Stereotactic cranial radiosurgery and radiotherapy

INTRODUCTION The potential utility of ionizing radiation to treat cancer was recognized shortly after the discovery of x-rays. The ability of radiation to kill tumor cells is thought to be derived from the induction of extensive DNA damage.

Prior to the development of stereotactic techniques, radiation was delivered to the cancer and surrounding normal tissues. Therapeutic efficacy was based upon the increased DNA-repair capacity after radiation exposure in normal cells compared to tumor cells. This fractionated treatment is known as radiation therapy (RT)

Major advances in stereotactic localization, noninvasive neuroimaging, and radiation physics made it possible to selectively irradiate a sharply defined target, largely sparing the surrounding normal tissue. This is achieved by converging multiple, non-parallel radiation beams. This approach is called stereotactic radiosurgery (SRS).

The biologic differences between fractionated RT and SRS and the technology of administering SRS are reviewed here. The application of SRS in various clinical settings (both malignant and nonmalignant) is discussed elsewhere in the topics on specific lesions, and the complications of cranial SRS and the application of SRS to extracranial sites are presented separately.

DEFINITIONS

Fractionated (conventional) RT Fractionated or conventional RT refers to the repeated administration of small doses of radiation in a relatively large target, as in whole brain RT or involved-field RT. This fractionation of the total dose minimizes damage to normal tissues and maximizes the killing of tumor cells. Conventional dose fractionation schemes for intracranial lesions typically consist of 1.8 to 2.0 Gy in daily sessions with cumulative doses of 30 to 60 Gy

Stereotactic radiosurgery SRS refers to the delivery of a single, relatively large dose of radiation administered to a small, precisely-defined target. This is achieved by using multiple, non-parallel radiation beams that converge on the target lesion. The full therapeutic dose is administered only to the area where all of the beams overlap, while nontarget areas receive much smaller doses from one or a limited number of the radiation beams. SRS requires accurate delineation of the lesion and positioning during treatment.

The SRS dose is defined by the amount of radiation given at the edge of the target lesion; this is referred to as the marginal dose. Typically, the marginal dose delivered in a single session ranges from 11 Gy (for the treatment of benign lesions) to as much as 70 Gy (for thalamotomy, in the treatment of movement disorders). The amount of radiation absorbed by tissues in adjacent nontarget areas decreases rapidly with increasing distance from the target.

Stereotactic radiotherapy SRS, in which the entire dose of RT is administered in a single session, and conventional RT (daily doses of 1.8 to 2.0 Gy delivered over 25 to 30 sessions) define the extremes of a spectrum of fractionation schemes. Hypofractionated regimens that utilize stereotactic guidance are intermediate between these two approaches and are referred to as stereotactic radiotherapy (SRT).

SRT typically involves the administration of dose fractions >2.0 Gy administered for less than 25 sessions. Clinically used SRT regimens range from weekly doses of 4 to 5 Gy with a cumulative dose of 20 Gy to doses of 8 Gy separated by eight hours summing to 24 Gy in one day. The efficacy of SRT compared to conventional RT or SRS remains to be determined.

SRT must be distinguished from multistage SRS. With SRT, the entire target volume is treated in sessions separated by hours to weeks. With multistage SRS, a different region of the target is irradiated in each session, and the sessions are separated by intervals of 3 to 12 months

RADIOBIOLOGY

Fractionated RT Small, daily fractions of radiation cumulatively damage rapidly proliferating tumor cells more than normal tissues. The theoretical framework for dose fractionation was established in the 1960s. The basic principles are often referred to as the four R's:

  • Repair Small doses of radiation cause sublethal levels of DNA damage, and normal tissues repair this damage more effectively than tumor cells do.
  • Reoxygenation Tumors often contain areas of hypoxia that cause resistance to radiation-induced cell killing. Dose fractionation can improve circulation and oxygenation within the tumor, thereby maximizing the effects of radiation.
  • Redistribution and repopulation Tumor cells proceed through the cell cycle differently from normal cells following irradiation. Most normal cells linger in the S phase of the cell cycle after exposure to radiation; during the S phase, cells are highly resistant to further damage. In contrast, tumor cells continue to proceed through the cell cycle (redistribute) and proliferate (repopulate) despite radiation exposure. Thus, the tumor cells move out of the radioresistant phase of the cell cycle and are more radiosensitive than normal cells during subsequent treatments.

Stereotactic radiosurgery SRS delivers a single, high dose of radiation to a well-defined tumor volume, rather than repeated small fractions to both cancer and normal cells. Protection of normal tissue is achieved through a progressive, steep decline in the dose outside the treatment target.

The focusing of radiation on the target results from the convergence of multiple, non-parallel beams of radiation . The dose of radiation received by the normal tissue in each path of the beam is small except where the beams converge. As an analogy, if everyone in an unlit, crowded stadium focused a flashlight on a single point, the convergence would be bright while the rest of the stadium remained relatively dark.

The prerequisites for SRS include precise delineation of the target using neuroimaging, an understanding of the neuroanatomy of the lesion, and the technology to reliably deliver radiation accurately to that lesion. The planning and administration of SRS requires close collaboration between radiation oncologists, neurosurgeons, and medical physicists.

The cellular processes triggered by a single, high-dose radiation treatment are poorly understood but appear to differ from those of fractionated RT. Impairment of DNA repair, redistribution, repopulation, and reoxygenation are less important in SRS compared to fractionated RT.

This is illustrated by clinical results from the treatment of patients with brain metastases. Whereas whole brain RT is only marginally effective for radioresistant tumors such as melanoma and renal cell carcinoma, SRS is as effective for these indications as it is in radiosensitive tumors (eg, breast cancer).

The effectiveness of SRS cannot be explained exclusively by high doses of radiation killing all the tumor cells in the lesion. Several observations support a more complex mechanism of action, possibly involving the host immune response:

  • The dose used to control cerebral metastasis (14 to 20 Gy) does not sterilize tumor cell lines in vitro. Following such irradiation in vitro, 0.01 to 1 percent of tumor cells survive, and the remaining tumor cells repopulate the tissue culture plate within days to weeks.
  • Biopsies after SRS typically reveal tumor cells, although active tumor growth is rarely observed.
  • Complete tissue destruction in vivo requires radiation doses significantly higher than those required for local tumor control. As an example, more than 70 Gy of radiation is required to achieve complete cell killing in thalamotomy for the treatment of movement disorders, whereas only 14 to 20 Gy of radiation is required to achieve local control in the treatment of cerebral metastasis
  • In patients with cerebral metastases that were resected because of CNS progression more than five months after SRS, pathology showed a moderate to intense inflammatory cell response. In contrast, when progression occurred less than five months after SRS such a response was absent or limited.

Dose homogeneity With fractionated RT, delivery of a homogeneous dose of radiation within the target volume is highly desirable. Uneven distribution of radiation doses may increase killing of tumor cells, but also may increase destruction of normal tissue. Since the goal of SRS is to treat well-circumscribed lesions with little or no normal parenchyma in the target, dose homogeneity is less critical.

CHOICE BETWEEN SRS AND FRACTIONATED RT Multiple factors influence the decision of whether to use SRS or conventional RT. These include the volume of the target lesion, its proximity to cranial nerves, and the specific area of the brain to be irradiated.

Tumor volume As the size of the target lesion for SRS increases, incidental irradiation to the surrounding normal tissue also increases. This may be important since a much higher dose of irradiation is administered with SRS compared to fractionated RT.

A dose escalation study conducted by the Radiation Therapy Oncology Group (RTOG) defined the maximally tolerated SRS dose in the treatment of cerebral metastasis as a function of tumor size. The recommended marginal doses of SRS were 24, 18, and 15 Gy for lesions less than or equal to2 cm, 2 to 3 cm, and 3 to 4 cm in the largest diameter. SRS was not recommended for lesions >4 cm because adequate control could not be achieved without an unacceptable level of radiation toxicity to surrounding normal tissue.

Proximity to cranial nerves The proximity of a target to cranial nerves can cause radiation neurotoxicity, despite the steep decrease in dose outside the intended target. Factors that increase the risk of damage to cranial nerves include previous surgery or radiation, a large volume irradiated, and a high total radiation dose. Fractionated RT should be considered when SRS may jeopardize cranial nerve function.

Cranial nerves II and VIII are more sensitive to radiation injury than the other cranial nerves. SRS is generally avoided if the maximal dose delivered to the optic nerve exceeds 10 Gy. Assessment of damage to cranial nerve VIII with SRS is difficult since it is often radiated during treatment of acoustic neuroma. In this situation, damage can be due to the tumor and/or treatment.

The proximity of target lesions to cranial nerves other than II and VIII is not a major factor in deciding between SRS and RT, since other cranial nerves are more resistant to damage:

  • Neuropathies of cranial nerves III, IV, and VI have not been reported for doses <15 Gy delivered to the cavernous sinus, while doses of 15 to 40 Gy are associated with injury in 10 to 15 percent of cases
  • Cranial nerve VII routinely receives doses of 11 to 15 Gy with SRS for acoustic neuroma, but facial neuropathy is rare (less than 1 percent in a series of 829 patients followed for 10 years)
  • SRS for jugular foramen schwannomas or skull base meningiomas has been associated with less than a 2 percent incidence of neuropathy involving cranial nerves IX, X, or XI using doses of 8 to 12 Gy

Location of the lesion The risk of developing permanent damage following SRS varies dramatically with the location of the lesion in the brain. This was illustrated by a series of 422 patients treated with SRS for arteriovenous malformations, 85 of whom (20 percent) developed significant toxicity. In a multivariate analysis, the maximum risk of neurologic complications was seen when the lesions were located in the deep gray matter (thalamus, basal ganglia) or brainstem (pons, midbrain), while complications were least likely with lesions in the frontal and temporal lobes. For this reason, fractionated RT is often preferred to SRS for the treatment of lesions in the deep gray matter or the brainstem.

TECHNIQUE OF SRS

Stereotactic guidance Precision in target localization is a prerequisite for successful SRS. This is accomplished through the attachment of a stereotactic head frame using four pins that penetrate the outer table of the skull. The head frame placement is usually done under local anesthesia, although sedation may be required.

After placement of a head frame, thin slice computed tomography (CT) or magnetic resonance imaging (MRI) is obtained to visualize its four posts. Spatial coordinates for the lesion are calculated relative to these landmarks. During the RT session, the frame is bolted to the treatment couch to immobilize the patient, allowing precise targeting of the radiation. With either the Gamma Knife or Linac, the patient is treated on the same day that the head frame is placed.

A frameless, image-guided stereotactic system has been developed for use with the CyberKnife SRS system

Radiation delivery Both gamma rays and x-irradiation are composed of photons. As photons penetrate tissue, energy deposition decreases exponentially

Several different systems are available for photon-based SRS. The most widely used are the Gamma Knife and Linac, which have similar efficacy. This was illustrated in a multicenter clinical trial that combined SRS with whole brain RT for the treatment of brain metastases; no differences were observed in either efficacy or toxicity in patients treated with the two systems

Gamma Knife The Gamma Knife system consists an array of 201 cobalt-60 sources surrounded by an 18,000 kg shield. The sources are oriented such that all the beams converge at a single point termed the isocenter. This array produces a target accuracy between 0.1 and 1 mm, which is at least as good as the best possible lesion delineation with current imaging technology

During treatment, the patient is positioned so that the target coincides with the isocenter of the Gamma Knife unit. Using techniques of beam blocking, multiple or overlapping isocenters, and differential isocenters weighting, the radiation volume is matched to that of the target lesion

Linac The principles of a Linac (linear accelerator) are identical to those of the Gamma Knife. Instead of using an array of cobalt sources, Linac SRS utilizes multiple non-coplanar arcs of radiation that intersect at the target volume. As a result, the radiation received by normal tissue in each beam path is minimal relative to the point of beam convergence. Linac-based devices achieve target accuracy between 0.1 and 1 mm . The radiation volume is carefully matched to the lesion [3].

CyberKnife The CyberKnife device combines a mobile linear accelerator with an image-guided robotic system  The mobility of the device, combined with real-time imaging, obviates the need for an invasive stereotactic head frame.

Prior to treatment, CT images are used to define the spatial relationship between the patient's bony anatomy and the target volume. During the actual treatment, patient movement is monitored with minimal time lag by the system's low dose x-ray cameras. These images are compared to radiographs derived from the pretreatment CT scan. Based upon these comparisons, the computer-controlled robotic arm adjusts the mobile linear accelerator in response to changes in patient position. A target accuracy of less than 1 mm is achieved without a stereotactic frame.

PROTON BEAM SRS A proton beam can be generated by stripping a hydrogen atom of its electron and accelerating the residual proton in a magnetic field. Charged protons have biologic properties that are different from a photon beam and offer advantages in selected situations.

The dose distribution of a proton beam consists of an entrance region through which there is a slowly increasing dose, followed by a rapid rise to a maximum (the Bragg peak), and a fall to near zero . In contrast, the dose administered to tissue with a photon beam undergoes exponential decay with increasing tissue penetration.

The depth of the Bragg peak is a function of the energy of the proton beam and can be modulated such that almost no irradiation is delivered beyond the intended target. If all protons have the same energy level, a beam will only irradiate an area approximately the size of a pituitary gland. Irradiation of larger targets is achieved by superimposing proton beams with different energies

Because of limited availability, patient selection for proton SRS is restricted to carefully defined indications. In general, small (<10 cm3), spherically-shaped lesions do not require proton SRS if they are not located close to critical anatomic structures, in eloquent regions, in deep subcortical areas, or in previously irradiated volumes. In these cases, equally effective results can typically be attained with photon SRS. Patients with a limited expected survival are also unlikely to derive additional benefit from proton SRS, since delayed radiation toxicity from photon irradiation does not develop until years after treatment.

SUMMARY Stereotactic radiosurgery (SRS) has emerged as an important option based upon advances in neuroimaging, medical physics, stereotactic neurosurgery, and radiation oncology. Its successful clinical application requires a team-based approach, with active collaboration between specialists from each of these fields.

Careful considerations must be given by the team members regarding the relative merits of SRS, conventional fractionated RT, surgery, and observation. In cases where SRS is indicated, additional consideration must be given to whether proton SRS, if available, offers additional clinical benefits.