Interstitial and LINAC-Radiosurgery for Brain Metastases

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Chapter 98 Interstitial and LINAC-Radiosurgery for Brain Metastases^∗

Guido Nikkhah, Jaroslaw Maciaczyk, Thomas Reithmeier, Michael Trippel, Marcus O. Pinsker

Brain metastases are diagnosed in approximately 20% to 40% of patients with neoplastic diseases ¹^–³ and thereby represent the most common intracranial malignancy, with lung, breast, and renal cancers, and melanoma as the most frequent primary tumors.^4,⁵ The incidence of brain metastatic lesions appears to be increasing, possibly due to an aging population, improved neuroimaging techniques, and more efficient treatment of the systemic disease, leading to a growing group of patients presenting multiple lesions within the central nervous system at the time of diagnosis. Brain metastatic tumors are predominantly encountered supratentorially within the cerebral hemispheres, followed by cerebellar and brain stem localization.⁶ Despite the significant improvement of the management of intracranial metastases in the last decades, the overall prognosis remains relatively poor. Thorough assessment of the individual prognosis is, therefore, required to offer the best possible care while avoiding unnecessary and possibly debilitating treatment. The extensive analysis of various demographic and clinical variables, including age, performance status (determined as on the Karnofsky performance scale, or KPS), type of primary tumor, number of cerebral metastases, and activity of the extracranial disease, based on Radiation Therapy Oncology Group (RTOG) trials⁷ using recursive partitioning analysis (RPA) led to the identification of prognostic groups (RPA groups 1-3 in modification of Lutterbach et al.;⁸ for details, see Table 98-1), with age below 65 years, a KPS score of at least 70, and no extracranial disease, as well as a single metastatic tumor, as the most important positive predictive factors concerning favorable outcome.

Table 98-1 Stratification of Prognostic Factors by RPA Class

	Median Survival (months)
RPA Class 1
KPS ≥ 70, age <65 years, controlled primary tumor, no extracranial disease Single metastasis Multiple metastases	7.1 13.5 6.0
RPA Class 2
All others Single metastasis Multiple metastases	4.2 8.1 4.1
RPA Class 3
KPS < 70	2.3

Modified from Kaal et al. 2005.⁵

Modern therapeutic management of brain metastases is based on approaches combining different therapeutic strategies (i.e., surgery or radiosurgery with whole brain radiation therapy [WBRT] or systemic chemotherapy). Surgical resection with adjuvant WBRT is considered the standard of treatment of brain metastases in many patients. However, in metastatic lesions localized in deep structures or in eloquent brain areas not amenable to surgery, patients may benefit from stereotactic radiosurgical (SRS) treatment. This chapter focuses exclusively on SRS, a fast-growing field that has been progressing over recent years from an experimental concept to an effective treatment modality for brain metastases.

SRS is based on focusing multiple, high-dose, ionizing radiation beams using stereotactic guidance on an intracranial target. It converges with the pioneering work of Leksell and Larsson,⁹ inventors of the first gamma knife (GK) unit at the Karolinska Institute in Stockholm in 1967.¹⁰ However, the growing importance of the SRS techniques has greatly benefited from the development of novel visualization methods—computed tomography (CT) and magnetic resonance imaging (MRI) based—that allow precise planning and safe execution of radiosurgical treatment. Classical radiosurgery requires application of either photon or charged particles radiation (usually proton beam radiation) using multiple cobalt-60 sources (GK), linear accelerators (LINACs) (XKnife or CyberKnife) or cyclotrons. The original definition of SRS has been significantly extended by application of ionized radiation.¹¹ Therefore, besides traditional SRS techniques based on external radiation sources, more invasive radiosurgical methods like iodine-125 (I-125) seeds implantation and the Photon Radiosurgery System for interstitial application of radiation in the case of metastatic brain lesions are discussed in this chapter.

Radiosurgical Techniques

Noninvasive radiosurgical treatment modalities consist of percutaneous or external irradiation using photon radiation technology (GK and LINACs). Current GK units use 201 cobalt-60 sources enclosed within a hemispheric vault, leading to the emission of gamma ray energy converged at the isocenter and allowing high-precision treatment of an intracranial target. The aperture of collimators differs from 4 to 18 mm, so the diameter of the radiation beam can be adapted to the size of the lesion. Due to high radiation activity (up to 300 TBq) the propagation of the dose reaches 2 Gy/min by 80 cm from the radiation source. However, during the therapy of irregular lesions, multiple spherical isocenters have to be superimposed to allow conformal treatment, resulting in anatomic regions that receive much higher radiation dosage than the marginal dose. GK technology is limited exclusively to the treatment of intracranial lesions and high cervical lesions (when GK perfexion is available).

LINAC radiosurgery was introduced in the early 1980s following modifications of standard LINACs used for external beam radiotherapy to obtain high conformity of the radiation. The frequency of the electromagnetic field is about 3 GHz, and the accelerating energy is 4 to 25 MeV. X-ray photons are bundled to achieve a collimated beam of radiation. The advantages of LINAC devices compared to GK units are better penetration and homogeneity of radiation, steeper falloff of the dose at the margins of the irradiated lesion, and no problems with radioactive waste disposal. Moreover, application of the multileaf collimators enabled safe treatment of irregular intracranial lesions with an accuracy of less than 1 mm. Originally, the LINAC is mounted to a gantry that rotates over the patient’s head fixed in a stereotactic apparatus. However, recent LINAC devices (i.e., CyberKnife) applying dynamic position adjustment of the rotating arm do not require head fixation to preserve high accuracy of the radiation.

Particle beam radiation therapy with protons or heavy helium nuclei based on the so-called Bragg peak phenomenon, applied in only few centers worldwide, are not discussed further due to the paucity of reliable clinical data.

Another important technique of radiosurgical brain metastases therapy is interstitial radiosurgery (brachytherapy), allowing direct intratumoral application of low-energy ionizing radiation (0.5-10 cGy/min). Following stereotactic serial biopsy that provides the confirmation of the histopathologic diagnosis, single or multiple radioactive sources are temporarily implanted, allowing optimal dose distribution (e.g., I-125, iridium-192, and gold-198).¹² I-125 seeds (0.8 × 4.5 mm titanium cylinder) are fixed in a Teflon catheter, sterilized, and inserted into the center of the lesion, where they are left for 3 to 4 weeks (delivering a dose of 60 Gy to the tumor margins). The steep radial dose falloff is inversely proportional to the square of the distance from the radiation source, which provides minimal exposure to radiation of the healthy surrounding brain tissue.

At the beginning of 1990s, Photoelectron (Lexington, Waltham, MA) developed the Photon Radiosurgery System. It is a battery-powered, miniature x-ray generator capable of delivering low-energy radiation (soft x-rays) directly to small brain lesions in a single therapeutic session. Thus, it combines the direct dose application of brachytherapy with the advantages of short-time exposure typical for external radiosurgical techniques (GK and LINAC).¹³ Brief characteristics of the physical parameters of the radiosurgical procedures discussed in this chapter are summarized in Table 98-2.

Table 98-2 Physical Parameters of the Radiosurgical Techniques

The rest of the chapter is devoted to the presentation of the clinical results of radiosurgical treatment of brain metastatic diseases, based on the literature data and the experience of the authors. Furthermore, algorithms of clinical decision making concerning treatment devices for brain metastases developed in University Medical Centre in Freiburg, Germany, are described.

Linac-Based Stereotactic Radiosurgery

Due to the pioneer work of Betti and Derechinsky,¹⁴ Colombo et al.,¹⁵ Winston and Lutz,¹⁶ and others in the 1980s, precision and stability of LINAC radiosurgery systems was dramatically enhanced and became comparable to GK units. Nowadays, several techniques exist for LINAC systems that can be used to achieve an exact and highly conformal dose distribution. Target dose distribution can be adjusted by varying the collimator size, eliminating undesirable arcs, manipulating arc angles, using multiple isocenters, and differentially weighting the isocenters.¹⁷ A highly conformal dose distribution can be achieved by generating nonspherical beam shapes that are conformal to the beam’s eye view of the tumor with a multileaf collimator (Fig. 98-1A-C). Comparison of a modern LINAC radiosurgery system with GK units showed no differences in efficiency and safety.^18,¹⁹ The most important difference between these two systems is the number of metastases that can be irradiated in a single session. In GK units, up to 25 brain metastases can be treated simultaneously when the lesions are diffusely scattered and the total tumor volume is less than 15 to 30 cm³²⁰ In contrast, LINAC radiosurgery systems can irradiate a maximum of 3 to 4 metastases as the multiple intersecting radiation arcs may cause a hot spot outside the target volume within normal brain tissue.²¹

FIGURE 98-1 LINAC-based SRS with micromultileaf collimators (Virtuoso 3.4 planning software, Stryker Leibinger, Freiburg). A, Conformal application of 20 Gy to an irregularly shaped target volume (blue line). B, Beam’s eye view. C, 3D reconstruction of target volume (blue) and rise structures (optic system and brain stem).

Brain metastases are ideal targets for SRS, because these tumors are usually pseudospherical and show, in contrast to glioma, a noninfiltrative growth pattern with a sharp delineation to normal brain tissue. In addition, brain metastases occur often multifocally and have a diameter of less than 3.5 cm at the time of diagnosis. In Freiburg, we usually treat a maximum of three metastases during one session, and the prescribed dose for metastases with a diameter below 2.5 cm is 20 Gy calculated on the 80% isodose surrounding the outer tumor margin. Metastases with a diameter greater than 2.5 cm are treated with 18 Gy to prevent radiation necrosis. With nonspherical, irregularly shaped tumor margins, the application of one isocenter is not adequate to spare healthy brain tissue, especially when the metastasis is located within eloquent areas (e.g., the central region or brain stem). In these cases, we apply techniques like the use of multiple isocenters or a micromultileaf collimator to achieve a highly conformal target volume. Nataf et al.²² showed the importance of an exact dose application to the target volume by comparison of patients with a 2-mm margin to patients without this additional radiation volume. In contrast to Nöel et al.,²³ who achieved improved local control with a 1-mm margin, the addition of a 2-mm margin resulted in more severe parenchymal complications, no increase in the 1- and 2-year local control rates, and no statistical significant difference in median overall survival (classic radiosurgery of 11.3 months vs. 2-mm margin radiosurgery of 19 months, p = 0.34).

Taking into account the usually limited life span of patients with brain metastases, SRS is a less invasive treatment method with the potential to treat several targets at one time and with the possibility to be repeated during the further course of the disease. In comparison to open surgery, the disadvantages of this method are that the diagnosis of a metastasis is not histologically proven, the mass effect is not relieved at once but over weeks or months, and the surrounding edema may be aggravated and become symptomatic.

For a solitary metastasis, one prospective ²⁴ and four retrospective studies²⁵^–²⁸ compared stereotactic radiosurgery (SRS) with open tumor resection. Because they generally found no difference in overall survival, open surgery and radiosurgery are not concurrent but complementary methods in the treatment of brain metastases. Therefore, indication for SRS versus open surgery is based on individual aspects of the patients.