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Basic Principles of Radiobiology Applied to Radiotherapy of Benign Intracranial Tumors
Neurosurg Clin N Am 17 (2006) 67–78
Basic Principles of Radiobiology Applied to Radiotherapy of Benign Intracranial Tumors Dennis C. Shrieve, MD, PhD Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, 1950 Circle of Hope, Salt Lake City, UT 84112-5560, USA
The use of ionizing radiation in the treatment of benign intracranial tumors may involve one of several types of ionizing radiation given as singlefraction radiosurgery or fractionated radiotherapy. An understanding of the biophysical and radiobiologic principles involved in these treatments is essential to the design and delivery of safe and efficacious treatment. This article discusses the basic radiobiologic principles applicable to radiotherapy of benign brain tumors. Although this issue primarily addresses the radiotherapy of benign brain tumors, much of our knowledge of fractionation schemes, central nervous system (CNS) toxicity, and CNS volume effects for benign brain tumors derives from clinical and animal data involving spinal cord or malignant brain tumors, and some of those data are necessarily included. Types of ionizing radiation Gamma rays and x-rays Gamma rays and x-rays are electromagnetic radiation with energies in the range of 100 to 2 billion electron volts. X-rays are produced when electrons ‘‘fall’’ from a higher to lower energy level, usually in the outer shell of heavy atoms, and are thus produced extranuclearly. X-rays may be the products of radioactivity (electron capture) or may be ‘‘man-made’’ from x-ray tubes or linear accelerators, which accelerate electrons onto a heavy metal target producing a continuous spectrum of photon energies termed bremsstrahlung and monoenergetic characteristic x-rays.
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Gamma rays are photons emitted by radioactive nuclei and have a much narrower range of energies than x-rays, 10 keV to 10 MeV. Gamma rays and x-rays are otherwise identical. The most common source of gamma rays used in radiotherapy is cobalt-60 (60Co). 60Co is commercially produced from 59Co and undergoes beta-decay with a half-life of 5.27 years. It is the subsequent gamma emission that makes it applicable to radiotherapy and, perhaps more commonly, to stereotactic radiosurgery, however. Two gamma energies are emitted, 1.17 and 1.33 MeV, with an effective average energy of 1.21 MeV. Protons The use of protons in radiotherapy is based on the physical properties of these particles and the related characteristics of dose deposition in irradiated tissues [1]. Dose deposition is characterized by the Bragg peak. Qualitatively, the entrance dose for particle beams is relatively low compared with photons. An unaltered beam deposits more than 50% of its energy over a 2- to 3-cm narrow path at a depth in water that depends on the beam energy. The beam may be altered to spread the Bragg peak to conform to the thickness and depth of the volume to be treated. The entrance dose is significantly increased in this case, however (Fig. 1). The biologic effectiveness of x-rays, gamma rays, and protons is roughly equivalent, and each is considered to be low linear energy transfer (LET) radiation. Of note, protons have only a slightly higher radiobiologic effectiveness (RBE) than 60Co. In practice, this small difference is adjusted for by calculating the dose for protons in cobalt Gray equivalent (CGE), whether for
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Depth Dose Distribution in Water Spread-out Bragg Peak
100
Surviving Fraction
Relative Dose (%)
120
80 60
10 MVp X rays
40 20 Unmodulated Proton Beam
0
0
4
8
12
16
20
1
0.1
0.01
Depth (cm)
Fig. 1. Depth dose curves shown schematically for a 160-MeV proton beam. Unmodulated and spread-out Bragg peak curves are shown. A 10-MV (peak) x-ray curve is shown for comparison.
single or multiple fractions. Proton radiotherapy and radiosurgery are fully discussed elsewhere in this issue.
Basic principles of radiobiology Direct versus indirect effects of radiation When cells are irradiated with low LET radiation, most photons interact with water molecules by stripping an electron from a hydrogen atom, resulting in a fast electron and an ionized water molecule through Compton scattering. The resulting fast electrons interact with water molecules through further ionizing events. The resulting positively charged water molecules have an extremely short half-life, dissociating into an Hþ ion and an OH$ free hydroxyl radical. The hydroxyl radical is reactive and with sufficient energy to break chemical bonds in nearby (within 2 nm) molecules. It is this indirect effect of radiation through the free radical intermediary that is responsible for approximately 70% of radiation damage. The remaining damage is attributable to the direct effect resulting when the fast electrons themselves interact with biologically important molecules (DNA) [2].
0.001
0
5
10
15
Dose (Gy)
Fig. 2. Curve for mammalian cell survival as a function of dose of radiation (solid line) given as a single fraction. The a/b is 10 Gy, a dose at which the contributions to cell killing by single events (aD, dashed line) and the interaction of sublethal events (bD2) are equal.
a steeply sloped, or more continuously bending, portion at higher doses. In vitro radiosensitivity of cultured human tumor cells has been limited to malignant tumor cell types. Studies on such cell lines have shown that the apparent radiosensitivity depends heavily on culture conditions and the assay used to assess cell survival [3–5]. The shoulder region is interpreted as accumulation of sublethal damage at low doses, with lethality resulting from the interaction of two or more such sublethal events [2,6,7]. It may be considered that DNA is the target molecule for cell killing by ionizing radiation and that a double-strand break in the DNA is necessary and sufficient to cause cell death (defined as loss of ability to divide). Double-strand breaks may be effectively produced by a single-particle track or by the interaction of two single-strand breaks caused by separate particle tracks and occurring closely in space and time (Fig. 3). Single-strand breaks alone may be repaired, and therefore represent sublethal damage. Such a model is described by the following linear-quadratic formula:
Mammalian cell survival curves Cell survival after single doses of ionizing radiation is a probability function of absorbed dose, measured in the unit Gray (Gy), 1 J/kg absorbed dose. Typical mammalian cell survival curves obtained after single-dose irradiation in culture (Fig. 2) have a characteristic shape, including a low-dose shoulder region followed by
2 SF ¼ eðaD þ bD Þ
where SF is the surviving fraction and D is dose of radiation in Gy [8], a is the coefficient related to single-event cell killing, and b is the coefficient related to cell killing through the interaction of sublethal events. a/b is the ratio of the relative
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RADIOTHERAPY OF BENIGN INTRACRANIAL TUMORS
Radiobiology of fractionated radiotherapy A spectrum of fractionation schedules is used to treat benign intracranial disease, ranging from single-fraction radiosurgery to fully fractionated courses of radiotherapy. For fractionated radiotherapy, each dose (fraction) produces similar biologic effects, given a sufficient interfraction interval (see Fig. 4B). The linear-quadratic formula for fractionated doses becomes
Fig. 3. Schematic representation of double-strand break production by single events (aD) or interaction of events (bD2).
contributions of these two components to overall cell kill. a/b is the single dose at which overall cell killing is equally attributable to these two components (see Fig. 2): aD ¼ bD2 or D ¼ a=b Most mammalian cell survival curves are well fit to the linear-quadratic model [3,4]. Cell survival after a single dose of radiation in vitro reflects the intrinsic radiosensitivity of a particular cell type to a particular type of radiation [3]. Cell types and tissues may vary in the a/b, resulting in slightly different-shaped response curves (Fig. 4A).
A
2 SF ¼ n eadbd where d is the dose per fraction and n is the total number of fractions. A basic principle of radiobiology and radiotherapy is that dose fractionation ‘‘spares’’ virtually all cell and tissue types. In this context, ‘‘sparing’’ means that for a given total dose, there is always less molecular damage and a lower level of biologic effect associated with multiple fractions compared with a single dose. As the number of fractions increases, the total dose (n d) required to achieve a certain level of biologic effect also increases (Fig. 5A). The magnitude of the sparing effect of dose fractionation varies, however, and depends on a/b. The biologically effective dose (BED) is represented by the following equation: d BED Gya=b ¼ nd 1 þ a=b where the BED is expressed in Gya/b to indicate that it should be used only to compare effects in
B
Low α/β
Effect
Effect
High α/β
Low α/β
Dose
High α/β
Dose
Fig. 4. Comparison of single-dose effect curves (A) and fractionated dose-effect curves (B) for low and high a/b tissues. The small advantage seen in the low-dose region sparing low a/b tissues (A) is amplified through dose fractionation (B).
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A 70 60 50 40 30 20 10 0
1.2 1 0.8 0.6 0.4 0.2 0
0
5
10
15
20
25
Relative BED of Fractionated vs Single-Dose RT
B
Relative BED
Total Dose (Gy)
80
Total Dose Required to Acheive BED Equivalent to 20 Gy in a Single Fraction
0
5
10
15
20
25
Number of Fractions
Number of Fractions
Fig. 5. The effect of dose fractionation on the biologic effectiveness of radiation for low a/b (solid lines) versus high a/b (dashed lines) tissues. (A) Isoeffect curves show the increase in total dose required to maintain biologic effectiveness with an increasing number of fractions. (B) Decreasing biologic effectiveness with an increasing number of fractions while maintaining the total dose.
tissues with the same a/b, n is the number of fractions of dose d, and nd is thus the total dose (D). The BED can be expressed as follows: BED Gya=b ¼ D F where F is a fractionation factor: d F¼ 1þ a=b F increases with increasing dose/fraction, d, but the effect is greatest for lower a/b and may be negligible for extremely high a/b, because as a/b increases, F approaches 1. The linear-quadratic formulation is a means of estimating the effects of dose fractionation. Other factors, such as a rapid doubling time, may be accounted for by additional terms [9]. In the context of benign brain tumors, a time factor is not likely to be important and thus has not been included. Mechanistically, a larger a/b indicates relatively little contribution from interaction of sublethal events. A lower a/b indicates a greater contribution from this type of damage. Because sublethal damage may be repaired after a dose of radiation, cells with a lower a/b ratio are spared to a greater extent by fractionation than are cell types with a larger a/b ratio (see Figs. 4 and 5). This is the basis for fractionated radiotherapy. Malignant tumors and other rapidly proliferating tissues (eg, skin, mucosa, bone marrow) demonstrate high a/b (8–12) and exhibit modest
sparing through dose fractionation. Many normal tissues, including those of the CNS, have lower a/b (2–4) and demonstrate marked sparing with dose fractionation [7,10]. This effect is demonstrated by comparing the total dose required to maintain the BED or the BED for a given total dose delivered in various numbers of fractions (see Fig. 5). The magnitude of this effect of dose fractionation is quantitatively different for low versus high a/b tissues. This forms the basis for simultaneously maintaining efficacy for tissues with high a/b while decreasing toxicity for tissues with low a/b through dose fractionation. Little information is available for the a/b of benign brain tumors. Using clinical data, it may be possible to estimate a/b based on isoeffective fractionation schedules. If two fractionation schedules result in an equivalent clinical effect, they may be assumed to have the same BED and the linear-quadratic model may be used to calculate the a/b [11]. Because BED Gya=b
d ¼D 1þ a=b
by setting BED1 ¼ BED2, the unknown a/b is calculated as follows: BED1 ¼ BED2 or d1 d2 ¼ D2 1 þ D1 1 þ a=b a=b
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RADIOTHERAPY OF BENIGN INTRACRANIAL TUMORS
to have a clear advantage in terms of therapeutic ratio, because each results in excellent tumor control and equivalent rates of preservation of useful hearing.
or a=b ¼
ðD2 d2 Þ ðD1 d1 Þ ðD1 D2 Þ
This approach has been used to estimate a/b for benign meningioma, assuming, based on clinical data, that single-dose radiosurgery of 15 Gy and fractionated treatment of 54 Gy in 30 fractions result in equivalent local control. The resulting a/b is 3.3 [11]. Although meningiomas have been almost exclusively treated with radiosurgery or fully fractionated radiotherapy, acoustic neuromas have been treated with a number of fractionation schedules (Table 1). Historically, single-fraction radiosurgery doses have decreased from approximately 18 Gy to 12 to 13 Gy without compromise of local tumor control and with a significant decrease in morbidity, including hearing loss and trigeminal and facial neuropathies [12]. Equivalent local control and levels of hearing preservation have been achieved with schedules of between 1 and 32 fractions without significant trigeminal or facial neuropathies [13–18]. Using these data, a/b of between 2 and 3 Gy provides a reasonable fit (Fig. 6). What is clear from this analysis is that a/b for acoustics is not near the 10-Gy value assumed and measured for many malignant tumors. It should also be pointed out that none of these fractionation schedules seems
Time interval required for maximal repair between fractions Allowing for a sufficient time between fractions to permit maximal repair of sublethal damage in normal tissues is crucial to take full advantage of the sparing effects of dose fractionation. The best information on the kinetics of repair of sublethal radiation damage in the CNS comes from the work of Ang and colleagues [19]. They found biexponential repair kinetics with half-times of 0.7 and 3.8 hours for the fast and slow components, respectively. This work indicates that even a 6- to 8-hour interval leads to accumulation of unrepaired sublethal damage and lowers the tolerance dose of the spinal cord [20]. This prediction has been supported by increased rates of myelopathy in patients treated for head and neck cancers with three fractions per day [21]. Model predicting tumor control probability based on cell survival The probability of tumor control (TCP) is a function of the likelihood of inactivating all tumor cells in a given tumor according to Poisson statistics. If it is assumed that every tumor cell
Table 1 Fractionation schedules used to treat acoustic neuromas Calculated a/ba
BED (Gy3)
Local control
Hearing preservation
1
d
69
21
3
2.75
70
[18]
25
5
3.67
67
Williams
[18]
30
10
4.65
60
Wallner et al
[17]
45
25
2.75
72
70% 6 years 77% 2 years 70% 3 years 100% 3 years d
Andrews et al
[13]
50
25
1.86
83
Chan et al
[14]
54
30
1.75
86
Combs et al
[15]
57.6
32
1.46
92
99% 6 years 97% 2 years 100% d 100% d 94% 15 years 97 3 years 98% 5 years 93% 5 years
Author
Reference
Total dose
Flickinger et al
[12]
13
Poen et al
[16]
Williams
a
Fractions
a/b calculated assuming isoeffectiveness with 13 Gy in one fraction.
70 3 years 88% 3 years 94% 5 years
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70
It should be appreciated that radiosensitivity is not equivalent to radioresponsiveness. Some CNS tumors are extremely radioresponsive but inevitably recur (eg, CNS lymphoma), whereas others may show little or no radiographic evidence of response but are well controlled by modest radiation doses (eg, meningioma, acoustic neuroma).
Total Dose (Gy)
60 2
50
3
40 30
10
20 10 0
5
0
10
15
20
25
30
35
Normal tissue radiobiology
Number of Fractions
Model predicting normal tissue complications
Fig. 6. Total dose versus number of fractions for reported treatment regimens used successfully to treat acoustic neuromas (see Table 1). Symbols represent data points. Curves represent modeling for a/b of 2, 3, and 10 Gy ‘‘anchored’’ at 13 Gy in a single fraction (see text for discussion).
The radiation oncologist must be concerned not only with the effects of treatment on tumor but with normal tissue effects. The normal tissues of particular interest in the treatment of benign brain tumors are the spinal cord, brain stem, optic apparatus, other cranial nerves, and brain parenchyma. Also of interest are effects on the vasculature within normal and tumor tissue. The probability of normal tissue complication (NTCP) after radiotherapy is, like the TCP, a function of dose and dose per fraction (BED), the tissue at risk (radiosensitivity), and the volume irradiated. The NTCP has been shown to be well represented by the following model:
must be killed to control a tumor, the TCP is given by the following equation: TCP ¼ eSFN where SF is the surviving fraction and N is the total number of cells in the tumor. SF N is then the average number of cells remaining in a tumor receiving a certain treatment. The TCP is then the probability of no cells remaining viable under these conditions. The TCP is a function of total dose and dose per fraction (BED), N (tumor bulk), and radiosensitivity of the tumor. This model leads to a sigmoid dose response curve for the TCP (Fig. 7).
A
NTCP ¼ 1 expR where R is the variable related to dose and volume: R ¼ ðd=d0 Þk
B
1
TCP
0.8 0.7 0.6 0.5 0.4
Uncomplicated Cures
0.3
0.6 0.5 0.4 0.3 0.2
0.1
0.1 0
5
10
15
Dose (Gy)
20
25
NTCP
0.7
0.2 0
TCP
0.8
NTCP
TCP/NTCP
TCP/NTCP
1 0.9
0.9
30
0
Uncomplicated Cures
0
20
40
60
80
100
120
Dose (Gy)
Fig. 7. Curves schematically comparing the probability of tumor control (TCP) with the probability of normal tissue complication (NTCP). (A) Curves are positioned relatively close to one another. Normal tissue complications may be avoided only by minimizing the dose to the critical normal structure. Such a situation may occur when a normal structure, such as the optic nerve, lies adjacent to a benign tumor being treated with single-dose radiosurgery. (B) Dose fractionation separates the TCP and NTCP curves, allowing for a higher probability of tumor control without a significant risk of normal tissue complication. The ‘‘Uncomplicated Cures’’ curve is TCP-NTCP.
RADIOTHERAPY OF BENIGN INTRACRANIAL TUMORS
with d0 determining the slope of the NTCP versus dose curve and k being a constant accounting for volume effects [22,23]. This is represented graphically as a sigmoid-shaped curve similar to that obtained for tumor cure (see Fig. 7). Curves for a wide variety of normal tissue end points have been generated. Although each has a similar shape, the relative placement of these curves along the dose axis may be quite different. In clinical radiotherapy, the relative positions of the curves for tumor cure and normal tissue complication define what is known as the therapeutic ratio. The therapeutic ratio may be calculated as follows: Probability of Tumor Cure Probability of Complication An ideal therapeutic ratio would be described by curves that allow 100% tumor cure without an appreciable NTCP. The opposite extreme would be exemplified by a tumor requiring high-dose radiation for cure located within a critical normal structure with a low tolerance to radiation. In practice, a regimen that maximizes the probability of an uncomplicated cure is optimal (see Fig. 7). For the situation where a/b for a tumor is higher than that for critical normal tissue, dose fractionation always serves to separate the TCP and NTCP curves and to increase the therapeutic ratio. The tolerance dose for specific tissues is a function of the selected toxicity end point, volume irradiated, total dose, dose per fraction used, and level of acceptable risk [24–27]. For example, the total dose to cause necrosis of the spinal cord in 5% of patients treated with a single dose of radiosurgery is vastly different than the dose associated with the same risk when conventional fractionation (1.8–2 cGy per day) is used [28]. The concept of tolerance dose may be useful in some situations. Tolerance doses may be expressed as D5/5, or the dose expected to produce complication in 5% of patients within 5 years of treatment [26]. This concept may be useful for effects like necrosis or pituitary dysfunction but is not useful for effects like optic neuropathy. Ideally, when dealing with benign tumor treatment, a dose regimen thought to be ‘‘safe’’ to the optic apparatus would seem to be the better choice. A dose and fractionation scheme that is effective in achieving tumor control and below the ‘‘threshold’’ for visual impairment would be optimal [11,29].
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Models to compare the biologically effective dose of different fractionation schemes It is important when investigating nonconventional fractionation schemes to have some basis for the choice of fraction size, total dose, and interval between fractions. If a/b were well established for all tumors and normal tissues, the linear-quadratic model would provide such a basis. The BED for a given total dose, D, and dose per fraction, d, is given by the following equation: d BED Gya=b ¼ D 1 þ a=b where the BED is expressed in Gya/b to indicate that the BED is applicable only to tissues with a given a/b. The formula for BED can be used to compare dose regimens of varying total doses and dose per fraction in a particular tissue. The equation may also be used to determine isoeffective total doses, D, associated with different doses per fraction, d, as follows: D1 =D2 ¼ ða=b þ d2 Þ=ða=b þ d1 Þ Sheline and coworkers [30] described a model for predicting the risk of brain necrosis as a function of total dose and number of fractions. The model defined an isoeffect line for total dose as a function of fraction number. They defined the neuret, similar to BED as follows: Neuret ¼ D N0:41 T0:03 where D is the total dose in cGy, N is the number of fractions, and T is the overall time in days. This relation demonstrated the strong dependence on N, a surrogate for fraction size, and the weak dependence on overall time, T. These data may also be well fit to the linear-quadratic model using an a/b of 2.0 without a time factor. The literature would indicate that the formula derived by Sheline and coworkers [30] could approximate isoeffect curves for other CNS effects, such as optic neuropathy and spinal cord injury (Table 2) [29,31,32]. Common features for these models are an exponent of N similar to that found by Sheline and coworkers [30] and a nearly 0 exponent of time, T. This emphasizes the importance of the number of fractions, or fraction
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Table 2 Clinical modeling of number of fractions and time for various central nervous system effects Author
Reference
Site/Effect
Exponent of N
Exponent of T
Sheline et al Wara et al van der Kogel Goldsmith et al
[30] [32] [31] [29]
Brain/Necrosis Spinal cord/Myelopathy Spinal cord/Myelopathy Optic nerve/Neuropathy
0.41 0.38 0.4 0.53
0.03 0.058 0 0
Abbreviations: N, number of fractions; T, time.
size, in determining the tolerance dose of normal tissues in the CNS. For normal tissue and, probably, most benign brain tumors, the overall time of treatment is relatively unimportant within the range normally encountered in a single radiation course up to approximately 8 weeks; at that time, repopulation may begin in the normal CNS tissue [31]. Attempts to model isoeffective dose regimens for the risk of optic neuropathy after fractionated radiotherapy have led to a similar model published by Goldsmith and colleagues [29]. They defined the optic ret as follows: Optic ¼ D N0:53 finding that the linear-quadratic model did not fit the data well. They defined a threshold for optic neuropathy defining a ‘‘safe’’ regimen as one resulting in no more than 890 optic ret. This corresponds to 5400 cGy in 30 fractions, 3750 cGy in 15 fractions, and 3000 cGy in 10 fractions, all commonly used fractionation schedules. Although not based on single-fraction data, the optic ret model predicts that a single fraction of 8.9 Gy would be safe to the optic apparatus. This agrees well with single-fraction tolerance doses proposed in the literature, which range from 8 to 10 Gy [33,34]. The total dose predicted by the optic ret model to be safe may be calculated as follows: DðGyÞ ¼
8:9 Gy N0:53
This model emphasizes the well-established importance of fraction size in determining optic nerve tolerance to radiotherapy [35,36]. These data do not seem to extrapolate to other cranial nerves. The tolerance of cranial nerves III through VI seems to be substantially higher than for the optic nerves. Leber and colleagues [34] studied 210 nerves among 50 patients who
received single doses of up to 30 Gy, with no patient developing neuropathy. Urie and coworkers [37] analyzed dose-response data for cranial neuropathies after proton radiotherapy. They found no neuropathies for doses less than 59.3 CGE among 594 cranial nerves and nuclei examined. They estimated a risk of 5% at 70 CGE.
Volume effects in central nervous system normal tissue tolerance In animal models, there is a clear effect of volume on spinal cord tolerance to radiation [27,38]. This effect is more related to length of cord irradiated than to volume. It is not clear what the volume effect on tolerance to noncircumferential irradiation of the spinal cord may be. Experiments done on large animal models, including primates, have shown that the effect of increasing the irradiated volume of spinal cord or brain stem is to lower the threshold and increase the slope of the sigmoid-shaped dose response curve [27]. The volume effect is much more important in the high-dose region than in the low-dose region. For example, increasing the volume-receiving dose associated with a low risk of myelopathy or necrosis does not affect the risk much. In the high-dose region, however, volume reduction may substantially lower the risk of toxicity. The dose-response work of Sheline and colleagues [30] was based largely on patients treated with whole-brain radiotherapy. Recent work has clearly shown the volume of brain irradiated to be a factor in development of postradiation toxicity. A study undertaken by the Radiation Therapy and Oncology Group (RTOG) examined the maximum tolerated dose (MTD) of single-fraction radiosurgery as a function of irradiated volume [39]. Volumes ranging up to 34 cm3 (40-mm diameter) were included, and all tumors were recurrent after previous radiotherapy. Single-dose MTDs were established for volumes of 4.2 to 14 cm3 and volumes of 14.1 to 34 cm3 as 18 Gy and 15 Gy to the
RADIOTHERAPY OF BENIGN INTRACRANIAL TUMORS
target margin, respectively. The MTD for tumors smaller than 4.2 cm3 was not reached at 24 Gy. Doses of 15, 18, and 24 Gy are well in excess of the tolerance dose predicted by the neuret model. The corresponding BEDs are 127.5, 180, and 312 Gy2, respectively. Equivalent doses given in 2-Gy fractions would be 64, 90, and 156 Gy, respectively. Volume effects for optic neuropathy are not well established. It has been proposed that small volumes of optic nerve or chiasm may tolerate higher doses of radiation [40,41], but clear dosevolume guidelines are lacking. Long-term recovery of radiation damage in the central nervous system Reirradiation of critical CNS structures presents an all too common dilemma in radiation oncology. Recurrence of benign disease many years after radiotherapy presents the question of the safety of reirradiation. Most commonly of concern is the tolerance of the optic pathway or spinal cord to reirradiation. There is clear evidence in animal models for long-term repair of radiation damage in the spinal cord. Hornsey and colleagues [42] reported on the long-term repair of rat spinal cord by measuring the dose required to cause myelopathy in 50% of animals 100 days after a dose of radiation. They found significant repair, with the extent of residual damage being dependent on the magnitude of the first dose. Wong and Hao [43] reported similar results, also in rat spinal cord, finding up to 50% recovery after sufficient time, approximately 1 year for the maximum effect. Ang and coworkers [19] have reported on recovery of occult radiation-induced spinal cord injury in rhesus monkeys. Their findings were that significant recovery occurred at 1, 2, and 3 years after fractionated radiation to the cervical and thoracic spine. Based on a 5% incidence of myelopathy, recovery was quantified as 76%, 85%, and 101% at the 1-, 2-, and 3-year intervals, respectively. Histologic analysis revealed a mixture of white matter necrosis and vascular injury in the symptomatic animals, whereas histologically normal spinal cords were found in asymptomatic animals. Nieder and colleagues [44] reported on clinical experience with spinal cord reirradiation. Based on review of the literature, they found that the risk of reirradiation was extremely low for a group of patients with a cumulative effective dose of 135 Gy2 or less, an interval of at least 6 months
75
between courses, and neither course exceeding a dose equivalent to 98 Gy2. There are no good animal models for radiation optic neuropathy. Clinical evidence does suggest that there is long-term repair of radiation damage in the visual pathway, however. Schoenthaler and coworkers [45] reported on 15 patients who underwent a second course of radiotherapy for recurrent pituitary tumors 2 to 17 years after initial treatment with radiotherapy. With follow-up of 1 to 30 years after the second course of treatment, no patient demonstrated an adverse effect of radiation on the optic system. Total doses ranged from 5865 to 10,400 cGy (median of 7935 cGy). Flickinger and colleagues [46] reported on 10 patients retreated for suprasellar tumors 1 to 17 years after initial treatment. Total doses ranged from 7600 to 9865 cGy (median of 8500 cGy). One patient developed optic neuropathy 1.5 years after the second radiation course. Using these data, they estimated that 40% of the initial radiation damage remained as residual and recommend that this value be used cautiously in retreating tumors near the optic nerves and chiasm. Overall, there is compelling evidence that long-term repair of radiation damage occurs in the CNS, particularly in the spinal cord and optic apparatus. This phenomenon is likely at least partly attributable to repopulation of normal cells from surviving stem cell populations or migration of cells from unirradiated tissue [31]. Extrapolation from the preclinical and retrospective clinical data available to clinical practice should be taken with caution, however. The potential benefit of reirradiation, treatment alternatives, and the risk of serious permanent sequelae need to be considered. Strategies to minimize central nervous system neurotoxicity The best approach to avoiding radiationinduced CNS toxicity is always to minimize the dose and volume of irradiated tissue. Careful treatment planning based on modern imaging using CT or MRI scans, effective patient positioning and immobilization devices, and accurate treatment delivery all contribute to the effort to minimize the treated volume and to measure doses to normal structures. Dose-volume histogram analysis is an essential element in the optimization of treatment planning. Inverse treatment planning and intensitymodulated radiotherapy have contributed to a reduction in the volume of normal tissue irradiated
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as well as a reduction in the dose per fraction and total dose. In many situations, when normal structures, especially the optic chiasm, brain stem, or spinal cord, lie adjacent to the tumor to be irradiated, dose fractionation is the better and perhaps only method to allow safe and efficacious treatment. An extreme example of a benign tumor surrounding the dose-limiting normal structure is the optic nerve sheath meningioma. Excellent tumor control has been reported for intracranial meningiomas using single doses of approximately 15 Gy or a fractionated dose of 54 Gy in 30 fractions [47]. In the case of an optic nerve sheath meningioma, however, single fractions are not recommended because the therapeutic dose exceeds the tolerance of the optic nerve. Different dose fractionation schemes may be considered. Based on an estimate of the a/b for meningioma of 3.3 Gy and the optic ret model of Goldsmith and coworkers [29], it has been estimated that at least 22 fractions would be required for the ‘‘safe’’ optic nerve dose to reach a BED to the tumor equivalent to 15 Gy in a single fraction or 54 Gy in 30 fractions [11]. Dose fractionation serves to separate the curves for the TCP and NTCP, thereby increasing the therapeutic index. Fully fractionated radiotherapy has proven to be extremely efficacious and safe for the treatment of optic nerve sheath meningiomas. Five studies published since 2002 using modern imaging and treatment planning demonstrate 100% local control, a 50% rate of visual improvement, and a 5% rate of visual deterioration among 94 patients [48–52]. All patients were treated with conventional fractionation and total doses of 50.4 to 54 Gy. The use of a few doses (hypofractionation) may not fully exploit the advantages of dose fractionation, may offer no significant advantage over a single dose, and is unlikely to improve on the excellent outcome after conventionally fractionated radiotherapy [11]. Early preclinical work has investigated the potential for growth factors to modulate the tolerance of spinal cord to radiation. Andratschke and colleagues [53] have studied the effects of platelet-derived growth factor (PDGF), insulinlike growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF) on rat spinal cord tolerance to radiotherapy. Based on the knowledge that the spinal cord undergoes long-term recovery from radiation, likely attributable to proliferation, differentiation, and migration of neuroepithelial stem cells, it was hypothesized that these growth factors may enhance the ability
of neural tissue to recover from radiation injury. In these studies, daily administration of growth factor significantly increased spinal cord tolerance to radiation. These studies reinforce the hypothesis that stimulation of multipotent neuroepithelial stem cells, endothelial cells, and fibroblasts using growth factors may modulate spinal cord tolerance to radiation. Specific study of the cellular mechanisms of damage and repair after radiation to the nervous system is required to improve our understanding of the potential to protect the CNS from radiation injury. Currently, careful imaging, treatment planning, dose-volume histogram analysis, and precise treatment delivery are the best available tools to prevent injury of the CNS secondary to radiotherapy. Dose fractionation has a long track record of safe and efficacious treatment of benign brain tumors. Single-dose radiosurgery may be preferable when tumor volumes are small and normal tissue tolerance is respected. Fractionated radiotherapy should be considered for larger volumes and when normal structures are at potential risk of injury by the use of high doses per fraction.
References [1] Munzenrider JE, Crowell C. Charged particles. In: Mauch PM, Loeffler JS, editors. Radiation oncology: biology and technology. Philadelphia: WB Saunders; 1994. p. 34–55. [2] Hall E. Radiobiology for the radiologist. 5th edition. Philadelphia: JB Lippincott; 2000. [3] Fertil B, Malaise EP. Intrinsic radiosensitivity of human cell lines correlated with radioresponsiveness of human tumors. Int J Radiat Oncol Biol Phys 1985; 11:1699–707. [4] Taghian A, Suit H, Pardo F, et al. In vitro intrinsic radiation sensitivity of glioblastoma multiforme. Int J Radiat Oncol Biol Phys 1992;23:55–62. [5] Weichselbaum RR, Nove J, Little JB. X-ray sensitivity of human tumor cells in vitro. Int J Radiat Oncol Biol Phys 1980;6:437–40. [6] Elkind MM, Sutton H. X-ray damage and recovery in mammalian cells in culture. Nature 1959;184:1293–5. [7] Withers H. Biologic basis for altered fractionation schemes. Cancer 1985;55(9):2086–95. [8] McBride WH, Withers HR. Biological basis of radiation therapy. In: Perez CA, Brady LW, Halperin EC, editors. Principles and practice of radiation oncology. 4th edition. Philadelphia: Lippincott, Williams & Wilkins; 2004. p. 96–136. [9] Travis EL, Tucker SL. Isoeffect models and fractionated radiation therapy. Int J Radiat Oncol Biol Phys 1987;13:283–7.
RADIOTHERAPY OF BENIGN INTRACRANIAL TUMORS
[10] Thames HD, Withers HR, Peters LJ, et al. Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationships. Int J Radiat Oncol Biol Phys 1982;8: 219–26. [11] Shrieve DC, Hazard L, Boucher K, et al. Dose fractionation in stereotactic radiotherapy for parasellar meningiomas: radiobiological considerations of efficacy and optic nerve tolerance. J Neurosurg 2004; 101:390–5. [12] Flickinger JC, Kondziolka D, Niranjan A, et al. Acoustic neuroma radiosurgery with marginal doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys 2004;60: 225–30. [13] Andrews DW, Suarez O, Goldman HW, et al. Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: comparative observations of 125 patients treated at one institution. Int J Radiat Oncol Biol Phys 2001;50:1265–78. [14] Chan AW, Black PM, Ojemann RG, et al. Stereotactic radiotherapy for vestibular schwannoma: favorable outcome with minimal toxicity. Neurosurgery 2005;57:60–70. [15] Combs SE, Volk S, Schulz-Ertner D, et al. Management of acoustic neuromas with fractionated stereotactic radiotherapy (FSRT): long-term results in 106 patients treated with a single institution. Int J Radiat Oncol Biol Phys 2005;63:75–81. [16] Poen JC, Golby AJ, Forster KM, et al. Fractionated stereotactic radiosurgery and preservation of hearing in patients with vestibular schwannoma: a preliminary report. Neurosurgery 1999;45:1299–305. [17] Wallner KE, Sheline GE, Pitts LH, et al. Efficacy of irradiation for incompletely excised acoustic neurilemomas. J Neurosurg 1987;67:858–63. [18] Williams JA. Fractionated stereotactic radiotherapy for acoustic neuromas. Int J Radiat Oncol Biol Phys 2002;54(2):500–4. [19] Ang KK, Price RE, Stephens LC, et al. The tolerance of primate spinal cord to re-irradiation. Int J Radiat Oncol Biol Phys 1993;25:459–64. [20] Ang KK, Jiang GL, Guttenberger R, et al. Impact of spinal cord repair kinetics on the practice of altered fractionation schedules. Radiother Oncol 1992;25: 287–94. [21] Dische S. Accelerated treatment and radiation myelitis [editorial]. Radiother Oncol 1991;20:1–2. [22] Lyman JT, Wolbarst AB. Optimization of radiation therapy. III. A method of assessing complication probabilities from dose-volume histograms. Int J Radiat Oncol Biol Phys 1987;13:103–9. [23] Alber N, Nusslin F. A representation of an NTCP function for local complication mechanisms. Phys Med Biol 2001;46:439–47. [24] Marks JE, Baglan RJ, Prassad SC, et al. Cerebral radionecrosis: incidence and risk in relation to dose, time, fractionation and volume. Int J Radiat Oncol Biol Phys 1981;7:243–52.
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[25] Marks LB, Spencer DP. The influence of volume on the tolerance of the brain to radiosurgery. J Neurosurg 1991;75:177–80. [26] Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21(1):109–22. [27] Ang KK. Radiation injury to the central nervous system: clinical features and prevention. In: Meyer JL, editor. Radiation injury: advances in management and prevention, vol. 32. Basel (Switzerland): Karger; 1999. p. 145–54. [28] Larson DA, Flickinger JC, Loeffler JS. The radiobiology of radiosurgery. Int J Radiat Oncol Biol Phys 1993;25(3):557–61. [29] Goldsmith BJ, Rosenthal SA, Wara WM, et al. Optic neuropathy after irradiation of meningioma. Radiology 1992;185:71–6. [30] Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys 1980;6(9):1215–28. [31] van der Kogel AJ. Central nervous system radiation injury in small animals. In: Gutin PH, Leibel SA, Sheline GE, editors. Radiation injury in the nervous system. New York: Raven Press; 1991. p. 91–111. [32] Wara WM, Phillips TL, Sheline GE, et al. Radiation tolerance of the spinal cord. Cancer 1975;35: 1558–62. [33] Tishler RB, Loeffler JS, Lunsford LD, et al. Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 1993; 27(2):215–21. [34] Leber KA, Bergloff J, Pendl G. Dose-response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg 1998;88:43–50. [35] Harris JR, Levene MB. Visual complications following irradiation for pituitary adenomas and craniopharyngiomas. Therapeutic Radiology 1976;120: 167–71. [36] Parsons JT, Bova FJ, Fitzgerald CR, et al. Radiation optic neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys 1994;30(4): 755–63. [37] Urie MM, Fullerton B, Tatsuzaki H, et al. A dose response analysis of injury to cranial nerves and/or nuclei following proton beam radiation therapy. Int J Radiat Oncol Biol Phys 1992;23:27–39. [38] Hopewell JW, Morris JH, Dixon-Brown A. The influence of field size on the late tolerance of the rat spinal cord to single doses of X-rays. Br J Radiol 1987;60:1099–108. [39] Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: Final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 2000;47:291–8. [40] Habrand JL, Austin-Seymour M, Birnbaum S, et al. Neurovisual outcome following proton radiation
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[44]
[45]
[46]
[47]
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therapy. Int J Radiat Oncol Biol Phys 1989;16: 1601–6. Martel MK, Sandler HM, Cornblath WT, et al. Dose-volume complication analysis for visual pathway structures of patients with advanced paranasal sinus tumors. Int J Radiat Oncol Biol Phys 1997; 38:273–84. Hornsey S, Myers R, Warren P. Residual injury in the spinal cord after treatment with X rays or neutrons. Br J Radiol 1982;55:516–9. Wong CS, Hao Y. Long-term recovery kinetics of radiation damage in rat spinal cord. Int J Radiat Oncol Biol Phys 1997;37:171–9. Nieder C, Grosu AL, Andratschke NH, et al. Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients. Int J Radiat Oncol Biol Phys 2005;61:851–5. Schoenthaler R, Albright NW, Wara WM, et al. Reirradiation of pituitary adenoma. Int J Radiat Oncol Biol Phys 1992;24(2):307–14. Flickinger JC, Deutsch M, Lunsford LD. Repeat megavoltage irradiation of pituitary and suprasellar tumors. Int J Radiat Oncol Biol Phys 1989;17(1): 171–5. Shrieve DC, Loeffler JS. Fractionated radiotherapy for meningioma. In: Black PM, Loeffler JS, editors. Cancer of the central nervous system. 2nd edition. Boston: Blackwell; 2004. p. 357–62.
[48] Becker G, Jeremic B, Pitz S, et al. Stereotactic fractionated radiotherapy in patients with optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 2002;54:1422–9. [49] Baumert BG, Villa S, Struder G, et al. Early improvement in vision after fractionated stereotactic radiotherapy for primary optic nerve sheath meningioma. Radiother Oncol 2004;72:169–74. [50] Andrews DW, Faroozan R, Yang BP, et al. Fractionated stereotactic radiotherapy for the treatment of optic nerve sheath meningiomas: preliminary observations of 33 optic nerves in 30 patients with historical comparison to observation with or without prior surgery. Neurosurgery 2002;51: 890–902. [51] Liu JK, Forman S, Hershewe GL, et al. Optic nerve sheath meningiomas: visual improvement after stereotactic radiotherapy. Neurosurgery 2002;50: 950–5. [52] Narayan S, Cornblath WT, Sandler HM, et al. Preliminary visual outcomes after three-dimensional conformal radiation therapy for optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 2003; 56:537–43. [53] Andratschke NH, Nieder C, Price RE, et al. Potential role of growth factors in diminishing radiation therapy neural tissue injury. Semin Oncol 2005; 32(Suppl):S67–70.
Basic Principles of Radiobiology Applied to Radiotherapy of Benign Intracranial Tumors Dennis C. Shrieve, MD, PhD Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, 1950 Circle of Hope, Salt Lake City, UT 84112-5560, USA
The use of ionizing radiation in the treatment of benign intracranial tumors may involve one of several types of ionizing radiation given as singlefraction radiosurgery or fractionated radiotherapy. An understanding of the biophysical and radiobiologic principles involved in these treatments is essential to the design and delivery of safe and efficacious treatment. This article discusses the basic radiobiologic principles applicable to radiotherapy of benign brain tumors. Although this issue primarily addresses the radiotherapy of benign brain tumors, much of our knowledge of fractionation schemes, central nervous system (CNS) toxicity, and CNS volume effects for benign brain tumors derives from clinical and animal data involving spinal cord or malignant brain tumors, and some of those data are necessarily included. Types of ionizing radiation Gamma rays and x-rays Gamma rays and x-rays are electromagnetic radiation with energies in the range of 100 to 2 billion electron volts. X-rays are produced when electrons ‘‘fall’’ from a higher to lower energy level, usually in the outer shell of heavy atoms, and are thus produced extranuclearly. X-rays may be the products of radioactivity (electron capture) or may be ‘‘man-made’’ from x-ray tubes or linear accelerators, which accelerate electrons onto a heavy metal target producing a continuous spectrum of photon energies termed bremsstrahlung and monoenergetic characteristic x-rays.
E-mail address: [email protected]
Gamma rays are photons emitted by radioactive nuclei and have a much narrower range of energies than x-rays, 10 keV to 10 MeV. Gamma rays and x-rays are otherwise identical. The most common source of gamma rays used in radiotherapy is cobalt-60 (60Co). 60Co is commercially produced from 59Co and undergoes beta-decay with a half-life of 5.27 years. It is the subsequent gamma emission that makes it applicable to radiotherapy and, perhaps more commonly, to stereotactic radiosurgery, however. Two gamma energies are emitted, 1.17 and 1.33 MeV, with an effective average energy of 1.21 MeV. Protons The use of protons in radiotherapy is based on the physical properties of these particles and the related characteristics of dose deposition in irradiated tissues [1]. Dose deposition is characterized by the Bragg peak. Qualitatively, the entrance dose for particle beams is relatively low compared with photons. An unaltered beam deposits more than 50% of its energy over a 2- to 3-cm narrow path at a depth in water that depends on the beam energy. The beam may be altered to spread the Bragg peak to conform to the thickness and depth of the volume to be treated. The entrance dose is significantly increased in this case, however (Fig. 1). The biologic effectiveness of x-rays, gamma rays, and protons is roughly equivalent, and each is considered to be low linear energy transfer (LET) radiation. Of note, protons have only a slightly higher radiobiologic effectiveness (RBE) than 60Co. In practice, this small difference is adjusted for by calculating the dose for protons in cobalt Gray equivalent (CGE), whether for
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Depth Dose Distribution in Water Spread-out Bragg Peak
100
Surviving Fraction
Relative Dose (%)
120
80 60
10 MVp X rays
40 20 Unmodulated Proton Beam
0
0
4
8
12
16
20
1
0.1
0.01
Depth (cm)
Fig. 1. Depth dose curves shown schematically for a 160-MeV proton beam. Unmodulated and spread-out Bragg peak curves are shown. A 10-MV (peak) x-ray curve is shown for comparison.
single or multiple fractions. Proton radiotherapy and radiosurgery are fully discussed elsewhere in this issue.
Basic principles of radiobiology Direct versus indirect effects of radiation When cells are irradiated with low LET radiation, most photons interact with water molecules by stripping an electron from a hydrogen atom, resulting in a fast electron and an ionized water molecule through Compton scattering. The resulting fast electrons interact with water molecules through further ionizing events. The resulting positively charged water molecules have an extremely short half-life, dissociating into an Hþ ion and an OH$ free hydroxyl radical. The hydroxyl radical is reactive and with sufficient energy to break chemical bonds in nearby (within 2 nm) molecules. It is this indirect effect of radiation through the free radical intermediary that is responsible for approximately 70% of radiation damage. The remaining damage is attributable to the direct effect resulting when the fast electrons themselves interact with biologically important molecules (DNA) [2].
0.001
0
5
10
15
Dose (Gy)
Fig. 2. Curve for mammalian cell survival as a function of dose of radiation (solid line) given as a single fraction. The a/b is 10 Gy, a dose at which the contributions to cell killing by single events (aD, dashed line) and the interaction of sublethal events (bD2) are equal.
a steeply sloped, or more continuously bending, portion at higher doses. In vitro radiosensitivity of cultured human tumor cells has been limited to malignant tumor cell types. Studies on such cell lines have shown that the apparent radiosensitivity depends heavily on culture conditions and the assay used to assess cell survival [3–5]. The shoulder region is interpreted as accumulation of sublethal damage at low doses, with lethality resulting from the interaction of two or more such sublethal events [2,6,7]. It may be considered that DNA is the target molecule for cell killing by ionizing radiation and that a double-strand break in the DNA is necessary and sufficient to cause cell death (defined as loss of ability to divide). Double-strand breaks may be effectively produced by a single-particle track or by the interaction of two single-strand breaks caused by separate particle tracks and occurring closely in space and time (Fig. 3). Single-strand breaks alone may be repaired, and therefore represent sublethal damage. Such a model is described by the following linear-quadratic formula:
Mammalian cell survival curves Cell survival after single doses of ionizing radiation is a probability function of absorbed dose, measured in the unit Gray (Gy), 1 J/kg absorbed dose. Typical mammalian cell survival curves obtained after single-dose irradiation in culture (Fig. 2) have a characteristic shape, including a low-dose shoulder region followed by
2 SF ¼ eðaD þ bD Þ
where SF is the surviving fraction and D is dose of radiation in Gy [8], a is the coefficient related to single-event cell killing, and b is the coefficient related to cell killing through the interaction of sublethal events. a/b is the ratio of the relative
69
RADIOTHERAPY OF BENIGN INTRACRANIAL TUMORS
Radiobiology of fractionated radiotherapy A spectrum of fractionation schedules is used to treat benign intracranial disease, ranging from single-fraction radiosurgery to fully fractionated courses of radiotherapy. For fractionated radiotherapy, each dose (fraction) produces similar biologic effects, given a sufficient interfraction interval (see Fig. 4B). The linear-quadratic formula for fractionated doses becomes
Fig. 3. Schematic representation of double-strand break production by single events (aD) or interaction of events (bD2).
contributions of these two components to overall cell kill. a/b is the single dose at which overall cell killing is equally attributable to these two components (see Fig. 2): aD ¼ bD2 or D ¼ a=b Most mammalian cell survival curves are well fit to the linear-quadratic model [3,4]. Cell survival after a single dose of radiation in vitro reflects the intrinsic radiosensitivity of a particular cell type to a particular type of radiation [3]. Cell types and tissues may vary in the a/b, resulting in slightly different-shaped response curves (Fig. 4A).
A
2 SF ¼ n eadbd where d is the dose per fraction and n is the total number of fractions. A basic principle of radiobiology and radiotherapy is that dose fractionation ‘‘spares’’ virtually all cell and tissue types. In this context, ‘‘sparing’’ means that for a given total dose, there is always less molecular damage and a lower level of biologic effect associated with multiple fractions compared with a single dose. As the number of fractions increases, the total dose (n d) required to achieve a certain level of biologic effect also increases (Fig. 5A). The magnitude of the sparing effect of dose fractionation varies, however, and depends on a/b. The biologically effective dose (BED) is represented by the following equation: d BED Gya=b ¼ nd 1 þ a=b where the BED is expressed in Gya/b to indicate that it should be used only to compare effects in
B
Low α/β
Effect
Effect
High α/β
Low α/β
Dose
High α/β
Dose
Fig. 4. Comparison of single-dose effect curves (A) and fractionated dose-effect curves (B) for low and high a/b tissues. The small advantage seen in the low-dose region sparing low a/b tissues (A) is amplified through dose fractionation (B).
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A 70 60 50 40 30 20 10 0
1.2 1 0.8 0.6 0.4 0.2 0
0
5
10
15
20
25
Relative BED of Fractionated vs Single-Dose RT
B
Relative BED
Total Dose (Gy)
80
Total Dose Required to Acheive BED Equivalent to 20 Gy in a Single Fraction
0
5
10
15
20
25
Number of Fractions
Number of Fractions
Fig. 5. The effect of dose fractionation on the biologic effectiveness of radiation for low a/b (solid lines) versus high a/b (dashed lines) tissues. (A) Isoeffect curves show the increase in total dose required to maintain biologic effectiveness with an increasing number of fractions. (B) Decreasing biologic effectiveness with an increasing number of fractions while maintaining the total dose.
tissues with the same a/b, n is the number of fractions of dose d, and nd is thus the total dose (D). The BED can be expressed as follows: BED Gya=b ¼ D F where F is a fractionation factor: d F¼ 1þ a=b F increases with increasing dose/fraction, d, but the effect is greatest for lower a/b and may be negligible for extremely high a/b, because as a/b increases, F approaches 1. The linear-quadratic formulation is a means of estimating the effects of dose fractionation. Other factors, such as a rapid doubling time, may be accounted for by additional terms [9]. In the context of benign brain tumors, a time factor is not likely to be important and thus has not been included. Mechanistically, a larger a/b indicates relatively little contribution from interaction of sublethal events. A lower a/b indicates a greater contribution from this type of damage. Because sublethal damage may be repaired after a dose of radiation, cells with a lower a/b ratio are spared to a greater extent by fractionation than are cell types with a larger a/b ratio (see Figs. 4 and 5). This is the basis for fractionated radiotherapy. Malignant tumors and other rapidly proliferating tissues (eg, skin, mucosa, bone marrow) demonstrate high a/b (8–12) and exhibit modest
sparing through dose fractionation. Many normal tissues, including those of the CNS, have lower a/b (2–4) and demonstrate marked sparing with dose fractionation [7,10]. This effect is demonstrated by comparing the total dose required to maintain the BED or the BED for a given total dose delivered in various numbers of fractions (see Fig. 5). The magnitude of this effect of dose fractionation is quantitatively different for low versus high a/b tissues. This forms the basis for simultaneously maintaining efficacy for tissues with high a/b while decreasing toxicity for tissues with low a/b through dose fractionation. Little information is available for the a/b of benign brain tumors. Using clinical data, it may be possible to estimate a/b based on isoeffective fractionation schedules. If two fractionation schedules result in an equivalent clinical effect, they may be assumed to have the same BED and the linear-quadratic model may be used to calculate the a/b [11]. Because BED Gya=b
d ¼D 1þ a=b
by setting BED1 ¼ BED2, the unknown a/b is calculated as follows: BED1 ¼ BED2 or d1 d2 ¼ D2 1 þ D1 1 þ a=b a=b
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RADIOTHERAPY OF BENIGN INTRACRANIAL TUMORS
to have a clear advantage in terms of therapeutic ratio, because each results in excellent tumor control and equivalent rates of preservation of useful hearing.
or a=b ¼
ðD2 d2 Þ ðD1 d1 Þ ðD1 D2 Þ
This approach has been used to estimate a/b for benign meningioma, assuming, based on clinical data, that single-dose radiosurgery of 15 Gy and fractionated treatment of 54 Gy in 30 fractions result in equivalent local control. The resulting a/b is 3.3 [11]. Although meningiomas have been almost exclusively treated with radiosurgery or fully fractionated radiotherapy, acoustic neuromas have been treated with a number of fractionation schedules (Table 1). Historically, single-fraction radiosurgery doses have decreased from approximately 18 Gy to 12 to 13 Gy without compromise of local tumor control and with a significant decrease in morbidity, including hearing loss and trigeminal and facial neuropathies [12]. Equivalent local control and levels of hearing preservation have been achieved with schedules of between 1 and 32 fractions without significant trigeminal or facial neuropathies [13–18]. Using these data, a/b of between 2 and 3 Gy provides a reasonable fit (Fig. 6). What is clear from this analysis is that a/b for acoustics is not near the 10-Gy value assumed and measured for many malignant tumors. It should also be pointed out that none of these fractionation schedules seems
Time interval required for maximal repair between fractions Allowing for a sufficient time between fractions to permit maximal repair of sublethal damage in normal tissues is crucial to take full advantage of the sparing effects of dose fractionation. The best information on the kinetics of repair of sublethal radiation damage in the CNS comes from the work of Ang and colleagues [19]. They found biexponential repair kinetics with half-times of 0.7 and 3.8 hours for the fast and slow components, respectively. This work indicates that even a 6- to 8-hour interval leads to accumulation of unrepaired sublethal damage and lowers the tolerance dose of the spinal cord [20]. This prediction has been supported by increased rates of myelopathy in patients treated for head and neck cancers with three fractions per day [21]. Model predicting tumor control probability based on cell survival The probability of tumor control (TCP) is a function of the likelihood of inactivating all tumor cells in a given tumor according to Poisson statistics. If it is assumed that every tumor cell
Table 1 Fractionation schedules used to treat acoustic neuromas Calculated a/ba
BED (Gy3)
Local control
Hearing preservation
1
d
69
21
3
2.75
70
[18]
25
5
3.67
67
Williams
[18]
30
10
4.65
60
Wallner et al
[17]
45
25
2.75
72
70% 6 years 77% 2 years 70% 3 years 100% 3 years d
Andrews et al
[13]
50
25
1.86
83
Chan et al
[14]
54
30
1.75
86
Combs et al
[15]
57.6
32
1.46
92
99% 6 years 97% 2 years 100% d 100% d 94% 15 years 97 3 years 98% 5 years 93% 5 years
Author
Reference
Total dose
Flickinger et al
[12]
13
Poen et al
[16]
Williams
a
Fractions
a/b calculated assuming isoeffectiveness with 13 Gy in one fraction.
70 3 years 88% 3 years 94% 5 years
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70
It should be appreciated that radiosensitivity is not equivalent to radioresponsiveness. Some CNS tumors are extremely radioresponsive but inevitably recur (eg, CNS lymphoma), whereas others may show little or no radiographic evidence of response but are well controlled by modest radiation doses (eg, meningioma, acoustic neuroma).
Total Dose (Gy)
60 2
50
3
40 30
10
20 10 0
5
0
10
15
20
25
30
35
Normal tissue radiobiology
Number of Fractions
Model predicting normal tissue complications
Fig. 6. Total dose versus number of fractions for reported treatment regimens used successfully to treat acoustic neuromas (see Table 1). Symbols represent data points. Curves represent modeling for a/b of 2, 3, and 10 Gy ‘‘anchored’’ at 13 Gy in a single fraction (see text for discussion).
The radiation oncologist must be concerned not only with the effects of treatment on tumor but with normal tissue effects. The normal tissues of particular interest in the treatment of benign brain tumors are the spinal cord, brain stem, optic apparatus, other cranial nerves, and brain parenchyma. Also of interest are effects on the vasculature within normal and tumor tissue. The probability of normal tissue complication (NTCP) after radiotherapy is, like the TCP, a function of dose and dose per fraction (BED), the tissue at risk (radiosensitivity), and the volume irradiated. The NTCP has been shown to be well represented by the following model:
must be killed to control a tumor, the TCP is given by the following equation: TCP ¼ eSFN where SF is the surviving fraction and N is the total number of cells in the tumor. SF N is then the average number of cells remaining in a tumor receiving a certain treatment. The TCP is then the probability of no cells remaining viable under these conditions. The TCP is a function of total dose and dose per fraction (BED), N (tumor bulk), and radiosensitivity of the tumor. This model leads to a sigmoid dose response curve for the TCP (Fig. 7).
A
NTCP ¼ 1 expR where R is the variable related to dose and volume: R ¼ ðd=d0 Þk
B
1
TCP
0.8 0.7 0.6 0.5 0.4
Uncomplicated Cures
0.3
0.6 0.5 0.4 0.3 0.2
0.1
0.1 0
5
10
15
Dose (Gy)
20
25
NTCP
0.7
0.2 0
TCP
0.8
NTCP
TCP/NTCP
TCP/NTCP
1 0.9
0.9
30
0
Uncomplicated Cures
0
20
40
60
80
100
120
Dose (Gy)
Fig. 7. Curves schematically comparing the probability of tumor control (TCP) with the probability of normal tissue complication (NTCP). (A) Curves are positioned relatively close to one another. Normal tissue complications may be avoided only by minimizing the dose to the critical normal structure. Such a situation may occur when a normal structure, such as the optic nerve, lies adjacent to a benign tumor being treated with single-dose radiosurgery. (B) Dose fractionation separates the TCP and NTCP curves, allowing for a higher probability of tumor control without a significant risk of normal tissue complication. The ‘‘Uncomplicated Cures’’ curve is TCP-NTCP.
RADIOTHERAPY OF BENIGN INTRACRANIAL TUMORS
with d0 determining the slope of the NTCP versus dose curve and k being a constant accounting for volume effects [22,23]. This is represented graphically as a sigmoid-shaped curve similar to that obtained for tumor cure (see Fig. 7). Curves for a wide variety of normal tissue end points have been generated. Although each has a similar shape, the relative placement of these curves along the dose axis may be quite different. In clinical radiotherapy, the relative positions of the curves for tumor cure and normal tissue complication define what is known as the therapeutic ratio. The therapeutic ratio may be calculated as follows: Probability of Tumor Cure Probability of Complication An ideal therapeutic ratio would be described by curves that allow 100% tumor cure without an appreciable NTCP. The opposite extreme would be exemplified by a tumor requiring high-dose radiation for cure located within a critical normal structure with a low tolerance to radiation. In practice, a regimen that maximizes the probability of an uncomplicated cure is optimal (see Fig. 7). For the situation where a/b for a tumor is higher than that for critical normal tissue, dose fractionation always serves to separate the TCP and NTCP curves and to increase the therapeutic ratio. The tolerance dose for specific tissues is a function of the selected toxicity end point, volume irradiated, total dose, dose per fraction used, and level of acceptable risk [24–27]. For example, the total dose to cause necrosis of the spinal cord in 5% of patients treated with a single dose of radiosurgery is vastly different than the dose associated with the same risk when conventional fractionation (1.8–2 cGy per day) is used [28]. The concept of tolerance dose may be useful in some situations. Tolerance doses may be expressed as D5/5, or the dose expected to produce complication in 5% of patients within 5 years of treatment [26]. This concept may be useful for effects like necrosis or pituitary dysfunction but is not useful for effects like optic neuropathy. Ideally, when dealing with benign tumor treatment, a dose regimen thought to be ‘‘safe’’ to the optic apparatus would seem to be the better choice. A dose and fractionation scheme that is effective in achieving tumor control and below the ‘‘threshold’’ for visual impairment would be optimal [11,29].
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Models to compare the biologically effective dose of different fractionation schemes It is important when investigating nonconventional fractionation schemes to have some basis for the choice of fraction size, total dose, and interval between fractions. If a/b were well established for all tumors and normal tissues, the linear-quadratic model would provide such a basis. The BED for a given total dose, D, and dose per fraction, d, is given by the following equation: d BED Gya=b ¼ D 1 þ a=b where the BED is expressed in Gya/b to indicate that the BED is applicable only to tissues with a given a/b. The formula for BED can be used to compare dose regimens of varying total doses and dose per fraction in a particular tissue. The equation may also be used to determine isoeffective total doses, D, associated with different doses per fraction, d, as follows: D1 =D2 ¼ ða=b þ d2 Þ=ða=b þ d1 Þ Sheline and coworkers [30] described a model for predicting the risk of brain necrosis as a function of total dose and number of fractions. The model defined an isoeffect line for total dose as a function of fraction number. They defined the neuret, similar to BED as follows: Neuret ¼ D N0:41 T0:03 where D is the total dose in cGy, N is the number of fractions, and T is the overall time in days. This relation demonstrated the strong dependence on N, a surrogate for fraction size, and the weak dependence on overall time, T. These data may also be well fit to the linear-quadratic model using an a/b of 2.0 without a time factor. The literature would indicate that the formula derived by Sheline and coworkers [30] could approximate isoeffect curves for other CNS effects, such as optic neuropathy and spinal cord injury (Table 2) [29,31,32]. Common features for these models are an exponent of N similar to that found by Sheline and coworkers [30] and a nearly 0 exponent of time, T. This emphasizes the importance of the number of fractions, or fraction
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Table 2 Clinical modeling of number of fractions and time for various central nervous system effects Author
Reference
Site/Effect
Exponent of N
Exponent of T
Sheline et al Wara et al van der Kogel Goldsmith et al
[30] [32] [31] [29]
Brain/Necrosis Spinal cord/Myelopathy Spinal cord/Myelopathy Optic nerve/Neuropathy
0.41 0.38 0.4 0.53
0.03 0.058 0 0
Abbreviations: N, number of fractions; T, time.
size, in determining the tolerance dose of normal tissues in the CNS. For normal tissue and, probably, most benign brain tumors, the overall time of treatment is relatively unimportant within the range normally encountered in a single radiation course up to approximately 8 weeks; at that time, repopulation may begin in the normal CNS tissue [31]. Attempts to model isoeffective dose regimens for the risk of optic neuropathy after fractionated radiotherapy have led to a similar model published by Goldsmith and colleagues [29]. They defined the optic ret as follows: Optic ¼ D N0:53 finding that the linear-quadratic model did not fit the data well. They defined a threshold for optic neuropathy defining a ‘‘safe’’ regimen as one resulting in no more than 890 optic ret. This corresponds to 5400 cGy in 30 fractions, 3750 cGy in 15 fractions, and 3000 cGy in 10 fractions, all commonly used fractionation schedules. Although not based on single-fraction data, the optic ret model predicts that a single fraction of 8.9 Gy would be safe to the optic apparatus. This agrees well with single-fraction tolerance doses proposed in the literature, which range from 8 to 10 Gy [33,34]. The total dose predicted by the optic ret model to be safe may be calculated as follows: DðGyÞ ¼
8:9 Gy N0:53
This model emphasizes the well-established importance of fraction size in determining optic nerve tolerance to radiotherapy [35,36]. These data do not seem to extrapolate to other cranial nerves. The tolerance of cranial nerves III through VI seems to be substantially higher than for the optic nerves. Leber and colleagues [34] studied 210 nerves among 50 patients who
received single doses of up to 30 Gy, with no patient developing neuropathy. Urie and coworkers [37] analyzed dose-response data for cranial neuropathies after proton radiotherapy. They found no neuropathies for doses less than 59.3 CGE among 594 cranial nerves and nuclei examined. They estimated a risk of 5% at 70 CGE.
Volume effects in central nervous system normal tissue tolerance In animal models, there is a clear effect of volume on spinal cord tolerance to radiation [27,38]. This effect is more related to length of cord irradiated than to volume. It is not clear what the volume effect on tolerance to noncircumferential irradiation of the spinal cord may be. Experiments done on large animal models, including primates, have shown that the effect of increasing the irradiated volume of spinal cord or brain stem is to lower the threshold and increase the slope of the sigmoid-shaped dose response curve [27]. The volume effect is much more important in the high-dose region than in the low-dose region. For example, increasing the volume-receiving dose associated with a low risk of myelopathy or necrosis does not affect the risk much. In the high-dose region, however, volume reduction may substantially lower the risk of toxicity. The dose-response work of Sheline and colleagues [30] was based largely on patients treated with whole-brain radiotherapy. Recent work has clearly shown the volume of brain irradiated to be a factor in development of postradiation toxicity. A study undertaken by the Radiation Therapy and Oncology Group (RTOG) examined the maximum tolerated dose (MTD) of single-fraction radiosurgery as a function of irradiated volume [39]. Volumes ranging up to 34 cm3 (40-mm diameter) were included, and all tumors were recurrent after previous radiotherapy. Single-dose MTDs were established for volumes of 4.2 to 14 cm3 and volumes of 14.1 to 34 cm3 as 18 Gy and 15 Gy to the
RADIOTHERAPY OF BENIGN INTRACRANIAL TUMORS
target margin, respectively. The MTD for tumors smaller than 4.2 cm3 was not reached at 24 Gy. Doses of 15, 18, and 24 Gy are well in excess of the tolerance dose predicted by the neuret model. The corresponding BEDs are 127.5, 180, and 312 Gy2, respectively. Equivalent doses given in 2-Gy fractions would be 64, 90, and 156 Gy, respectively. Volume effects for optic neuropathy are not well established. It has been proposed that small volumes of optic nerve or chiasm may tolerate higher doses of radiation [40,41], but clear dosevolume guidelines are lacking. Long-term recovery of radiation damage in the central nervous system Reirradiation of critical CNS structures presents an all too common dilemma in radiation oncology. Recurrence of benign disease many years after radiotherapy presents the question of the safety of reirradiation. Most commonly of concern is the tolerance of the optic pathway or spinal cord to reirradiation. There is clear evidence in animal models for long-term repair of radiation damage in the spinal cord. Hornsey and colleagues [42] reported on the long-term repair of rat spinal cord by measuring the dose required to cause myelopathy in 50% of animals 100 days after a dose of radiation. They found significant repair, with the extent of residual damage being dependent on the magnitude of the first dose. Wong and Hao [43] reported similar results, also in rat spinal cord, finding up to 50% recovery after sufficient time, approximately 1 year for the maximum effect. Ang and coworkers [19] have reported on recovery of occult radiation-induced spinal cord injury in rhesus monkeys. Their findings were that significant recovery occurred at 1, 2, and 3 years after fractionated radiation to the cervical and thoracic spine. Based on a 5% incidence of myelopathy, recovery was quantified as 76%, 85%, and 101% at the 1-, 2-, and 3-year intervals, respectively. Histologic analysis revealed a mixture of white matter necrosis and vascular injury in the symptomatic animals, whereas histologically normal spinal cords were found in asymptomatic animals. Nieder and colleagues [44] reported on clinical experience with spinal cord reirradiation. Based on review of the literature, they found that the risk of reirradiation was extremely low for a group of patients with a cumulative effective dose of 135 Gy2 or less, an interval of at least 6 months
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between courses, and neither course exceeding a dose equivalent to 98 Gy2. There are no good animal models for radiation optic neuropathy. Clinical evidence does suggest that there is long-term repair of radiation damage in the visual pathway, however. Schoenthaler and coworkers [45] reported on 15 patients who underwent a second course of radiotherapy for recurrent pituitary tumors 2 to 17 years after initial treatment with radiotherapy. With follow-up of 1 to 30 years after the second course of treatment, no patient demonstrated an adverse effect of radiation on the optic system. Total doses ranged from 5865 to 10,400 cGy (median of 7935 cGy). Flickinger and colleagues [46] reported on 10 patients retreated for suprasellar tumors 1 to 17 years after initial treatment. Total doses ranged from 7600 to 9865 cGy (median of 8500 cGy). One patient developed optic neuropathy 1.5 years after the second radiation course. Using these data, they estimated that 40% of the initial radiation damage remained as residual and recommend that this value be used cautiously in retreating tumors near the optic nerves and chiasm. Overall, there is compelling evidence that long-term repair of radiation damage occurs in the CNS, particularly in the spinal cord and optic apparatus. This phenomenon is likely at least partly attributable to repopulation of normal cells from surviving stem cell populations or migration of cells from unirradiated tissue [31]. Extrapolation from the preclinical and retrospective clinical data available to clinical practice should be taken with caution, however. The potential benefit of reirradiation, treatment alternatives, and the risk of serious permanent sequelae need to be considered. Strategies to minimize central nervous system neurotoxicity The best approach to avoiding radiationinduced CNS toxicity is always to minimize the dose and volume of irradiated tissue. Careful treatment planning based on modern imaging using CT or MRI scans, effective patient positioning and immobilization devices, and accurate treatment delivery all contribute to the effort to minimize the treated volume and to measure doses to normal structures. Dose-volume histogram analysis is an essential element in the optimization of treatment planning. Inverse treatment planning and intensitymodulated radiotherapy have contributed to a reduction in the volume of normal tissue irradiated
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as well as a reduction in the dose per fraction and total dose. In many situations, when normal structures, especially the optic chiasm, brain stem, or spinal cord, lie adjacent to the tumor to be irradiated, dose fractionation is the better and perhaps only method to allow safe and efficacious treatment. An extreme example of a benign tumor surrounding the dose-limiting normal structure is the optic nerve sheath meningioma. Excellent tumor control has been reported for intracranial meningiomas using single doses of approximately 15 Gy or a fractionated dose of 54 Gy in 30 fractions [47]. In the case of an optic nerve sheath meningioma, however, single fractions are not recommended because the therapeutic dose exceeds the tolerance of the optic nerve. Different dose fractionation schemes may be considered. Based on an estimate of the a/b for meningioma of 3.3 Gy and the optic ret model of Goldsmith and coworkers [29], it has been estimated that at least 22 fractions would be required for the ‘‘safe’’ optic nerve dose to reach a BED to the tumor equivalent to 15 Gy in a single fraction or 54 Gy in 30 fractions [11]. Dose fractionation serves to separate the curves for the TCP and NTCP, thereby increasing the therapeutic index. Fully fractionated radiotherapy has proven to be extremely efficacious and safe for the treatment of optic nerve sheath meningiomas. Five studies published since 2002 using modern imaging and treatment planning demonstrate 100% local control, a 50% rate of visual improvement, and a 5% rate of visual deterioration among 94 patients [48–52]. All patients were treated with conventional fractionation and total doses of 50.4 to 54 Gy. The use of a few doses (hypofractionation) may not fully exploit the advantages of dose fractionation, may offer no significant advantage over a single dose, and is unlikely to improve on the excellent outcome after conventionally fractionated radiotherapy [11]. Early preclinical work has investigated the potential for growth factors to modulate the tolerance of spinal cord to radiation. Andratschke and colleagues [53] have studied the effects of platelet-derived growth factor (PDGF), insulinlike growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF) on rat spinal cord tolerance to radiotherapy. Based on the knowledge that the spinal cord undergoes long-term recovery from radiation, likely attributable to proliferation, differentiation, and migration of neuroepithelial stem cells, it was hypothesized that these growth factors may enhance the ability
of neural tissue to recover from radiation injury. In these studies, daily administration of growth factor significantly increased spinal cord tolerance to radiation. These studies reinforce the hypothesis that stimulation of multipotent neuroepithelial stem cells, endothelial cells, and fibroblasts using growth factors may modulate spinal cord tolerance to radiation. Specific study of the cellular mechanisms of damage and repair after radiation to the nervous system is required to improve our understanding of the potential to protect the CNS from radiation injury. Currently, careful imaging, treatment planning, dose-volume histogram analysis, and precise treatment delivery are the best available tools to prevent injury of the CNS secondary to radiotherapy. Dose fractionation has a long track record of safe and efficacious treatment of benign brain tumors. Single-dose radiosurgery may be preferable when tumor volumes are small and normal tissue tolerance is respected. Fractionated radiotherapy should be considered for larger volumes and when normal structures are at potential risk of injury by the use of high doses per fraction.
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[48] Becker G, Jeremic B, Pitz S, et al. Stereotactic fractionated radiotherapy in patients with optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 2002;54:1422–9. [49] Baumert BG, Villa S, Struder G, et al. Early improvement in vision after fractionated stereotactic radiotherapy for primary optic nerve sheath meningioma. Radiother Oncol 2004;72:169–74. [50] Andrews DW, Faroozan R, Yang BP, et al. Fractionated stereotactic radiotherapy for the treatment of optic nerve sheath meningiomas: preliminary observations of 33 optic nerves in 30 patients with historical comparison to observation with or without prior surgery. Neurosurgery 2002;51: 890–902. [51] Liu JK, Forman S, Hershewe GL, et al. Optic nerve sheath meningiomas: visual improvement after stereotactic radiotherapy. Neurosurgery 2002;50: 950–5. [52] Narayan S, Cornblath WT, Sandler HM, et al. Preliminary visual outcomes after three-dimensional conformal radiation therapy for optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 2003; 56:537–43. [53] Andratschke NH, Nieder C, Price RE, et al. Potential role of growth factors in diminishing radiation therapy neural tissue injury. Semin Oncol 2005; 32(Suppl):S67–70.