Key points

Generating therapeutic radiation

It is useful to be familiar with the scale of radiation under discussion. Table 1 outlines radiation doses delivered in typical diagnostic and therapeutic procedures compared with common nonmedical radiation exposures.

When describing radiation doses, radiation oncologists use gray as the unit of choice. Proton doses are often expressed in Cobalt-Gray-Equivalents (CGE). Gray is a measurement of energy absorbed by tissue (joules per kilogram of tissue). Radiation safety typically uses units such as the sievert. The sievert expresses gray (absorbed dose) adjusted with a known constant, Q, which depends on the type of radiation in question. Protons, photons, and α particles each have different Q factors. The curie is a measurement that expresses radioactivity of a source before reaching a tissue. The curie is medically relevant when radioactive sources are used in brachytherapy. A detailed explanation of different means of measuring radiation is beyond the scope of this article.

Photons are the most commonly used therapeutic particle. High-energy electrons guided by a powerful magnet are directed toward a tungsten target. When the electrons strike the target, photons are generated via either the photoelectric or Compton effect, depending on the energy of the incident electron. Linear accelerators achieve this effect on a massive scale. Photons and γ rays are biologically and physically equivalent. Photons (or X-rays) are man-made whereas Gamma rays are generated by natural decay of a radioisotope. Both protons and γ rays can be used in the treatment of skull base tumors.

Protons are typically generated via a cyclotron. Only a few centers in the United States have proton machines, but the number of centers is rapidly increasing. Protons differ from photons in their dose distribution. The proton beam deposits maximum dose at a certain tissue depth determined by its energy, and then dose decreases precipitously, so-called “Bragg Peak” phenomenon. Its use has been favored for pediatric tumors because of the theoretic lower risk of radiation exposure to nontarget tissues.

Generating therapeutic radiation

It is useful to be familiar with the scale of radiation under discussion. Table 1 outlines radiation doses delivered in typical diagnostic and therapeutic procedures compared with common nonmedical radiation exposures.

When describing radiation doses, radiation oncologists use gray as the unit of choice. Proton doses are often expressed in Cobalt-Gray-Equivalents (CGE). Gray is a measurement of energy absorbed by tissue (joules per kilogram of tissue). Radiation safety typically uses units such as the sievert. The sievert expresses gray (absorbed dose) adjusted with a known constant, Q, which depends on the type of radiation in question. Protons, photons, and α particles each have different Q factors. The curie is a measurement that expresses radioactivity of a source before reaching a tissue. The curie is medically relevant when radioactive sources are used in brachytherapy. A detailed explanation of different means of measuring radiation is beyond the scope of this article.

Photons are the most commonly used therapeutic particle. High-energy electrons guided by a powerful magnet are directed toward a tungsten target. When the electrons strike the target, photons are generated via either the photoelectric or Compton effect, depending on the energy of the incident electron. Linear accelerators achieve this effect on a massive scale. Photons and γ rays are biologically and physically equivalent. Photons (or X-rays) are man-made whereas Gamma rays are generated by natural decay of a radioisotope. Both protons and γ rays can be used in the treatment of skull base tumors.

Protons are typically generated via a cyclotron. Only a few centers in the United States have proton machines, but the number of centers is rapidly increasing. Protons differ from photons in their dose distribution. The proton beam deposits maximum dose at a certain tissue depth determined by its energy, and then dose decreases precipitously, so-called “Bragg Peak” phenomenon. Its use has been favored for pediatric tumors because of the theoretic lower risk of radiation exposure to nontarget tissues.

The effects of radiation

A detailed discussion about the manner in which ionizing radiation interacts with living cells is beyond the scope of this article. For the practicing physician or surgeon, it suffices to know that ionizing radiation exerts antitumor properties via a variety of potential effects on DNA. Direct radiation damage to DNA is probably less important. The most accepted primary cause of cell death is the double strand break, which triggers the apoptotic pathway. DNA suffers double strand breaks after interacting with free radicals, which are in turn generated by radiation effects on oxygen and water.

Given the importance of the presence of oxygen, more oxygenated cells in theory suffer greater radiation-induced damage. Fractionation allows tumors to reoxygenate, thereby fueling the DNA damaging process.

Fractionated external beam radiation therapy (EBRT) exploits the decreased ability of malignant cells to repair sublethal DNA damage. With each fraction, a new portion of abnormal cells reach a damage threshold. Although normal tissue repairs the damage more effectively, a greater portion of abnormal cells undergo cell death. Therefore it is possible to include normal tissue within a treatment field without completely destroying it. Even if tissues do not reach a lethal threshold, significant radiation damage may impair cellular function. The ability of normal tissues to recover from radiation injury varies by tissue type. Also, tissue dose tolerances vary when single high doses are given compared with fractionated radiotherapy (RT). For example, the optic chiasm does not seem to sustain clinically relevant damage if total fractionated dose is less than 50–54 Gy versus 8 Gy for single dose ( Fig. 1 ). This is a particularly critical concept in the skull base, to which we return later in this article.

Intensity modulated radiation therapy plan for a patient being treated for a WHO grade I meningioma that was resected 3 years before coming to our clinic. She presented with diplopia, headaches, and right lateral gaze palsy. Notice that the maximum radiation dose is focused around the tumor and a smaller, but not negligible, amount of radiation is delivered to surrounding structures. The red area represents the 95% isodose line. The other colors represent a gradient down to the 45% isodose line, which is in purple.

Target cells that do not reach lethal threshold with initial fractions accumulate more damage as they seek to replicate their DNA during mitosis. Tumors with a low mitotic fraction, number of cells undergoing active mitosis from a total tumor cell population, may experience a lesser response to radiation, Many skull base tumors are in this category with characteristically low mitotic activity, such as meningiomas and schwannomas. Tumor control for these tumors is often defined as lack of growth rather than diminished size.

Radiosurgery uses very high doses of radiation, obliterating tumors and often inducing necrotic cell death. The entire target area receives 1 to 5 high, supralethal doses of radiation. These are often called ablative treatments because a greater portion of cells are directly destroyed by radiation rather than accumulating damage over time. The biological mechanisms underlying radiosurgical treatments are not well understood. A single fraction radiosurgery treatment may range from 10 to 80 Gy, whereas a typical fraction in conventionally fractionated RT is 1.8 to 2 Gy.

Often an increase in size may be observed after radiosurgery because of inflammatory reactions to necrotic tissue. For example, Kollova and colleagues observed perilesional edema in 15% of patients treated with stereotactic radiosurgery (SRS) for meningiomas. Once the necrotic tissue is cleared, tumors treated with SRS should decrease in size.

A brief introduction to delivery system

With SRS of the skull base, it is critical to spare normal tissues in the immediate vicinity of the target in order not to cause normal tissue injury; therefore, tumors that encase functional structures are often not suitable for radiosurgical treatments. Radiosurgery is ideal for small targets (typically less than 2–3 cm), When targets are larger, the dose falloff with radiosurgery is less steep, the dose within the target less homogeneous, and the surrounding tissue exposed to significant levels of radiation increases. Radiosurgery can be accomplished with photons, γ rays, or protons. Linear accelerator based radiosurgery is performed with CyberKnife or a modified linear accelerator. Gamma Knife uses a Cobalt-60 source. There has been much debate about the merits of one SRS system over the other, but generally they are applied similar clinical situations Some institutions favor use of one radiosurgical modality over another despite absence of robust clinical data to justify such decisions. Most often, the use and type of radiosurgical modality is governed by its availability. SRS is also accomplished with protons as well ( Fig. 2 ).

( A ) CyberKnife plan for a patient being treated for a vestibular schwannoma. She initially presented to our department with subjective hearing loss, poor word discrimination on audiometry, and some mild disequilibrium. Notice how the isodose lines compare with the plan shown in Fig. 1 . This patient has a very high, yet inhomogeneous dose delivered to her tumor. The prescription is to 25 Gy, but, because 25 Gy is delivered to the 55% isodose line, 25 Gy is only 55% of the maximum dose within the tumor volume. Because of the physics of photons, dose falloff is sharpest near the 50% isodose line, so most SRS plans prescribe near this isodose curve. ( B ) Close-up on the target area to further define isodose curves. The brainstem, cochlea, and vestibular apparatus have been highlighted in this plan for the purposes of calculating dose to these structures. Contouring normal structures is one of the means of ensuring that dose tolerances of normal structures are not exceeded.

Conventional radiation therapy delivered with linear accelerators is more widely available than SRS. Such treatments are ideal for larger targets not amenable to radiosurgery. EBRT is less conformal than radiosurgery and generally uses fewer beams. Each beam accounts for a higher portion of the total target dose, so exposure to surrounding tissues is inevitable (see Fig. 1 ).

All radiation treatments rely on strict, reproducible patient positioning and high-quality image guidance. The term “stereotactic” refers to the use of a three-dimensional coordinate space to which patient’s anatomy and treatments are registered. Patient immobilization is therefore stricter for radiosurgery plans because high-doses of radiation are applied and the error is not distributed over many fractions. Patients being treated with Gamma Knife are immobilized with a metal frame affixed to the head. CyberKnife and EBRT treatments may be delivered with the patient’s head immobilized using a custom-fitted thermoplastic mask that is used in conjuction with image-based corrections for deviations in patient position. New immobilization techniques are constantly evolving.

High-quality images are critical to radiation delivery. Obtaining images during treatment, the CyberKnife can automatically verify patient positioning in real time before delivering radiation. Conventional linear accelerators use cone beam computed tomography (CBCT) devices mounted on the linear accelerator to verify daily position with the images used to plan treatment. In the skull base, magnetic resonance imaging (MRI) scans fused with CT scans are increasingly used for planning purposes.

Brachytherapy is the use of a radioactive source isotope implanted into a patient (internal radiation) for dose delivery via catheters, seeds, or plaques. These sources are typically designed to have a rapid decline in dose delivered as a function of distance. They are particularly useful when it is necessary to deliver a high dose to an area that is readily accessible but not amenable to surgical excision. Cavities of various types fit this description.

Electrons are generally delivered only to body surfaces. They are generated with the linear accelerator by essentially removing the tungsten target from the path of the electrons. Electrons do not travel far through tissue and penetrate only deep enough to treat relatively superficial structures.

There are several reports in the literature of improved results after radiation therapy with the addition of image-guidance or MRI-based planning. For example, local control (LC) rates for meningiomas treated with radiation are excellent and seem to be improving with modern treatment techniques (MRI-based planning, strict treatment setup). Goldsmith and colleagues reported that subtotally resected meningiomas treated with postoperative radiation after 1980 had better local control (LC) compared with meningiomas treated before 1980. Several more modern studies have shown excellent LC rates. For example, a series reported by Mendenhall and colleagues showed that EBRT may be equivalent to subtotal resection followed by EBRT; these investigators’ 15-year LC rates exceeded 90% for both groups.

Atypical and Malignant Meningiomas

Meningiomas are the most common benign brain tumor. Atypical and malignant meningiomas represent only a small subset: 4% to 7% and less than 5%, respectively. Since the World Health Organization (WHO) definitions changed in 2007, many believe that the proportion of all meningiomas that are reported as atypical may have increased to as much as 25%. Much of the meningioma data combines or aggregates benign, atypical, and malignant meningiomas. Because of their relative rarity, specific data on atypical and malignant meningiomas are expectedly sparse, but evolving. The following discussion extrapolates the existing data on radiotherapeutic principles and outcomes to the skull base location. Table 2 summarizes some relevant studies.

Table 2

Summary of relevant studies regarding adjuvant RT in the treatment of WHO II and III meningiomas

Series (Number)	Treatments	Histology	Outcomes	Comment
Adeberg et al, 2012 (85)	EBRT, S + EBRT, S→EBRT	WHO II-III	II: 5-y OS 81%, 5-y PFS 50% III: 5-y OS 53%, PFS 13%	Some patients treated with carbon ion
Aghi et al, 2009 (108)	S (GTR), S + EBRT, S→EBRT	WHO II	5-y recurrence rate: 41% 5-y recurrence rate 0% if EBRT	No recurrences if EBRT (n = 8) 2.7 craniotomies per patient if recurrence
Attia et al, 2012 (24)	SRS (salvage or primary)	WHO II	>50% OS 5 y 5-y LC 44%	Improved LC with SRS >14 Gy
Dziuk et al, 1998 (27)	Primarily surgery + RT	WHO III	All: 5-y OS 57% GTR + RT: 5 y DFS 40% RT No adjuvant: 5-y DFS 16%	Benefit >60 Gy adjuvant RT ↑ recurrence interval
Goldsmith et al, 1994 (23) (grade III)	Surgery + RT	WHO III	58%	>53 Gy
Goyal et al, 2000 (22)	Surgery, surgery + RT in only 8 patients	WHO II	GTR: 5-y OS 87% STR: 5-y OS 100%	No benefit with RT mean dose 54 Gy
Huffman et al, 2005 (21)	GKRS 18 Gy	WHO II	40% recurrence at 18–36 mo	Ref.
Hug et al, 2000 (16)	EBRT + S Some protons	WHO II-III	II: 5-y OS 38% III: 5-y OS 52%	Benefit with higher doses and protons
Mattozo et al, 2007 (12)	SRS, EBRT	WHO I-III	II: 3-y PFS 83% III: 3-y PFS 0%	Recurrence in resection cavity common
Milosevic et al, 1996 (42)	Primarily surgery + RT, some surgery only	WHO II-III	5-y OS 28% 5-y CSS = 42% if >50 Gy given	Better outcome if >50 Gy Reduced LR with RT
Pasquier et al, 2008 (119)	S + EBRT, S only	WHO II-III	GTR: 5-y OS 46% GTR + RT: 5-y OS 78% STR: 5-y OS 0% STR + RT: 5-y OS 56%	RT improves OS in all patients
Rosenberg and Prayson et al, 2009 (13)	S + RT S + SRS	WHO III	5-y OS: 47%	Trend toward longer survival if RT given
Sughrue et al, 2010 (63)	S + RT	WHO II-III	61% 40% at 10 y (RFS 57%, 5 y) (RFS 40%, 10 y)	Survival benefit for less extensive resection
Yang et al, 2008 (33 atypical, (41 anaplastic)	S, S + EBRT	WHO II-III	II: OS atypical 11.9 y RFS atypical 11.5 y III: OS anaplastic 3.3 y RFS anaplastic 2.7 y	Adjuvant RT improved outcomes in WHO III tumors and WHO II with brain invasion
Boskos et al, 2009 (24)	EBRT Protons and photons	WHO II-III	5-y OS 65% 5-y LC 61%	OS significantly associated with higher doses

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