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Adaptive radiation therapy

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1997 Phys. Med. Biol. 42 123
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Phys. Med. Biol. 42 (1997) 123132. Printed in the UK

PII: S0031-9155(97)67292-9

Adaptive radiation therapy

Di Yan, Frank Vicini, John Wong and Alvaro Martinez
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073, USA
Received 11 August 1995, in final form 29 August 1996
Abstract. Adaptive radiation therapy is a closed-loop radiation treatment process where the
treatment plan can be modified using a systematic feedback of measurements. Adaptive radiation
therapy intends to improve radiation treatment by systematically monitoring treatment variations
and incorporating them to re-optimize the treatment plan early on during the course of treatment.
In this process, field margin and treatment dose can be routinely customized to each individual
patient to achieve a safe dose escalation.

1. Introduction
One of the major efforts in radiotherapy has been in reducing the effect of treatment
variations, such as beam placement errors and geometric variation of treatment target
and critical normal organs. To compensate for these variations, a pre-defined uniform
margin or nonuniform margin around the clinical target volume (CTV) has been suggested
for treatment planning (ICRU 1993). Different strategies on margin design have been
explored in treatment planning (Goitein 1985, Kutcher et al 1995, Leong 1987, Urie et al
1991). However, radiation treatment planning with current compensation strategies has not
been customized to the individual patients variation. This could diminish the application
of treatment planning optimization, and the application of conformal therapy and dose
escalation.
With advanced technology, treatment position variation due to beam displacement and
target geometric variation becomes measurable in the process of radiation treatment. It also
becomes practical to adapt the treatment plan to measured variations during the treatment
course of an individual patient. A radiation treatment process where the treatment plan
can be modified using a systematic feedback of measurements is named adaptive radiation
therapy (ART). In this paper, ART is conceptually introduced and discussed with the
consideration of the positional variation of treatment beam and target.
2. Methods and materials
2.1. Implementation of the ART process
A closed-loop feedback process needs to be implemented for ART. In this process, the
positional variation of treatment beam and internal organ motion for each individual patient
are systematically monitored and characterized. Position variation can be detected using
E-mail: dyan@beaumont.edu
c 1997 IOP Publishing Ltd
0031-9155/97/010123+10$19.50

123

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Di Yan et al

an electronic portal imaging device (EPID) and a CT scanner. For the individual patient,
systematic error and the standard deviation of beam placement can be estimated using daily
portal images from a few initial treatments (Bel et al 1993, Denham et al 1993, Yan
et al 1995). Meanwhile, geometric distribution of the treatment target variation can be
estimated using a few sequential CT scans. Parameters in an initial treatment plan such as
treatment dose and field margin as well as field shape, beam intensity and geometry will be
modified, if necessary, incorporating the characterized variation. Successive treatments then
will proceed using the modified treatment plan. This process can be repeated if necessary
during the entire treatment course.
To implement the ART process efficiently, advanced technologies such as an EPID,
a CT scanner, a treatment verification tool, a 3D treatment planning system, a computer
controlled multileaf collimator (MLC) and a therapy machine need to be integrated. A
controller can be implemented to manage the whole process. This controller will track the
status of the treatment process and make decisions when adaptive modifications need to be
applied.

2.2. Safe dose escalation in the ART process

Volume effect or normal tissue tolerance in radiation treatment has been the main barrier
for radiation dose escalation. In order to achieve larger dose escalations, reductions in the
treatment field margin are clearly helpful. A recent RTOG study (3D-CRT Oncology Group
1995) on prostate conformal therapy demonstrated that treatment dose could be escalated
to approximately 10% higher than the conventional treatment dose if a 0.8 cm field margin
was used to replace the conventional margin, and 19% higher if a 0.5 cm margin was used.
However, margin reduction has been limited partially due to the positional variation in the
treatment process, which could create a large dose deviation inside the treatment target if
an inadequate margin is used. As pointed out by Goitein in earlier studies (Goitein and
Busse 1975, Goitein 1985, 1986), approximately two standard deviations (95% confidence)
of positional variation are necessary for the treatment field margin to prevent significant
reductions on tumour local control. There has been less opportunity to reduce treatment field
margin in the conventional treatment process. This is because the margin in a treatment plan
is designed to compensate for a variation averaged from patient populations, and remains
unchanged in whole treatment process.
Field margin used in the initial treatment planning commonly refers to the standard
deviation of positional variation measured from patient populations, which is also equal to
the mean of the standard deviations calculated from individual patient variations. The
treatment dose in conventional radiotherapy has been designed based on this margin.
Therefore, the margin could appear too large for a patient with smaller variation such
that the opportunity of a larger dose escalation would be missed. On the other hand, when
a patient is treated with a larger variation, the margin might be too small such that the
target dose would be significantly deviated, and adjacent normal tissue would suffer more
radiation dose.
In the ART process, the field margin in the treatment plan can be customized to
the individual patient variation, and treatment dose can be safely escalated based on the
customized margin. Implementation of the ART process may not enlarge, on average, the
level of dose escalation significantly. However, it will be more appropriate and more safe
since a customized field margin and treatment dose are applied to the individual patient.

Adaptive radiation therapy

125

2.3. Optimization of the ART process

Safe dose escalation in the ART process can be implemented considering two main factors.
One indicates a relationship between the customized field margin and appropriate treatment
dose. The appropriate treatment dose can be obtained using a 3D planning simulation.
In the simulation, the individual variation and field margin can be applied to the initial
treatment plan, and the treatment dose can be defined under a condition of fixed normal
tissue tolerance such as the normal tissue complication probability (NTCP). Meanwhile,
incorporating the same variation, the other relationship between customized field margin
and target dose deviation can also be obtained.
It is assumed that the target dose in the initial treatment plan has the mean D0 , defined
as treatment dose, and the standard deviation D0 , defined as target dose deviation. Both are
calculated by applying an uniform margin, b , and the mean variation, , in the treatment
planning, where is the standard deviation of position variation measured from patient
populations, and b is the confidence factor (b = 1.52 has been commonly used). On the
other hand, a modified plan has an appropriate treatment dose, D, and a customized margin
ci , where i represents the standard deviation of position variation for the patient i, and
c is the corresponding factor for the confidence. Furthermore, D indicates the target dose
deviation in the modified plan where the customized margin, ci , and position variation, i ,
are presented. Therefore, by normalizing to D0 and D0 respectively, the two relationships
can be denoted as D/D0 = f (c, i ), and D /D0 = g(c, i ).
Treatment optimization in the ART process focuses on searching for the best compromise
between customized margin and appropriate treatment dose by incorporating the individual
patients variation measured from initial treatments. Optimal solutions of treatment dose,
D, and margin, ci , can be applied to the remaining treatments in the ART process after
the individual variation, i , is estimated. An optimization model for the ART process, with
the intention of maximizing tumour control probability (TCP) under a limited NTCP, is
proposed as follows (see the appendix for details):
max{1TCP(D, c) = TCP1
int 1}
=

2 2
D )/(1 2 D2 )]
(1 2 D2 )1/2 exp[(m D + 0.52 D 2 + 0.5m
2 1/2
2
2
2
2
(1 D0 )
exp[(m D0 + 0.5 D0 + 0.5m D2 0 )/(1 2 D2 0 )]

with constraints, D 6 D0 f (c, i ), D = D0 g(c, i ), where the objective function 1TCP(D,

c) represents the increment of the TCP related to the initial treatment plan, when customized
margin ci and appropriate treatment dose, D, are applied to the successive treatments of
patient i. TCPint represents the tumour control probability of the initial treatment plan when
treatment dose D0 and margin b are applied to the treatment. m and are the mean
and standard deviation of radiation sensitivity of human tumours.
To apply the optimization in the ART process some pre-knowledge is required. Radiation
sensitivities of human tumours have been reported from different clinical studies (Peacock
et al 1992, Thames et al 1989, William et al 1985). A random spread around a mean
sensitivity m has been suggested in previous works (Bentzen et al 1990, Kallman et al
1992, Webb and Nahum 1993) to fit the shallow clinical dose response by using the linear
quadratic model of tumour survival. Analytic function forms of f and g are not necessary,
and the optimal solution can be iteratively searched for by substituting a customized margin
and appropriate dose to the initial treatment plan. However, if the analytic forms of f and
g were obtained from a planning simulation, the optimal solution of treatment dose, D ,
and the confidence factor, c , could be expressed as explicit functions for each individual
variation, i . This could be achieved by applying the KuhnTucker (1951) optimization

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Di Yan et al

Figure 1. Treatment dose and target dose deviation in the planning simulation corresponding to
different treatment field margins and confidence levels.

condition to the above optimization problem.

Optimal compromise between the customized field margin and appropriate treatment
dose is related to not only the dose response for a given tumour and normal tissues but
also the initial treatment plan. Treatment beam arrangement and geometry in the initial
treatment plan will affect the optimal solution in the ART process, since the function form
of f (c, i ) and g(c, i ) are directly related to them. Finally, instead of using TCP and
NTCP in the optimization model, maximizing the minimum dose in the target with limits of
normal tissue tolerance and target dose heterogeneity can also be used for the optimization.

3. Discussion
The importance of using an adaptive process in radiation therapy is that the treatment plan,
especially the margin and treatment dose, can eventually be customized to the individual
patient. Optimization can then be more efficiently implemented incorporating the actual
variation of the individual patient. Optimization in the ART process emphasizes the tradeoff between customized field margin and appropriate treatment dose. A customized margin
with a fixed confidence level such as 95% (c = 2) can be applied to each case in the ART
process; however this may not be optimal. In fact, the optimal confidence level for a given
treatment site is most likely dependent on the patients variation and treatment dose. This
will be discussed in detail using the following example of a prostate treatment.
3.1. Simulation of the ART process
It was assumed that a patient with locally advanced prostate cancer and pre- treatment
PSA > 10 ng ml1 was treated with the ART process, where a customized margin

Adaptive radiation therapy

127

Figure 2. A TCP curve for locally advanced prostate cancer with pre-treatment PSA>
10 ng ml1 . The two squares on the plot indicate the clinical data used for the fit.

and appropriate dose were applied after the deviation (i ) was estimated. It was also
assumed that a standard technique of four beams (four-field box) was used for the initial
treatment plan, where 1 cm field margin was used with a confidence level of 95% to
compensate for a global variation ( = 0.5 cm) averaged from patient populations. Under
the constraint of a rectal complication rate less than or equal to 5%, the treatment dose,
D0 = 72 Gy, and dose deviation, D0 = 1.8 Gy (2.5% of treatment dose), were calculated
incorporating the global variations. The rectal complication was calculated using the
Lyman NTCP model (Burman et al 1991, Kutcher and Burman 1989, Lyman and Wolbarst
1987).
It is assumed that the i = 0.3 cm was estimated using the initially measured variations.
A planning simulation was accomplished to determine the relations D = D0 f (c, i ) and
D = D0 g(c, i ). Applying different confidence factors on customized margin, ci , the
function f (c, i ) for the appropriate treatment dose, D, was resolved by employing each
margin ci in the initial plan with the same limit of rectal complication. Meanwhile,
the function g(c, i ) for target dose deviation D was also calculated. The values of
appropriate treatment dose and target dose deviation are plotted in figure 1 for each
corresponding confidence factor from c = 1 (68% confidence), which represented an
aggressive margin, to c = 2.5 (98% confidence), which represented a conservative margin.
Different combinations of treatment dose and margin could be selected from these data for
the rest of the treatments. Among them, the optimal one could be determined using the
optimization model introduced in the last section, where the doseresponse relationship of
prostate cancer is required.

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Di Yan et al

Figure 3. Iso-samples of 1TCP against target dose deviation for each treatment dose from 74
to 77 Gy. The overlaid curve indicates the TCP increment when each of the modified treatment
doses and margins were applied for remaining treatments in the ART process.

3.2. The TCP curve for prostate cancer

The TCP curve for locally advanced prostate cancer was created by using the TCP expression
(A1) in the appendix to fit the clinical dose response data reported from different clinical
studies (Horowitz et al 1996). Only patients with known pre-treatment PSA > 10 ng ml1
were used for this TCP curve. The tumour local control rate was assumed to be equal to the
actuarial biochemical control rate, which was defined as post-treatment PSA 6 1.5 ng ml1
and not more than one consecutive increase in 5 years. It was also assumed that the
average number of clonogenic cells, N0 , for prostate cancer was equal to 8 107 (assuming
an average prostate volume of 80 cm3 and an initial clonogenic cell density of 106 cm3 ).
An approximately 30% control rate has been reported (Horowitz et al 1996) using
conventional treatment with the approximate treatment dose of 66.6 Gy. There have been
no official publications regarding 5 year biochemical control rates for patients with prostate
cancer treated using conformal therapy and dose escalation. An assumption of 55% control
rate was used in this study for prostate conformal therapy at a dose level of approximately
72 Gy. These data were used in the TCP curve fitting in the study. Furthermore, we
assumed that the average dose deviation in the treatment target was 2.5% of the treatment
dose (d = 0.025 treatment dose), which was defined with the consideration of a 95%
confidence level for the field margin. Substituting these values into the TCP expression (A1)
in the appendix, such that TCP(66.6 Gy, 1.67 Gy) = 0.3, and TCP(72 Gy, 1.83 Gy) = 0.55,
we had the sensitivity factor of prostate cancer, m = 0.4, and = 0.0623. Using
these parameters a shallow curve of TCP was produced (figure 2), which demonstrates a
reasonable fit for the clinical data.

Adaptive radiation therapy

129

3.3. The optimal margin and treatment dose

The objective function 1TCP(D, c) in the optimization model was maximized by searching
for the optimal combination of c and D under conditions of D 6 D0 f (c, i ) and
D = D0 g(c, i ) for the given variation, i (0.3 cm). Given the treatment dose from 74 to
77 Gy, iso-sample plots of the objective function are represented in figure 3 as functions
of target dose deviation. Superimposing the values in figure 1 on figure 3, the level of
improvement on TCP was indicated for each confidence factor (c = 12.5).
By inspection of figure 3, for each selection of c from 1 to 2.5, the TCP was always
improved to a certain degree if the corresponding margin and treatment dose were applied
for the successive treatments. This was because the patient in this example demonstrated a
smaller variation. However, the level of improvement could be quite different. The largest
improvement, 1TCP = 0.22 or 22% increase in TCP compared to the initial treatment plan,
was achieved with an optimal combination of the treatment dose, D = 75.576 Gy, and
the customized margin of approximately 0.5 cm at c = 1.51.75. On the other hand, a
large margin with a higher confidence (> 95%) such as c > 2 could not reduce the target
dose deviation too much, but only the treatment dose. If a confidence of 68% or less (c 6 1)
was applied, the target dose deviation could be significantly increased. In both cases, the
improvement in TCP would be considerably diminished.
4. Summary
Adaptive radiation therapy has been introduced to incorporate the position variation of the
individual patient into the treatment optimization process during the course of radiotherapy.
This process can be efficiently implemented with the integration of advanced technologies
in current radiotherapy clinic. The ART process has the potential to provide further
enhancement in radiation treatment by modifying the treatment dose and margin based
on the individual patients variation.
Optimal modification can be obtained by searching the optimal margin and treatment
dose. This optimization process is relatively simple, and can be implemented on line. For
an optimal field margin, it is not necessary to have an identical confidence level, which is
most probably dependent on the treatment dose, tumour dose response, and magnitude of
the patients variation. There is no conflict between the ART process and the conventional
treatment process. In fact, the capability of the ART process relies on the initial treatment
planning and treatment implementation. Finally, in addition to treatment position variation,
the concept of ART can also be applied to compensate for other treatment variations such as
radiation sensitivity and density of clonogenic cells when they become measurable during
the treatment course.
Appendix
A general TCP model with conventional dose fractionation scheme has been proposed
(Brahme and Agren 1987) as
Z
Ns =
(r) exp[(r)d(r)] dV
TCP = exp(Ns )
V

where Ns is the number of surviving clonogenic cells after irradiation of a total dose d;
represents the radiation sensitivity of clonogenic cells defined in the linearquadratic model;
r is a spatial vector in tumour volume V ; and is the initial density of clonogenic cells.

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Di Yan et al

This model could be applied to the radiation treatment when exact knowledge of
clonogenic cell density and radiation sensitivity as well as the dose distribution in the
treatment target had been obtained. Without this knowledge, different approximations have
been accomplished to study the TCP with effect of non-uniform dose (Brahme 1984, Goitein
and Busse 1975), non-uniform clonogenic cell density (Brahme and Agren 1987, Webb and
Nahum 1993), and non-uniform sensitivity (Kallman et al 1992, Webb and Nahum 1993).
In this paper, the concepts and assumptions from previous studies will be adopted, and the
TCP form will be recast for the optimization problem introduced for the ART process.
It is assumed that the distribution of actual treatment dose in clonogenic cells can
be characterized using first and second moments (Brahme 1984), or approximated as a
Gaussian distribution, d N(dm , D2 ). In the case of uniform clonogenic cell density, this
assumption implies that the shape of the dosevolume histogram (differential version) in
the target can be approximated using a Gaussian. Furthermore, it is also assumed that the
radiation sensitivity of clonogenic cells has a Gaussian distribution, N (m , 2 ) (Webb
and Nahum 1993). Using these assumptions, the TCP model can be re-written as
Z
Ns = N0
exp(d)(d)() dd d
TCP = exp(Ns )
V

where (d) and (a) are both Gaussian as defined above; N0 is the initial number of
clonogenic cells in the target volume V .
The above TCP expression can be expressed explicitly as
2 2
d )/(12 d2 )]}.
TCP(dm , d ) = exp{N0 (1 2 d2 )1/2 exp[(m dm + 0.52 dm2 + 0.5m
(A1)

This implies that the TCP for a given distribution of radiation sensitivity is a function of
the mean, dm , and the standard deviation, d , of the target dose.
To derive this form, first consider the integral
Z
exp(d)(d) dd
V


Z
(d dm )2
1
exp

dd
=
exp(d)
(2)1/2 d
2d2


Z
2dd2 + d 2 2ddm + dm2
1
=
exp
dd.
(2)1/2 d
2d2
Observing 2dd2 + d 2 2ddm + dm2 = [d (dm d2 )]2 + [(2dm 2 d2 )d2 ], and
substituting it back into the above integral, we have
Z

 
[d (dm d2 )]2
1
2 2
exp
dd
exp(dm + 0.5 d )
(2)1/2 d
2d2
= exp(dm + 0.5 2 d2 )
since the integral term in the curly bracket is equal to unity due to the integral of a Gaussian.
Therefore
Z
Z
exp(d)(d)() dd d =
exp(dm + 0.5 2 d2 )() d
V
V


Z
1
( m )2
2 2
exp(dm + 0.5 d )
exp
d
=
(2)1/2 a
22
V

Z
2 
2dm 2 2 d2 2 + 2 2m + m
1
exp
d.
=
(2)1/2
22

Adaptive radiation therapy

131

Observing
2
= [ (m dm 2 )/(1 2 d2 )]2 (1 2 d2 )
2dm 2 2 d2 2 + 2 2m + m
2 2
+[(2m dm 2 dm2 m
d )2 ]/(1 2 d2 )

and using a similar derivation, the above integral will be equal to

2 2
d )/(1 2 d2 )].
(1 2 d2 )1/2 exp[(m dm + 0.52 dm2 + 0.5m

Therefore, the TCP expression follows.

Now, let TCPint (D0 , D0 ) represent the TCP from the initial treatment planning, which
has mean dose D0 as the reference dose, and D0 as a dose deviation in target. On the other
hand, when an individual patient is considered in the ART process, the corresponding TCP
can be expressed as TCPART (D, D ), where D is a modified treatment dose and D is the
target dose deviation when a customized margin is applied. Therefore, the relative change
of the TCP due to adaptive modification will be
1TCP = (TCPART TCPint )/TCPint = TCP1
int 1
=

2 2
D )/(1 2 D2 )]
(1 2 D2 )1/2 exp[(m D + 0.52 D 2 + 0.5m
.
2 2)/(1 2 2 )]
(1 2 D2 0 )1/2 exp[(m D0 + 0.52 D02 + 0.5m
D0
D0

This can be easily derived considering ln(TCPART )/ln(TCPint ).

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