The British Journal of Radiology, 73 (2000), 892±894 E 2000 The British Institute of Radiology

Short communication
Dose equivalents of tumour repopulation during
radiotherapy: the potential for confusion
1
R G DALE, PhD, FIPEM, FInstP, 2B JONES, MD, FRCR, FRCP and 1J A SINCLAIR, MSc
1
Radiation Physics and Radiobiology and 2Clinical Oncology, Hammersmith Hospitals NHS Trust and
Imperial College School of Medicine, Charing Cross Hospital, London W6 8RF, UK

Abstract. When employing linear quadratic equations to calculate compensation for changes in
overall treatment time, a potential confusion exists regarding use of the parameter commonly
described as the dose equivalent of tumour repopulation. The more correct term for this factor is
the biologically effective dose equivalent of tumour repopulation. The distinction between the two
concepts is discussed and the potential errors arising from their confusion are illustrated by means
of an example.

Linear quadratic (LQ) calculations of biologi- effective doubling time, assumed here to be
cally effective dose (BED) are utilized in a wide constant throughout treatment.
range of clinical situations. When it is necessary Re-arrangement of Equation (1) leads to the
to compare tumour BEDs between regimens well known LQ equation for calculating tumour
involving different overall treatment times, or BED in fractionated radiotherapy [4]:
when calculating a compensation for an inter-  
rupted treatment, it is always necessary to make { ln S d 0:693T
BED~ ~nd 1z { …2†
allowance for the effects of tumour repopulation a a=b aTeff
[1, 2]. Tumour repopulation rates are frequently
referred to in terms of an appropriate dose The right-hand subtractive factor in Equation (2)
equivalent value K, expressed in units of Gy is often referred to as being the tumour repopula-
day21 [3, 4]. Owing to the units in which K is tion factor (RF) for the treatment [5] and may be
expressed, it is possible to assume erroneously written as KT, where K5(0.693/aTeff). Because K
that K is the single physical dose equivalent appears in an expression calculating a biological
required to offset the repopulation occuring in a dose (BED), K is properly referred to as being the
single day. In fact this is not the case: K is rather daily BED equivalent of repopulation. Similarly,
the BED equivalent of one days worth of KT is the BED equivalent of the total repopula-
repopulation. The purpose of this communication tion occurring in T days.
is to elaborate on this potential source of error in Next we consider how much physical dose is
LQ calculations. required to offset one days worth of tumour
repopulation. If a single fraction of magnitude d
Gy is required, then, substituting K into Equation
(2) and putting n5T51, we have:
Method
 
Considering the analytical arguments from ®rst d
d 1z ~K
principles can help identify and clarify the essence …a=b†
of the problem. For a treatment consisting of n
fractions of magnitude d delivered in an overall Leading to:
time of T days, the net surviving fraction of s
   2  
tumour clonogens is S, where: a a a
{ z z4 K
2 b b b
S~ne{ad e{bd 2T =Teff …1† d~ …3†
2

and where a and b are the respective LQ Equation (3) de®nes the relationship between K,
radiosensitivity constants and Teff is the average the daily BED equivalent, and d, the single
fraction dose equivalent of K.
Received 26 November 1999 and accepted 10 April 2000. What should be done to combat the effects of

892 The British Journal of Radiology, August 2000

Short communication: Dose equivalents of tumour repopulation during radiotherapy
tumour repopulation occurring over a longer time
period? If n fractions, each of x Gy, are delivered
to offset T days worth of repopulation (where T
includes the time required to deliver those n
fractions), then:
 
x
nx 1z ~KT
a=b
Leading to:
s
   2  
a 2
a a
{n z n z4n
b b b 
x~
2n
Although Equation (3) essentially represents a
special case of Equation (4), the difference
between the two is instructive. Whereas
Equation (3) de®nes the true single dose equiva-
lent d of one days worth of repopulation,
Equation (4) makes it clear that practical
compensation for T days of repopulation (con-
tinued throughout at the same ®xed BED rate of
K Gy day21) cannot be achieved by using a simple
multiple of either d or K. This is entirely as
expected because the underlying relationship
between dose and BED is pseudo-logarithmic.
However, when performing simple repopulation
calculations following an unintended treatment
interruption there might be instances where this
non-linear relationship between dose equivalent
and BED equivalent could easily be overlooked
because of the similarity of the units in which
each parameter is expressed.
Results
The following example illustrates the type of
case where confusion between these two concepts
might become clinically important.
Consider a head and neck treatment that has
been interrupted for one week and then resumed
without alteration to the fractionation frequency,
i.e. the overall time on completion is 7 days longer
than intended. If the BED equivalent K is
0.64 Gy day21 [1, 6], then the resultant tumour
BED is lower than that prescribed by an amount
calculated as 0.646754.48 Gy.
To restore this missing BED use of an
additional two daily fractions might be consid-
ered. This will mean that the net treatment
extension is 9 days rather than 7, i.e. the true
tumour BED to be restored is 960.6455.76 Gy.
If a generic value of a/b for tumour of 10 Gy is
assumed, then, from Equation (4), the daily
fraction dose x to use is:
The British Journal of Radiology, August 2000
p
{2|10z 4|102 z4|2|10|0:64|9
x~
2|2
~2.33 Gy per fraction
This is the correctly derived physical dose that,
when given in two fractions, will deliver to the
tumour the required missing BED equivalent.
For any critical late responding tissue receiving
the same dose as the tumour, and assuming a
generic a/b value of 3 Gy, the BED3 value
associated with two fractions of 2.33 Gy is:
KT

…4† 2:33
2|2:33| 1z ~8:3 Gy3
3
Suppose, however, that the BED equivalent was
mistakenly considered as a physical dose equiva-
lent, i.e. it was assumed that the physical dose to
be restored is 5.76 Gy. If this were delivered as
two 2.88 Gy fractions then the associated normal
tissue BED would be:
 
2:88
2|2:88| 1z ~11:3 Gy3
3
i.e. the extra BED3 delivered would be 3.0 Gy3
greater than necessary. The error becomes more
signi®cant for smaller values of tumour a/b. For
example, if the tumour a/b value is 5 Gy rather
than 10 Gy, then the excess BED3 delivered
increases to 4.5 Gy3. If the originally prescribed
treatment is designed to take the late responding
tissues close to full tolerance, such increases in the
BED may be signi®cant.
The problem is further exacerbated by use of
smaller fraction numbers. If the compensation in
the above example is to be achieved in only one
fraction, the correct fractional dose (via Equation
(3) and using a/b510 Gy) is 4.09 Gy rather than a
single fraction of 5.76 Gy as might be erroneously
assumed. In this instance, the respective added
BED3 values would be 9.7 Gy3 and 16.8 Gy3, i.e.
the erroneous use of a single dose of 5.76 Gy
would deliver a normal tissue BED that is 7.1 Gy3
greater than necessary.
Discussion
It is necessary to draw attention to this
potential source of error as more centres are
making use of BED calculations to aid in the
design of treatment gap compensation. Those
already aware of the difference between BED
equivalent and physical dose equivalent may well
have their own methods for correctly calculating
top-up doses to compensate for unscheduled
interruptions and may not ®nd it necessary to
893

use Equation (4). However, provided it is under-
stood that the time factor T in the equation must
additionally include the extra time in which the n
doses are delivered (which do not have to be at a
once-daily rate as assumed in the above example),
Equation (4) does provide a simple and fool-proof
method of correctly calculating a compensation
for lost tumour dose. Whether or not the
compensation should proceed on the basis of
the calculated d values must additionally depend
on a clinical judgement (backed by appropriate
BED calculations for the critical normal tissues)
of the likely excess in morbidity that may be
induced.
To limit the scope for confusion, we suggest
that the repopulation factor in BED equations
henceforth be termed a BED repopulation factor
(BRF), i.e. the generic calculation method for
tumour BEDs should be written as:
BED~TD|RE{BRF
where TD is the total physical dose and RE is the
associated relative effectiveness factor. In doing
this, the BRF symbolism acts as a reminder
that biological, rather than physical, units are
involved. Calculated BRFs should be written
894
R G Dale, B Jones and J A Sinclair
with the appropriate a/b units as a suf®x, i.e. a
BRF calculated as 5.2 Gy using an a/b value of
10 Gy would be written as 5.2 Gy10, etc. For most
late responding normal tissues, the BRFs can be
taken as zero.
References
1. Hendry JH, Bentzen S, Dale RG, Fowler JF, et al. A
modelled comparison of the effects of using different
ways to compensate for missed treatment days in
radiotherapy. Clin Oncol 1996;8:297±307.
2. Sinclair JA, Oates JP, Dale RG. BED±time charts
and their application to the problems of interrup-
tions in external beam radiotherapy treatments. Int
J Radiat Oncol Biol Phys 1999;44:381±9.
3. Travis EL, Tucker SL. Iso-effect models and
fractionated radiation therapy. Int J Radiat Oncol
Biol Phys 1987;13:283±7.
4. Fowler JF. The linear-quadratic formula and pro-
gress in fractionated radiotherapy. Br J Radiol 1989;
62:679±94.
5. Dale RG. Time-dependent tumour repopulation
factors in linear-quadratic equations Ð implications
for treatment strategies. Radiother Oncol 1989;15:
371±82.
6. Hendry JH. Treatment acceleration in radiotherapy:
the relatives time factors and dose±response slopes
for tumours and normal tissues. Radiother Oncol
1992;25:308±12.
The British Journal of Radiology, August 2000