Since the introduction of radiosurgery by Leksell in 1951 [1], stereotactic radiosurgery (SRS) with delivery of a high dose of radiation in a single session has been used for the treatment of lesions in the brain and spine [2]. He developed the first commercially available dedicated radiosurgical device called the “Gamma Knife” (GK) in 1968. This machine made it possible to precisely deliver a single, large dose of highly conformal radiation to any number of intracranial sites using 201 fixed cobalt sources aimed at a center point. Since he coined the term “stereotactic radiosurgery”, 330 centers of GK radiosurgery in 54 countries currently treat a total of 80,000 new patients each year. Through approximately 70 years of SRS experience that began with GK radiosurgery, the role of radiosurgery has expanded to a wide variety of benign brain tumors, arteriovenous malformations, functional disorders (trigeminal neuralgia, movement disorder, epilepsy, and pain), and malignant brain tumors.

On the other hand, radiation oncologists were unfamiliar with SRS such as high-dose irradiation. They did not believe in the effectiveness of high-dose irradiation of the body from a radiobiological perspective, and were even concerned that radiation side effects would increase. These physicians had been treating with fractionated radiotherapy (RT) to reduce radiation side effects and planning target volume margins to minimize treatment uncertainty, as they were in an era of undeveloped imaging techniques. However, advances in radiotherapeutic and radioimaging technology have eliminated uncertainty in precision and high-dose radiation therapy. Subsequently, stereotactic body radiotherapy (SBRT) was derived from SRS with improvements in radiation technology, using a small number of fractions with a high degree of precision within the body, unlike traditional fractionated RT [3].

The terms “SRS” and “SBRT” were used for central nervous system (CNS) and non-CNS anatomic sites, respectively, and in both cases involve the delivery of a high biologically effective dose in 1-5 fractions to small, focal, well-defined targets while minimizing nontargeting dose. Some physicians favor alternative nomenclature such as “SABR” (“stereotactic ablative radiotherapy” or “stereotactic ablative brain radiation” or “stereotactic ablation body radiotherapy”).

Linear accelerator (LINAC)-based systems for SBRT are more readily available, and due to the low fractionation dose, larger tumors can be treated. The radiobiological rationale for dividing the prescribed total dose into 25-30 fractions is mainly to increase the likelihood of targeting tumor cells at the most radiation-sensitive stage of the cell cycle [4]. In contrast, SRS relies on a single high radiation dose, potentially affecting tumor cells in the non-dividing phase. The physical properties of SRS allow steep radiation gradients in the tumor margins, which are important for maintaining a low dose for adjacent structures. Although it is known that some tumors that resist fractionated RT may respond to SRS, differences in the exact radiobiological properties of the two modalities are still an issue of debate to some extent [5]. Along with the evolution of hypofractionated regimes a continuum has also emerged between RT and SRS, and sometimes the distinction might be unclear. The most widely accepted definition of what constitutes radiosurgery seems to be that of the Association of Neurological Surgeons and the Congress of Neurological Surgeons in 1996, which defines radiosurgery as a maximum of five treatment sessions (however, it is typically performed in a single session) [6]. The aim of this review is to discuss the distinction between RT and SRS based on radiobiology and radiophysics as well as several radiotherapeutic instruments.

Although Leksell first introduced the concept of radiosurgery, SRS became more popular in the late 1980s through technological advances. SRS delivers radiation at a very high intensity, all at once, to a small area. It is a way of treating brain disorders with a precise delivery of a single high dose of radiation in a one-day session. The benefits of SRS are that it is a non-invasive treatment for patients who are not candidates for open neurosurgery (due to age, medical condition, or personal preference) that use irradiation and computer targeting to direct focused radiation to specific targets in the brain, thus minimizing injury to surrounding structures.

SBRT developed approximately a decade after SRS in 1994. Swedish physicist Lax and radiation oncologist Blomgren, both of the Karolinska Hospital in Stockholm, demonstrated that similar local control outcomes could be achieved at nonbrain body sites with one or a few fractions, even if the targeting and immobilization issues for nonbrain sites were more complicated [7,8].

Although the original concept of SRS is treated as single-session irradiation, fractionated SRS has recently been considered for relatively large volume lesions. However, the therapeutic basis for fractionated SRS based on traditional radiobiology has yet to be explained. Nevertheless, many clinical studies have demonstrated the safety and efficacy of fractionated SRS as well as the fact that it potentially reduce SRS-related complications [9-12]. More research is needed on the optimal radiation dose and frequency for each disease.

During the 1920s to 1940s, French radiation oncologists Coutard [13] and Francois Baclesse treated with various fractionations of RT lasting from 2 weeks to 10 months for patients with laryngeal and breast cancers. They demonstrated that the uncomplicated control rate peaked at 6 to 8 weeks.

Stereotactic RT delivers radiation at different times, at lower intensities, and to larger areas. One benefit of this technology is its ability to easily treat very large tumor volumes by treating overtime during cell division. Conventional fractionated RT has been developed on the basis of radiobiology, that is, the 4Rs. The 4Rs represent repair, repopulation, redistribution, and reoxygenation of cells, and have recently been expressed as the 5Rs, including radiosensitivity. “Repair” means that an initially damaged cell regains or keeps its ability to contribute to organ function for a normal organ. “Repopulation” is when cancer cells and cells of acutely reacting normal tissues proliferate during the course of therapy. “Redistribution” refers to differential cell-killing effects in which radiation sensitivity varies depending on the cell cycle. “Reoxygenation” is a phenomenon characterized by the reduction of oxygen use and the reoxidation of hypoxic cells and the sensitivity to more radiation, as radiation kills more sensitive toxic cells. In summary, “repair” and “repopulation” contribute to radiation protection or radioresistance, and “redistribution” and “reoxygenation” contribute to radiosensitivity.

Unlike conventional RT, hypofractionated RT has been devised to reduce the number of fractions by increasing fractionated doses. This had caused confusion as regions overlapped with fractionated SRS, and the distinction between SRS and RT became more ambiguous in the mixture era. SRS and RT are compared in Table 1. With these changes over times, the investigation of the optimal dose and fraction number is becoming a more important area of study.

Historically, conventional fractionated RT has been interpreted biologically with the parameters, repair, reoxygenation, redistribution, repopulation, and (less commonly) radiosensitivity. From this traditional radiobiologic perspective, the pros and cons of SRS are summarized in Table 2.

Additionally, biological evidence of SRS is suggested to indicate immunologic effects and vascular damage. High-dose irradiation may have immunologic effects that differ substantially from conventional fractionation [14]. Furthermore, SRS is believed to contribute to cancer cell destruction by causing circulatory failure and apoptosis by vascular damage [15]. This biological basis provides therapeutic evidence for SRS, which has not been explained by traditional radiobiology.

The characteristics of each radiotherapeutic machine are described in Table 3.

Leksell used the GK prototype for 12 years from 1967 to treat patients with brain tumors as well as functional neurosurgery, i.e., pain, movement disorders, and even specific behavioral disorders that did not respond to conventional psychiatric treatments. Since that time, the patient indications for treatment have not changed much. Currently, SRS is adopted primarily to treat benign brain tumors, arteriovenous malformations, acoustic neuromas, brain metastases, and other brain tumors, as well as trigeminal neuralgia (Table 4) [26-39].

In particular, the use of SRS without whole-brain RT (WBRT) has increasingly been used to avoid WBRT-related toxicity for patients with a limited number of brain metastases [40]. Based on several studies, the omission of WBRT in patients with ≤3 brain metastases has been widely adopted [41,42]. Currently, SRS treatment for >3 brain metastases has been adopted by the National Comprehensive Cancer Network guidelines [43].

Through the advancement of radiotherapeutic technology, the boundaries between RT and radiosurgery are blurring. This mixture era creates confusion for many doctors, especially novice neurosurgeons. Deeper radiotherapeutic knowledge will certainly be of help to neurosurgeons dealing with radiation therapy. Therefore, this review provides radiotherapeutic information for neurosurgeons to familiarize them with radiation therapy.