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A modeled comparison of the effects of using different ways to compensate

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Article in Clinical Oncology · February 1996

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Clinical Oncology (1996) 8:29%307
© 1996 The Royal College of Radiologists Clinical
Oncology

Original Article

A Modelled Comparison of The Effects of Using Different Ways to

Compensate for Missed Treatment Days in Radiotherapy
J. H. Hendry_ a, S. M. Bentzen 2, R. G. Dale 3, J. F. Fowler 4, T. E. Wheldon 5, B. Jones 6,
A. J. Munro7, N. J. Slevin s and A. G. Robertson9
1Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK, 2Danish Cancer Society,
NCrrebrogade, Aarhus, Denmark, 3Hammersmith Ho~itals NHS Trust, Chafing Cross Hospital, London, UK,
4University Hospital Gasthuisberg, Leuven, Belgium, Beatson Laboratories, Glasgow, UK, 6Clatterbridge Centre for
Oncology, Bebington, UK, 7St Bartholomew's Hospital, London, UK, SDepartment of Clinical Oncology, Christie
Hospital NHS Trust, Manchester, UK and 9Beatson Oncology Centre, Western Infirmary, Glasgow, UK

Abstract. There is much evidence for the detrimental
effect on tumour control of missed treatment days
during radiotherapy, amounting for example to
approximately a 1.6% absolute decrease in local
control probability per day of treatment prolongation
in the case of head and neck squamous cell cancer.
Various methods to compensate for missed treatment
days are compared quantitatively in this article, using
the linear-quadratic formalism. The overall time and
fraction size can be maintained by either treating on
weekend days (the preferred way (Method la),
although with unsocial hours and at extra cost) or
using two fractions per day to 'catch up' (Method lb).
The latter might incur a small loss of tolerance
regarding late reactions, when intervals of 6-8 h are
used rather than 24 h, and there may be logistical/
scheduling difficulties with larger numbers of patients
in some centres when using this method. A second
type of strategy retains overall treatment time, and
also one fraction per day, but the size of the dose per
fraction is increased. For example, this may be done
for the same number of 'post-gap' days as gap days
(Method 2). However, with this method, calculated
isoeffect doses regarding late reactions indicate a
probable decrease in tumour control rate (Method
2a). Otherwise, isoeffective doses regarding tumour
control result in an increase in late reactions (Method
2b). In addition, this method is unsuitable for short
regimens already using high doses per fraction. To
reduce this problem, overall treatment time can also
be retained by using fewer fractions, all of greater size
in the case of planned gaps (statutory holidays), or
larger remaining fractions after unplanned gaps
(Method 2c). The problem also with this method is
that equivalence for tumour control gives an increase
in late reactions. The least satisfactory strategy
(Method 3) is to accept the protraction caused by the
missed treatment days, and give either the same
prescribed number of (slightly larger) fractions or the
planned treatment followed by one (or more) extra
fraction to compensate for the gap. This would retain
the expected local control rate, but there would be an
increase in late reactions. An example of this, using
average parameter values, is that a 3-day gap
(necessitating four extra days to complete treatment
with one fraction of 2.4 Gy) might maintain a 70%
local control rate for glottic carcinoma, but severe
reactions might rise from 1% to 4% and minor/
moderate reactions from 37% to 50%. In this exam-
ple, the inclusion of an extra weekend would increase
the required extra dose and hence may further
increase the morbidity rates. A final point is that the
effect of treatment interruptions for an individual
patient is expected to be greater than that for a group
of patients because of interpatient heterogeneity
tending to flatten dose-response curves. Calculations
show that the above value of 1.6% loss of local
control per day for a group of patients may reflect
values for individual patients that range around a
median value of as much as 5% per day, so stressing
further the importance of gaps in treatment.
It is concluded that, wherever possible, treatment
days should not be missed. If they are missed, it is
important to compensate for them, preferably by one
of the first of the above methods (la or lb), in order to
keep as close as possible to the original/standard
prescription in terms of total dose, dose per fraction
and overall time.
Keywords: Fractionation; Gaps in treatment; Radio-
therapy days missed; Time factors in radiotherapy;
. Treatment interruptions

Correspondence to: Professor J. H. Hendry, Cancer Research INTRODUCTION

Campaign Department of Experimental Radiation Oncology,
Paterson Institute for Cancer Research, Christie Hospital NHS
Trust, Manchester M20 4BX, UK.
Offprint requests to: Mr A. Cowles, Royal College of Radiologists,
38 Portland Place, London W1N 3DG.
Realization of the detriment to local tumour control
of missed treatment days arose from experience with
split-course techniques, which were instigated to
298 J. H. Hendry et al.

allow recovery from early reactions [1-3]. Even in centres of over 2000 patients with laryngeal carci-
conventional treatments, there may be many non- noma has shown similar time factors for prescribed
treatment days, besides weekend days, due to: (a) treatment time and for 'gap' time when analysed
public and statutory holidays; (b) machine break- separately from detailed data on conventional treat-
down/servicing, social/travel arrangements; and (c) ments (C. Robertson, A. G. Robertson, J. H.
toxicity and concurrent illness. The first two categor- Hendry, et al., unpublished observations). For
ies can be compensated for by modification of the cervical cancer, the site for which there are the next
treatment schedule; this is the subject of the present most extensive data, the loss of local control per day's
article. Toxicity that might be indicative of an unusual extra treatment time tends to be less, at around 0.8%
degree of radiosensitivity in a particular patient is an per day (Table 1) (i.e. probably around half that for
important but separate issue. At many centres, in head and neck cancer). Nevertheless, even these
particular those using the longer treatment regimens, lower values can still be important clinically. Prolong-
non-treatment days can be a significant proportion of ing the prescribed treatment time for a variety of
the total [4-7]. Apart from non-treatment days, reasons has been shown to reduce the local control
which produce extensions to overall treatment times, rate and the overall survival rate (Table 3 [33]). For
there are conventional treatments of different other sites there are much less data available (e.g. for
(planned) durations that have also provided data lung [34], bladder [35-37], breast [38], and prostate
concerning the time factor for tumour control. The [39-41]), and generally the effects of gaps or the
results have been given either in terms of the absolute deduced time factors are smaller in the case of solid
percentage loss of local control per day (Table 1 tumours other than squamous cell carcinomas as
[8-23]) or as the dose per day necessary to keep the would be expected on the basis of their cell kinetics
same level of tumour control (often called the time [42].
factor, Table 2 [24-29]). The majority of data on There is some clinical evidence suggesting that the
this topic pertain to cancer of the head and neck, position of the gap during treatment is important
and in particular, stages T2 and T 3. The values show [43,44], but the relative importance of early versus
that on average there is a 1 . 5 % - 1 . 7 % absolute loss late gaps remains controversial. Whilst it is expected
of local control per extra day, either during intervals that late gaps would be important because this is
of up to a few weeks' duration (split-course) or where purported tumour clonogen population
arising during conventional treatments [updated increases are occurring, it is also true that a gap early
from 30-32]. Also, a recent analysis from four in treatment will incur an extension to treatment time
and this may well have the same effect. It is only if the
Table 1. Loss of local control (absolute % per day) with increase in early gap is sufficient to alter the cell loss/repopu-
overall treatment time of split-course or conventional treatments lation kinetics fairly dramatically that gap position
(updated from [30-32])
might be expected to have some influence. For very
short schedules (e.g. the Manchester 3-week treat-
% loss Reference ments), a gap of a day or two would be expected to
of local
control/day have less influence than in longer treatments if the lag
period, before purported tumour clonogen repopu-
lation becomes important, is also around 3 weeks
H e a d and neck cancer
Split course [45].
Larynx 1.4 Budihna et al. [8] The analyses performed to calculate the additional
Head and Neck 1.2 Parsons et al. [2] dose per day of protraction necessary to keep the
Larynx 1.6 Overgaard et al. [3] same level of tumour control have produced values
Head and Neck 2.5 Amdur et al. [9] on average, of 0.5-0.6 Gy/day when using 2 Gy
Larynx 0.7 van den Bogaert et al. [10] fractions (Table 2). Maximum values (applicable at
Mean 1.5 very low doses per fraction) are up to around 0.8 Gy/
Conventional day (=)~/00 [46,47]. There has been much discussion
Larynx 2.5 Maciejewski et al. [11] of the influence of selection biases in these estimates
Oropharynx 2.3 Wang [12] [48], for example the influence of treating larger or
Tonsil 2.0 Bataini et al. [13] unresponsive turnouts in longer times in some
Tongue 1.7 Mendenhall et al. [14] centres. However, recent analyses have shown the
Larynx 2.9 Taylor et al. [15] presence of similar time factors in the Manchester
Sup. larynx 0.4 Hoekstra et al. [16] and Toronto centres, where such practices are not a
Head and Neck 1.0 Pajak et al. [4] feature of treatment philosophy [49]. The data in
Larynx 1.7 Barton et al. [17] Tables 1 and 2 are compatible with each other, and
Larynx 1.6 Robertson et al. [18,19] some authors have calculated the values both ways.
Head and Neck 1.2 Roberts et al. [46] Ways to calculate one from the other have been
Mean 1.7 discussed [50]. The few analyses for early normal
Cervical cancer
tissue reactions in head and neck treatments show a
1.1 Fyles et al. [75] time factor at least as great as that for tumours, if not
0.3 Lanciano et al. [20] higher (Table 1). This is expected in repopulating
1.4 Girinsky et al. [21] normal tissues. For late reactions, the time factors are
0.7 Petereit et al. [22] smaller, but sometimes not zero. Significant time
0.5 Pedersen et al. [23] factors are expected if there are 'consequential' late
Mean 0.8 reactions arising as a result of the early reactions, [51]
or if there is slow recovery or slow repair in the tissue
Ways to Compensate for Missed Treatment Days in Radiotherapy 299

Table 2. Extra dose per day (maximum values given as k/c~ (Gy/day)) necessary to keep the same level of tumour control in split or
conventional treatments of head and neck cancer (updated from [66])

Dose (Gy/day)
Tumour control Tumour site Using 2 Gy/ Maximum Reference
or reaction or stage fraction

Split course Larynx 0.4 0.5 Budihna et al. [8]

T 2 Larynx 0.6 0.7 Overgaard et al. [3]
Mean 0.5 0.6
Conventional Head and neck 0.6 0.7 Withers et al. [24]; Hendry [66]
Oral cavity 0.6 0.7 Maciejewski et al. [11]
Oropharynx 0.7 (0.1-1.3) 0.8 (0.1-1.6) Bentzen et al. [47]
T2 + T3 0.7 0.8 Rezvani et al. [25]
T2 + T3 0.5 (0.1-2.8) 0.6 (0.1-3.3) Slevin et al. [45]; Hendry et al. [49]
T1 + T4 0.7 (0.2-1.8) 0.8 (0.2-2.1) Barton et al. [17]; Hendry et al. [49]
T 1 + T3 0.7 (0.4-0.9) 0.8 (0.5-1.1) Roberts et al. [46]
Mean 0.64 0.74
Early reactions
Towards the end of a 6 week treatment 1.5 1.8 Thames et al. [26]
Head and neck, 11-49 days 0.5 0.6 Fowler [27]
Laryngeal mucosa 0.25 0.3 Kaanders et al. [28]
Late Reactions
Larynx 0 0 Maciejewski et al. [11]
Laryngeal oedema 0-0.06 0.0.10 ~ Overgaard et al. [3]
Fistula secondary to salvage surgery 0-0.05 0-0.09 [ Bentzen and Overgaard [29]
Head and neck, 2-week split 0 0 Amdur et al. [9]
Oral cavity, 15-80 days 0.3 0.46 Maciejewski et al. [51]

et
Maximum values divided by (1 + ~ ) give the values applicable for fixed dose per fraction d.
/

cd[3 = 10 Gy (tumour and early reactions) and 3 Gy (late reactions).

Table 3. Local control and survival figures for cervix carcinoma specific worked example, using each method in turn,
treated solely by radiotherapy. Data pooled from Fyles et al. [75], is given in Table 6.
Lanciano et al. [20], Girinsky et al. [21], Petereit et al. [22] and
Perez et al. [33]. Prolonged treatment is any treatment longer than
the prescribed (normal) schedule

CALCULATION OF ISOEFFECTIVE DOSES

Stage n % Local control % Survival
(95% CI) (95% CI)

The conventional linear-quadratic formalism was

Normal Prolonged Normal Prolonged used (see Appendix) in the forms:

I 836 95 (93-96) 85 (80-90) 85 (83-88) 77 (71-83) D1 x dl) = x d2)

II 905 83 (80-86) 77 (73-81) 73 (70-77) 64 (59-69) and
III 480 70 (64-76) 57 (51-63) 51 (44-58) 44 (39-50)
BED = D (1 + -~/~)

where BED is the biologically effective dose (i.e. the

target cells (see below). The latter would have more
of an effect in conventional treatments where inter-
fraction intervals are 1 day, than in split-course
treatments where there is one big gap. Hence, the
presence of gaps will have little effect on late
reactions, but they will tend to spare acute reactions
and also be detrimental to tumour control.
Missed treatment days can be of two types: due to
unforseen circumstances or 'planned' in advance
because, for example, of intervening public and
statutory holidays. Regarding unplanned gaps, three
strategies are available for compensating for them
(Table 4). Each of these has its specific radiobio-
logical and logistic advantages and disadvantages,
and these will be discussed below. The effects of
different gap lengths are considered in Table 5. A
theoretical dose, which, if delivered in infinitely small
fractions, would produce the same biological end-
point as that under consideration), D is the total dose
given in fractions of size d in schedule 1 or 2, and 0d[~is
the ratio of the two coefficients in the linear-quadratic
formalism that characterizes the fractionation sensiti-
vity of a tissue. In the following comparisons, a
common value of 0d~ = 10 Gy was chosen for tumour
control and 3 Gy for late reactions. These are generic
values used for calculation purposes. For some criti-
cal normal tissues (e.g. the spinal cord), the ~/~ value
may be smaller than the 3 Gy assumed here, thus
placing a further limit on the extra dose that can be
delivered before the tissue tolerance is exceeded. A
dose per fraction of 2 Gy was used as a baseline.
In general, BED values are about 60-70 Gyl0
300 J. H. Hendry et al.

Table 4, Compensation methods for treatment gaps

Method Benefits Dificulty/detriment

1. Retain overall time and dose per fraction

la. Weekend treatment days Overall time, fraction size, Extra cost, unsocial hours
interfraction interval/>24 hours, May be impractical for gaps near the end
all retained of the intended schedule
lb. 2 fractions/day to catch up Overall time, fraction size kept Potential small loss of tolerance for late
the same reactions when interfraction intervals of
6-8 h vs. 24 h
Logistical/scheduling constraints
2. Retain overall time, increase dose per fraction
2a + b. Increase size of dose/fraction for same Overall time retained Not suitable for short regimens already
number of post-gap days as gap days Still 1 fraction/treatment day using high dose/fraction
2a. Isoeffect on tumour Equivalence for tumour control gives
increase in late reactions
2b. Isoeffect on NTCP Equivalence for late reactions gives
tumour underdosage
2c. Fewer fractions, all of greater size for Overall time retained Same as for 2a and 2b
planned gaps, or larger remaining fractions
after unplanned gaps
3. Accept protraction, give I (or more) extra Retains expected local control Increase in late reactions
fraction to compensate for gap rate

NTCP, normal tissue complication probability.

Table 5. Changes in tumour control probability (TCP) and late normal tissue complication probability (NTCP) from baseline values
respectively of 70% and 1% (severe complications) or 37% (minor/moderate complications), when gaps are introduced into treatments
using 2 Gy daily fractions

Method Effect probabilities (%)

Gap (days)

1 3 5

No compensation TCP 68 65 61
NTCP severe 1.0 1.0 1.0
NTCP moderate 37 37 37
1.Maintain overall time and dose per fraction
la. Weekend treatments TCP 70 70 70
NTCP severe 1.0 1.0 1.0
NTCP moderate 37 37 37
lb. 2 fractions/day TCP 70 70 70
NTCP severe 1.0-1.2 1.0-1.5 1.0-2.0
NTCP moderate 37-38 a 37-41 a 37-43 a
2. Maintain overall time, increase size of dose~fraction for same number of post-gap treatment days as gap days
2a. Iso-TCP TCP 70 70 70
NTCP severe 1.5 2.9 5.2
NTCP moderate 41 48 55
2b. Iso-NTCP TCP 69 66 63
NTCP severe 1.0 1.0 1.0
NTCP moderate 37 37 37
2c. Maintain overall time, fewer fractions all of greater TCP 70 70 70
size for planned gaps NTCP severe 1.3 2.1 3.4
NTCP moderate 39 44 50
3. Accept protraction, give 1 extra fraction TCP 70 70 70
NTCP severe 1.9b-4.0c 4.0b-7.7 c 12c
NTCP moderate 44b-52 c 52b--61c 69c

Calculations based on the equations and parameter values given in the Appendix.
With Method 2c, the changes in effect probability are less when this method is used with unplanned gaps, where the number of
fractions with increased size is a smaller proportion of the total number of fractions.
With Method 3, the corresponding doses to be delivered as the extra fraction would be 1.31-2.39, 2.39-3.33 and 4.18 Gy
respectively.
aBased on 10% reduction in tolerance dose for 8 h interfraction interval compared with 24 h.
bwithout extra weekend.
cWith extra weekend.
Ways to Compensate for Missed Treatment Days in Radiotherapy
Table6. Summary comparison of methods using a schedule of 66 Gy in 33 fractions over 6.5 weeks, with compensation for a 3-day gap
Method Schedule (Gy/F) Overall time (weeks)
la 66/33 6.5
lb 66/33 6.5
2a,b 54/27 + (9.66-10.64)/3 6.5
2c 65/30 6.5
3 66/33 + 2.4/1 6.5a
NTCP, normal tissue complication probability; TCP, tumour control probability.
aplus i> 1 day.
for tumour control and about 110-120 Gy3 for late
reactions.
METHODS OF COMPENSATING FOR
MISSED TREATMENT DAYS
Method 1: Maintain Overall Time, Total Dose
and Prescribed Dose per Fraction
This method is sometimes referred to as 'post-gap
acceleration' and has already been discussed in the
literature as being the preferred strategy [52,53]. The
idea is to maintain the dose per fraction but to treat on
weekend days (Method la) or twice a day (Method
l b ) to be able to finish at the planned date. Thus,
overall treatment time is maintained.
Method la: Weekend Treatments
The m e t h o d that involves the fewest uncertainties is
to 'catch up' by treating on weekend days. In this way,
the overall time and dose per fraction are kept the
same, and the interfraction intervals remain at 24 h.
The m a j o r disadvantages are not radiobiological, but
relate to the extra costs involved and the unsocial
hours worked by staff. For gaps occurring late in the
treatment course, the n u m b e r of available weekend
days m a y be too small to allow compensation by this
method.
Method lb: Two Fractions per Day
A n o t h e r method that maintains the overall time and
the fraction size, is to give two fractions per day on the
same n u m b e r of days subsequent to the n u m b e r of
gap days. With two fractions per day, interfraction
intervals should be at least 6 h and preferably 8 h or
more. Even with these fairly long interfraction inter-
vals, there is now good experimental evidence in the
case of spinal cord [54], lung [55], skin [56] and kidney
cells [57] for a slow c o m p o n e n t of repair. This
provides one likely reason for the small time factor
noted for various late reactions in experimental
301
Comment
1 fraction on each of 3 weekend days - same
outcome expected
2 fractions per day on each of 3 weekdays -
potential small increase in complications
27 fraction of 2 Gy + 3 fractions of 3.55 Gy -
some increase in NTCP for same TCP, or + 3
fractions of 3.22 Gy - slight fall in TCP for same
NTCP
3 less fractions, all fractions 2.17 G y - slightly higher
NTCP for same TCP
1 extra fraction of 2.40 Gy - slight increase in NTCP
for same TCP
systems [42,58]. In rat spinal cord, it was shown that
when 2 G y fractions were separated by 6 h or 8 h
compared with 24 h, the tolerance dose was reduced
by 16.5% and 13.5% respectively [54].
Clinical data on repair kinetics are sparse. Yet,
there is some support for the notion that repair half-
times may be fairly long in h u m a n tissues [59].
Telangiectasia in h u m a n skin also shows a similar
p h e n o m e n o n [60]. A reduction of 10% in isoeffect
dose due to this incomplete repair p h e n o m e n o n was
reported for 8 h c o m p a r e d with 24 h intervals for
telangiectasia in h u m a n skin [61]. Hence, this poten-
tial dose reduction is a caveat which is attached to this
method of 'catching up'. Of course, the effect would
be diluted by the proportion of the total course that is
delivered in this way. For a 3 - d a y gap in a 30-fraction
schedule, it would occur 3/30 times (i.e. a tenth of the
m a x i m u m amount), giving about a 1 . 0 % - 1 . 5 %
reduction in tolerance dose. It is still an open question
if tumours would have a long repair half-time too
[59]. If this is so, treating twice a day m a y not
necessarily be associated with a loss of therapeutic
ratio. The application of this method m a y be con-
strained by the logistics of treatment scheduling (e.g.
for large numbers of patients after a 2 - d a y statutory
holiday).
Method 2: Maintain Overall Treatment Time
with Increased Dose per Fraction
One way to compensate for missed treatment days is
to increase the dose per fraction for one or m o r e , or
even all, of the remaining fractions after the gap.
W h e r e the gaps are relatively small and occur early in
the treatment, the preferred method is to distribute
the missing dose across all the remaining fractions. In
this way, the overall treatment time is maintained and
so is the n u m b e r of fractions after the gap. This
method may be implemented in two slightly different
ways.
Method 2a + 2b: One Large Fraction on Day
After 1-Day Gap
The simplest idea is to give one larger fraction on the
next treatment day after a 1-day gap, calculated to be
302
equivalent to the two fractions that would otherwise
have been given. With a 3-day gap, this would mean
giving a larger fraction on each of the three subse-
quent days. This is attractive in practice because the
overall time is kept the same, and only one fraction is
still delivered per treatment day. The difficultyhere is
deciding what the dose should be, because the
equivalent dose for late reactions will not be equiva-
lent for tumour control. Assuming od[3 = 3 Gy for late
reactions, the single dose per fraction equivalent to 2
x 2 Gy would be 3.22 Gy. However, for isoeffect with
respect to late reactions (Method 2a), tumours would
be underdosed by 11% per fraction (0d~ = 10 Gy).
This difference would be much diluted by applying
this method only once in a 30-fraction course of 2 Gy
fractions. Once would reduce the under dosage to
only 1%, twice to 2%. Similarly, if a sufficient dose is
given to ensure isoeffect for tumour control (Method
2b), the incidence of late sequelae will increase.
Method 2c: Fewer but Larger Fractions
The overall treatment time could still be kept the
same, if there were gaps, by reducing the number of
fractions and increasing their size. For example, with
a planned 2-day gap in a 30-fraction schedule, a total
course of 28 fractions of 2.10 Gy instead of 2.0 Gy
could be given. (Note that this is only a 5% increase in
dose, which emphasizes the importance of even a
small percentage change in delivered dose.) This
would be expected to give equivalence for late
reactions, with a reduction of only around 1% in
BED for tumour control. Alternatively, a dose per
fraction of about 2.12 Gy would be equivalent for
tumour control, with an increase of around 1% in
BED for late reactions. With unplanned gaps, the
radiobiological problems with this method depend
critically on the position of the gap. If the gap is early,
the necessary increase in dose per fraction for the
remaining fractions is modest and this method may do
relatively well. However, for late gaps it is just as
poor as Method 2a or 2b.
Method 3: Accept Protraction but Compensate
Using Extra Fractions
Another possibility with longer gaps would be to give
one (or more) extra fractions to restore the level of
local control to what it should have been. For several
reasons, this is the least attractive method. One
problem is that a 1-day gap would, in 1/5 of all
patients, be on a Friday and lead to the inclusion of an
extra weekend [62]. Hence, with the latter, a l-day
gap becomes a 3-day gap; add to this that delivering
the extra dose fraction requires one more treatment
day. Thus, the 1/5 of all patients with a 1-day gap on a
Friday (the other 4/5 being on a Monday to a
Thursday) would need compensation for four extra
days before completion of treatment. Similar con-
siderations apply for the 3/5 of all patients with a 3-
day gap including a Friday (six extra days) and all the
patients with 5-day gaps (eight extra days).
J. H. Hendryet al.
C A L C U L A T I O N OF CHANGES IN
PROBABILITY OF AN EFFECT
How do the above differences in BED,translate into
differences in effect? This can be calculated using the
linear-quadratic formalism with, for example, a Pois-
son function for the probability of an effect (P):
In(- lnP) = InK - D(0~ + [3d) + )~T
where lnK is a constant, and ~, is the increase in lnK
for each day's extension of treatment time. The time
factor in Gy (maximum value X/0~,k/(0~ +2[3) using 2
Gy fractions or k/(0~ + 213d) using an increasing
fraction size and a fixed number of fractions) is the
extra dose needed to compensate for each day's
prolongation of treatment.
Appropriate values of P have to be chosen for
tumour control and for late reactions. In the follow-
ing example calculations, P = 0.7 was chosen as being
close to the average value achievable for T2 glottic
cancer at five major radiotherapy centres in the UK
and North America [63]. A total dose of 66 Gy in 2 Gy
fractions was used in the calculations. The value of
lnK and 0~depend on the amount of heterogeneity in a
particular dataset, with low values of both parameters
reflecting a larger amount of heterogeneity. Various
datasets have been collated in the literature, using
different parameters to quantify the steepness of
dose-response curves [64-66]. For example, in terms
of the 'T37' parameter (the percentage point change in
tumour control for a 1% change in dose at the
steepest part of the dose-response curve (tumour
control probability (TCP) = 37%)), values range
from 0.5 to at least 2.8, with a median value of about
1.7 [67]. A value of 2.2 was chosen to reflect a fairly
steep dose-response curve (actually the value calcu-
lated for T2 laryngeal carcinoma in an early Manches-
ter series [65,68], to emphasize the importance of
gaps. In this case, InK = 5.98 (= ~'37"e), and the
corresponding value of o~would thus be 0.0885/Gy to
satisfy the above equation (with D = 66 Gy). Such
low values reflect the large variation in response
between patients, due to differences in intrinsic
radiosensitivity and other radiobiological factors.
However, it should be noted that even lower values of
0~ by two- to threefold (i.e. flatter dose-response
curves), have been deduced in the analysis of several
large data sets in the literature [46,49,69].
For late reactions, a 1% severe late complication
rate was chosen (i.e. P -- 0.01), as well as a level of
37% minor/moderate complications. It is convenient
that a value of 37% is at the steepest part of the dose-
response curve using the above equation. The value
of lnK was chosen to be 10.87 (i.e. 4.0-e, a Y37-value
of 4.0 being in the mid-range of values reported in the
literature [67]. The corresponding value for ot was
0.0849/Gy for 1% severe late complications at 66 Gy
(0d[3 = 3 Gy), and 0~ = 0.0988/Gy for 37% minor/
moderate late complications at 66 Gy. These values
of 0~ are near those reported for telangiectasia
[60,70,71] as well as being near the average for other
late endpoints such as fibrosis, pneumonitis, and skin,
gut, bladder and liver complications (reviewed in
[72]). A value of 0.09/Gy is also compatible with
Ways to Compensate for Missed Treatment Days in Radiotherapy
the very limited data reported for the increasing
incidence of laryngeal necrosis with increasing dose
from 0% (using 52.0 Gy/16 fractions in 21 days), to
4% (at 55.5 Gy in the same schedule) and 6% (at 58.0
Gy) [68], assuming 0d~ = 3 Gy. The time factor (k/00
for tumour control was taken to be 0.74 Gy/day
(Table 2).
Table 5 shows a comparison of the various methods
described above, either maintaining the complication
rate and allowing a decrease in tumour control rate,
or keeping the latter the same and allowing the
former to rise. These examples are only for compara-
tive illustration of the various methods described for
trying to compensate for the gaps. They depend on
the values of 0¢and 0d[3chosen. For tumour control, 0~
has been found to vary by an order of magnitude
amongst various series of patients treated and ana-
lysed in different centres [66], and the 0d[3 ratio can
vary by at least a factor of two among different
tumour and normal tissue types. The changes in effect
probability will be greater in cases where the 0d[3ratio
for late reactions is less than 3 Gy, the prescribed dose
per fraction is greater than 2 Gy, or the dose-response
curves are steeper than in the examples used here.
Also, the changes in effect probability will be less for
very high or very low effect levels compared with
levels in the steeper middle range (30%-70%) of the
sigmoid dose-response curve (e.g. less effect of gaps
would be expected to be found for T1 stage carcino-
mas where control levels are high at 90%). All this
can be modelled using particular sets of parameter
values in the linear-quadratic formalism, including,
for example, cases where, by design, normal tissue
doses are kept lower than tumour doses. In the
present example, the absolute loss of tumour control
per day starting from 70% is about 1.75%/day, which
is near the mean value of 1.7% per day for the
reported range for head and neck cancer (Table 1).
For treatments already at tolerance, it would clearly
be inadvisable to increase the complication rate from
1% to several per cent or more, or to go above 40%
minor/moderate complications; a slight lowering of
tumour control probability would probably be a
better option.
A particular example of the comparison of
methods is given in Table 6. This shows how a
standard treatment for head and neck cancer could be
modified to compensate for a 3-day gap, and the
dosage changes that might be employed. A compari-
son of the various methods can be made directly from
Tables 5 and 6, by ranking them in the order that the
radiotherapist considers most appropriate for a parti-
cular endpoint(s). Another approach is the figure of
merit (FOM) described by Dale and Sinclair [73].
This method may be applied to any type of fractio-
nated radiotherapy. The relative merits of several
different compensation schemes are compared in
terms of a single number (the FOM), which is derived
from the expected changes in the tumour and normal
tissue BED values. The method is not restricted to
considering any particular type of gap compensation.
Any scheme that can increase the tumour BED and/
or decrease the critical tissue BED is rewarded with a
high FOM score; conversely_, bad methods of com-
pensation "are penalized with low FOM Values. This
approach allows a compaiative ranking of the
303
methods available for compensation, with the radio-
therapist using clinical judgement to choose between
only those schemes that are shown by their FOM
scores to be at least moderately satisfactory.
INDIVIDUAL PATIENTS
Up to this point, the arguments have been based on
considering what might happen to a population of
patients rather than to an individual patient. The
patients who will be most disadvantaged by prolon-
gation of treatment without compensation will be
those whose probability of local control is around
50% (i.e. at the steep part of the sigmoid dose-
response curve). In any population, tumours will
have a spectrum of sensitivities to radiation, varying
from the very sensitive to the very resistant; the less
sensitive the tumour, the flatter the dose-response
curve. Also, the more variation there is, in terms of
radiosensitivity between individual tumours, the flat-
ter will be the dose-response curve for the population
as a whole.
Those individual patients with relatively resistant
tumours are probably destined to fail radiotherapy
anyway: the dose-response curve is relatively flat and
the adverse effect of prolonged treatment time is of
little significance. Patients with sensitive tumours are
those who are likely to benefit from radiotherapy: the
dose-response curve is steep and small compromises
in the BED, for example through prolongation of
treatment, may profoundly affect the probability of
controlling these tumours. The problem in inter-
preting the clinical data is to detect the signal
(prolongation causing decreased tumour control
probability in particular for sensitive tumours)
against the background noise (heterogeneity of popu-
lation causing flatter dose-response curves, which
leads to a less obvious effect of prolongation upon
average TCP). The above arguments based on con-
sideration of groups of patients will therefore tend to
underestimate the adverse effects of treatment pro-
longation upon those individual patients with sensi-
ti~e tumours.
For head and neck cancer, it was deduced that a
median value for clonogen SF2 (surviving fraction
after one dose fraction of 2 Gy) of 0.58 would be
consistent with clinical local control data 1174]. This
value translates into an 0~value of 0.23Gy- for 0d13--
10 Gy (i.e. an o~value more than twice that for the
group as a whole). Hence, for the 'median patient',
an extension in treatment by I day without somehow
accounting for the 0.74 Gy/day BED for tumour
control, could potentially reduce the TCP by as much
as 5% from 70%. Lesser, or potentially even greater,
changes could apply for respectively more or less
resistant tumours.
Although these values for individual patients are
speculative, they emphasize the problem of gaps and
they do suggest that the importance of gaps in
treatment on an individual patient basis may be even
more importaii't than the average values suggest.
Also, there is a possible further role for predictive
assays in this COlitext, to assess the potential loss of
304
tumour control per day and the compensatory
treatment for particular patients using individual
measurements of relevant parameters including those
for tumour cell sensitivity and proliferation, and
hypoxia.
COMBINED TELETHERAPY AND
BRACHYTHERAPY
In the case of tumours such as carcinoma of the
cervix, in which the treatment consists of both tele-
therapy and brachytherapy techniques, there are
further causes for an extension in the overall
treatment time. These include time gaps between
cessation of teletherapy and the use of brachytherapy
for a variety of reasons, and, sometimes, supplemen-
tary teletherapy is given after brachytherapy (e.g.
parametrial boosting). This form of treatment gap
can be corrected by the use of brachytherapy on a day
just before completion of the initial teletherapy
regimen. The loss of tumour control with increasing
overall time is found mainly in bulky and high stage
tumours [75], which suggests that, for smaller
tumours, both the high prevailing cure probability
and the beneficial effect of exponential tumour
volume shrinkage [76] result in a smaller reduction in
tumour control for short gaps. In the case of more
advanced tumours, the prescribed time is usually
considerably longer and the treatment is usually more
hyperfractionated [77].
The corrections for treatment gaps in the case of
turnouts treated by teletherapy and brachytherapy
are similar to those described for teletherapy alone
but there are additional options in that the time of
brachytherapy may be brought forward. In extended
gap situations where brachytherapy is used alone but
fractionated, there are alternative approaches:
1. In the case of low dose rate brachytherapy, a
higher total dose can be given by the use of a lower
prescription dose rate.
2. Where low dose rate treatment is interrupted for
patient-related reasons, the remainder of the
treatment can be given by high dose rate tech-
niques, providing a method of dose recalculation
is used [78].
3. In the case of high dose rate brachytherapy, the
remaining dose per fraction and interfraction
intervals in the remaining treatment course should
be adjusted appropriately, using the same princi-
ples given for teletherapy.
CONCLUSIONS
It is concluded that gaps of even a few days in
radiotherapy treatments should be avoided if poss-
ible. They lead to significant decreases in local
tumour control, a feature confirmed in many pub-
lished series. The decreases are expected to be even
greater for individual patients than for a group of
patients as a whole. Of the various methods of
J . H . Hendry et al.
compensation for gaps in treatment, the 'safest'
methods are those that keep as close as possible to the
original/standard prescription in terms of total dose,
dose per fraction, and overall times (i.e. preferably
treating on weekend days, or using two fractions per
day to 'catch up'. Other methods lead to uncertainty
in the changes in local control or in complications
when attempts are made to keep one or the other at
the same level.
Acknowledgements. Other members of the Royal
College of Radiologists' Working Party on Guide-
lines for Treatment Interruptions, in addition to A.
G. R., N. J. S. and J. H. H., namely Mrs S. E.
Griffiths and Drs H. MacDougall, D. A. Morgan, H.
Porter, M. F. Spittle and H. Yosef, also provided
helpful comments and some suggestions for the
compensation methods that formed the basis of the
comparisons in this article.
We thank Mrs M Regan for expert help with the
manuscript.
APPENDIX
Summary of the Formulae Used
Dose-response relationships for tumour control
probability (TCP) or normal tissue complication
probability (NTCP) were assumed to follow the
Poisson formulation of the linear-quadratic model.
Assume that the reference schedule delivers a dose D
with dose per fraction 6 in a planned overall time T.
After a gap of length At, the probability of an effect,
P, is given by
P(V,d,At) = exp[-exp(lnK-oc.D-f3.D.d+~,.AT) ( A 1 )
where lnK is a constant, ocand ~ are the coefficients of
the linear-quadratic model, and )v is the increase in
lnK for a 1-day extension of overall treatment time x.
Mechanistically, )v is the growth constant of the
assumedly exponential growth of target cells during
the time At.
In equation A1, the probability of response
depends only on At. Thus, P is independent of the
position of the gap and the temporal distribution of
missed treatment days for one or more gaps. Also,
the much debated existence of a lag time before the
onset of accelerated repopulation does not matter if
this lag time is shorter than the prescribed overall
time.
Fractionation sensitivity was represented by the
linear-quadratic model. Thus, two doses were
assumed to be isoeffective provided that:
D od[3+dl
D2= 1"~/-7-~z (A2)
The 0d[3 ratios were assumed to be 10 Gy for
tumour control and 3 Gy for late normal tissue effects
to agree with some clinical data.
1Some authors have used the symbol y instead of k for this
parameter. We prefer the latter symbol to avoid confusion with the
normalized dose-response gradient.
Ways to Compensate for Missed Treatment Days in Radiotherapy
Table A1. Summary of parameters used in estimating the change in treatment outcome after various types of gap compensation. Reference
schedule delivering 66 Gy using 2 Gy per fraction
Endpoint P% ~p
Tumour control 70 1.75
Severe late reactions 1 0.43
Minor/moderate late reactions 37 4.0
P is the response probability (tumour control or normal tissue reactions); ye is the ,/-value at that response level.
The change in TCP or NTCP for a given change in
dose depends on the steepness of the dose-response
curve and this is most conveniently quantified by the
normalized dose-response gradient [79] defined as
V = D.p'(D) (A3)
where the prime indicates differentiation with respect
to dose. The y-value may be interpreted as the
percentage point change in response for a 1% change
in dose. Of particular interest is the y-value at the
steepest part of the dose-response curve. For the
Poisson model, this is at the 37% response level
(more exactly at = 1/e, where e is the base of the
natural logarithm), and the corresponding y-value is
denoted 737. If treatment is delivered with a constant
dose per fraction, the following simple relation holds:
InK
737- e (A4)
Thus, from literature reviews of 7 for clinical end-
points [67], InK can easily be obtained. From this
value and the 0¢/[3ratio, equation A1 can be used to
calculate 0¢ for a specific fractionation schedule,
producing a specific probability of response. Table
A1 summarizes the parameters used in this report.
Isoeffect calculations may conveniently be done in
terms of the biological effective dose defined as
BED = D.[l+d/(a/~)] (A5)
The physical dimension of BED is dose and it is
measured in Gy. Following Fowler [80], we use the
notation Gyl0 and Gy3, where the subscripts indicate
the value of 0d[3 used in calculating BED.
If the treatment is protracted, the BED will be
lowered according to the formula
B E D = BED~ef - L_.A T
0c (A6)
The relative change in BED may be converted into a
change in response probability simply by multipli-
cation by the y-value at the relevant point of the dose-
response curve. This approximation is good for small
changes in BED, but becomes poorer for large
changes in BED because of the sigmoid shape of the
dose-response curve. A more exact value may be
obtained by combining equations A1 and A5. It
follows that
ln(lnP) = InK - o¢.BED (A7)
305
]t37 InK a (Gy -1) ~/[3 (Gy) BEDr~e
2.2 5.98 0.0885 10 79.2 Gyl0
4.0 10.87 0.0849 3 110 Gy3
4.0 10.87 0.0988 3 110 Gy3
Thus, the change in response for a given change in
BED may be calculated from the equation
ln(-lnP2) = ln(-lnP1) - o~.(BEDz-BED1) (A8)
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tumour-control data. Radiother Oncol 1993;29:69-74.
70. Bentzen SM, Turesson I, Thames HD. Fractionation sensiti-
vity and latency of telangiectasia after postmastectomy radio-
therapy: A graded-response analysis. Radiother Oncol
1990;18:95-106.
Book Review
Cancer of the Breast, 4th edition. Edited by W. L. Donegan and J.
S. Spratt. Saunders, Philadelphia, 1995. Pages: 860; Price: £115.00;
Hard cover; ISBN 0-7216-4694-8.
In this 4th edition of this standard American textbook first
published almost 30 years ago (1967), the huge explosion of
interest and information about breast cancer is reflected by a
contents list of over 40 chapters. Some are inevitably more
thoughtfully written than others. It is surprising, for example, to
find a detailed and fully illustrated chapter on surgical management
which is over 60 pages long, whereas the discussion of radiation
therapy and its role occupies less than a quarter of this length.
Recent advances in adjuvant chemotherapy, one of the hottest
issues of the day, are dealt with swiftly in just four pages, with most
of the references to this chapter now seriously out of date.
Endocrine therapy of breast cancer is very well covered, however,
in a section that discusses the important issue of tamoxifen as
a potential means of breast cancer prevention. There is also
an excellent account of recent laboratory and clinical
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71. Bentzen SM, Overgaard M. Relationship between early and
late normal-tissue injury after postmastectomy radiotherapy.
Radiother Oncol 1991;20:159-65.
72. Hendry JH. Response of human organs to single (or fractio-
nated equivalent) doses of irradiation. Int J Radiat Biol
1989;56:691-700.
73. Dale RG, Sinclair JA. A proposed figure of merit for the
assessment of unscheduled treatment interruptions. Br J
Radiol 1994;67:1001-7.
74. Bentzen SM. Steepness of the clinical dose-control curve and
variation in the in vitro radiosensitivity of head and neck
squamous cell carcinoma. Int J Radiat Biol 1992;61:
417-23.
75. Fyles A, Keane TJ, Barton M, et al. The effect of treatment
duration on the local control of cervix cancer. Radiother Oncol
1992;25:273-9.
76. Tan LT, Jones B, Green JA, et al. Treatment of carcinomas of
the uterine cervix which remain bulky after initial external
beam radiotherapy: A pilot study using integrated cytotoxic
chemotherapy prior to brachytherapy. Br J Radiol
1995;69:165-71.
77. Jones B, Tan LT, Blake PR, et al. Results of a questionnaire
regarding the practice of radiotherapy for carcinoma of the
cervix in the UK. Br J Radiol 1994;67:1226-30
78. Tan LT, Jones B, Frestone G, et al. Case report: Low dose
rate and high dose rate intracavitary brachytherapy in a
patient with carcinoma of the cervix. Br J Radiol 1996; 69:85-
6.
79. Brahme A. Dosimetric precision requirements in radiation
therapy. Acta Radiol Oncol 1984;23:379-91.
80. Fowler J. The linear quadratic formula and progress in
fractionated radiotherapy. Br J Radiol 1989;62:679-94.
Accepted for publication August 1996
research with pure antioestrogens, aromatase inhibitors, LHRH
agonists and combination endocrine therapy. Likewise, I was
impressed with the section on screening and follow-up, which was
another well illustrated chapter, and by the earlier chapters on
breast imaging and staging.
In summary, the latest edition of this surgically dominated text is
beginning to show its age. There is insufficient coverage of
important issues such as neoadjuvant and high dose chemotherapy
(barely mentioned), the emergence of BRCA1 and BRCA2 as
important genetic predeterminants, and the management of pain,
which rather oddly merits a chapter to itself, although far too brief
(under four pages) to be helpful. This volume will end up in our
library, but I doubt whether many colleagues will need to purchase
a personal copy.
J, S. TOBIAS
The Meyerstein Institute of Oncology
London