Historical Perspective on Radiosurgery

Radiosurgery was first proposed in 1951² and then clinically implemented at the University of California Berkeley cyclotron in 1954.³ The first patient was treated at the Uppsala University cyclotron facility in 1957.⁴ In comparison, the first Gamma Knife and LINAC radiosurgery treatments were delivered in 1967 and 1985, respectively.⁵ The majority of radiosurgery is currently performed with compact hospital-based LINACs or Gamma Knife units because of the significantly lower cost and complexity of these systems. Particle accelerators such as cyclotrons or synchrotrons have not been commonly adopted by hospital clinics because of the space required, cost, and necessary infrastructure to support such facilities. Today, radiosurgery programs of various modality involving the Gamma Knife (Elekta; U.S. office, Norcross, GA) number nearly 300; there are many more that use LINACs but less than a handful of proton therapy centers worldwide. Proton radiosurgery offers improved dose uniformity within large targeted volumes and reduced doses to nontarget normal tissues when compared with its photon counterparts. These benefits have created sufficient interest in the technology to motivate the construction and development of increasingly more clinical proton therapy centers.

Dose Principles: Photons and Protons

The clinical radiation dose is measured in the unit gray (Gy) and represents the energy deposited by ionization processes in material per unit mass of material (1 Gy = 1 J/kg). The energy absorbed causes damage at the molecular level in DNA and proteins that results in arrest of cell growth and death. The biologic effect of γ-rays or x-rays, which are both forms of photons, is essentially the same for given doses. Tissue responses vary with the cell type, as well as the radiation modality. The radiobiologic effectiveness (RBE) describes the equivalence between radiation modalities in terms of net biologic effects.⁶ Despite the complex dependence on many variables and the variation in RBE along the length of the proton path, a generic RBE of 1.1 for protons as compared with cobalt 60, the representative standard for photons, has been accepted in the radiation therapy community.^7–9 Thus, a 10% reduction in proton physical dose is delivered to achieve the same biologic effect on the target if treatment were given by cobalt 60 or other photon sources.¹⁰ For ease of clinical use, the biologically equivalent dose to photons is expressed in standard fashion as units of Gy with RBE weighted absorbed dose Gy(RBE).^10a

The difference in the biologic effects of radiation sources is a function of their physical properties. As a photon beam passes through material and is absorbed, the overall intensity of the beam is reduced. In contrast, particles such as protons and ions travel a finite distance, which is termed the range. They deposit a disproportionate amount of energy in the last few millimeters of their path. This large transfer of energy is known as the Bragg peak. The physical depth penetrated by the particles depends on tissue density and the beam’s energy. Figure 254-1 demonstrates the difference in dose deposition in tissue with various radiation sources. The dose deposited in the region of normal tissues leading to the target and extending beyond the target is termed the integral dose. The integral dose can be reduced by using multiple treatment beams from different directions such that a therapeutic dose is achieved at the intersection whereas the integral dose remains reasonably low. Proton radiosurgery typically uses 2 to 6 beams. Similarly, LINAC x-ray radiosurgery commonly uses 2 to 6 conformal beams or arcs of continuous radiation sweep. The Gamma Knife differs in that 201 narrow beams are used to deliver the treatment. Other modern conformal radiation therapies with photons, such as intensity-modulated radiation therapy (IMRT), achieve fairly high dose conformality at the expense of producing very large low-radiation dose baths to much of the surrounding normal tissue. Even though this dose bath may be below the clinical threshold for acute side effects, it introduces a potential risk for a significantly high rate of radiation-induced malignancies and late complications in normal tissue that are as yet poorly characterized. IMRT is widely used with fractionated radiation therapy for targets of variable size and shape. For small intracranial targets, it offers little advantage over stereotactic radiotherapy with fractionated treatment. IMRT is not typically used for stereotactic radiotherapy because of the unacceptably high surrounding dose bath to normal tissues.

FIGURE 254-1 Relative dose curves normalized at a water equivalent target center depth of 12.6 cm. The curves represent single-beam dose profiles as a function of depth for cobalt 60 γ-rays (dark red), 6-MeV x-rays (green), protons (orange), and carbon ions (purple). The region of maximum dose near the end of the range of particles such as protons and carbon is called the Bragg peak.

The indication for radiosurgery is dictated by the diagnosis; target volume, shape, location, and proximity to critical structures; and the patient’s clinical condition. Because of the high doses used in radiosurgery, it is more critical than in fractionated radiation therapy that the unavoidable dose to normal tissue be reduced by distributing the radiation into multiple beams directed from multiple incident orientations and by the use of resources such as protons, where the finite range of proton beams inherently limits the amount of excess nontarget tissue irradiation and the dose profiles are characteristically more homogeneous than with photon-based therapies. The doses most commonly used with proton radiosurgery typically range within 8 to 24 Gy (RBE).

The Original Approach: Proton Cross-Fire

When Lawrence in 1954 and Leksell in 1957 pioneered radiosurgery, they used protons as their radiation source. Rather than using the effects of the Bragg peak, they relied on the flat portion of the proton depth dose profile that precedes the Bragg peak, termed the plateau. This technique was coined “strålkniven,” or ray knives, by Leksell. The plateau region of a 340-MeV proton beam provided a sharper lateral dose falloff than did the end of the Bragg peak or the x-ray beams that were available at the time. Typical 80% to 20% lateral dose falloffs, also known as the penumbra, for 340- and 185-MeV proton beams are 1.0 mm and 2.0 mm, respectively. These falloffs serve as much sharper lateral penumbras than the 5.0-mm falloff from the end of a Bragg peak. In addition, the end of the Bragg peak has inherent uncertainties when directed through heterogeneous tissue. Lawrence and colleagues at Berkeley treated pituitary targets with multiple proton cross-fire arcs from each side of the head, with the beams being oriented to avoid dose overlap in normal tissue but intersecting at the center of the target (Fig. 254-2).¹¹ Bragg peaks occurred after exiting the patient on the contralateral side and were thus irrelevant in this early form of radiosurgery. Thirty patients were treated with protons at Berkeley from 1954 to 1957.¹² Leksell used the same cross-fire principles with a 185-MeV proton beam and achieved superior targeting precision because of the use of a stereotactic fixation device.⁴ It also permitted treatment in a single session rather than the multiple sessions used at Berkeley. The lower proton energy generated by the Uppsala cyclotron in contrast to the Berkeley facility resulted in doses with a slightly less uniform depth. From 1957 to 1976, 73 patients were treated with protons at Uppsala in similar fashion.^12,13 Subsequently, this technique was adopted by other groups with high-energy cyclotrons.¹⁴

FIGURE 254-2 Coronal and axial planes demonstrating the cross-fire approach. Angles were selected to avoid overlap of the entrance and exit paths of the high-energy protons by tilting the patient. Each of the six arcs (three right, three left) was rotated ±35 degrees in the axial plane while irradiating the patient.

The Second Approach: Proton Bragg Peak and Minimizing the Uncertainty

The team at the Harvard Cyclotron Laboratory (HCL) initiated its proton radiosurgery program in 1961.^15,16 This facility was limited to a 160-MeV proton beam that had an insufficient beam range to use the cross-fire approach, the group was the first to implement the Bragg peak as the primary therapeutic source. The purpose of this new technique was to significantly reduce the dose to normal brain tissue. Unlike the cross-fire approach, beams aimed from the vertex of the head toward the feet could be used with no downstream dose to the thorax because of the finite range of protons, which were calculated to stop within the target. The technical challenge remained the ability to precisely stop the protons at the desired location in an era before computed tomography (CT). In comparison, the beam energies needed to achieve the desired depth of penetration are currently calculated readily from CT-derived tissue densities.

Delivery of the Bragg peak to the target was enabled by a system in which a variable amount of material was placed upstream in the proton beam path to adjust its depth in patients. A telescoping column of water was used to pull the Bragg peak back to the desired depth. Calibration of each treatment beam preceded positioning of the patient in the treatment unit. Three orthogonal plain films were taken to confirm alignment before treatment.¹⁶ A complex scattering and filtering system was used to prepare the beam for clinical use. Patients were placed in a positioner that rotated a maximum of 45 degrees to either side. Fine adjustments were made to the head while a nurse manually adjusted the positioner to ensure patient comfort and safety.

Aside from some technical improvements, the multistep treatment technique of using the Bragg peak as the primary therapeutic source remains the same today. The dose is delivered by first treating the most distal segment of the target with the Bragg peak. The second peak is delivered at a shallower depth by increasing the amount of water or equivalent material within the path of the proton beam before reaching the patient. The weight or relative dose delivered with the shallower peak is reduced in comparison to the first peak because it is additive to the dose of the first peak. This process, termed “lamination” planning, is repeated to cover the target width with 90% of the maximum dose. The combined peaks are called the spread-out Bragg peak (SOBP). The width of the SOBP 90% to 90% dose is known as the modulation. Corrections are required to account for the difference in density between air, bone, brain, and other tissues. To minimize uncertainty, ports are preferentially selected so that they penetrate bone perpendicular to the surface and avoid heterogeneous regions such as sinuses, mastoids, ears, and the base of the skull, which may introduce small errors in dosimetry calculations.¹⁷ The dose profiles of proton beams also vary as a factor of field size.^17a A proportionally higher dose to the surface of tissues is delivered with smaller field sizes because of the reliance on more direct ionization as compared with the dose from scatter radiation.¹⁷ Therefore, lamination plans must be adjusted to account for the field size to generate a uniform SOBP.

In 1965, the first proton radiosurgery procedure was performed by Kjellberg for the treatment of an arteriovenous malformation (AVM). However, it was not until 1972 that the second and subsequent AVM patients would be treated by the Massachusetts General Hospital (MGH)/HCL radiosurgical group.¹⁸