. dose) after exposure to sparsely ionizing radiation, such as photons and gamma rays, follows a characteristic shape starting with a curving portion called the “shoulder” and then becoming linear with increasing dose. With CFRT, daily treatment is given on the shoulder of the survival curve (daily dose range of 1.5 to 3.0 Gy), where cells are able to repair some of the inflicted damage. The survival data in this region can be mathematically “fit” by a second order polynomial to give a simple functional representation. The predictive model related to is called the linear-quadratic (LQ) model.⁶⁴,⁶⁵,⁶⁶ Although this formula had served the field of radiobiology quite well for decades, several authors have pointed out that this formalism is not applicable in the range of high doses applied with SBRT.⁶⁷,⁶⁸,⁶⁹ In effect, the LQ model grossly overestimates the potency of treatment for daily dose delivery beyond the shoulder (i.e., 6 to 8 Gy for most tumor cell lines) caused by erroneous extrapolation outside the area of fit. Guerrero and Li⁶⁹ have proposed modifying the LQ formula by incorporating features of the so-called lethal-potentially lethal (LPL) model. The LPL model differs from the LQ model primarily insofar as it accounts for ongoing radiation repair processes that occur during the radiation exposure. Marks⁶⁸ and Park et al.⁶⁷ have borrowed formalism from the older multitarget model⁷⁰ to determine a “single fraction equivalent dose” for hypofractionated treatments with daily dose levels greater than 7 to 10 Gy that avoids any use whatsoever of the erroneous LQ model. The net result of more appropriate estimation from tumor cell kill models is a substantial difference in the predicted tumor cell kill at SBRT-level doses. For example, for a dose of approximately 20 Gy, the LQ
model would erroneously predict several orders of magnitude greater cell kill than the LPL model.⁶⁹