Clinical Oncology (2002) 14: 382393

doi:10.1053/clon.2002.0111, available online at http://www.idealibrary.com on

Original Article
Practical Methods for Compensating for Missed Treatment
Days in Radiotherapy, with Particular Reference to Head
and Neck Schedules
R. G. Dale*, J. H. Hendry, B. Jones*, A. G. Robertson, C. Deehan,
J. A. Sinclair*
*Hammersmith Hospitals NHS Trust/Imperial College School of Medicine, London, U.K.; Paterson Institute for
Cancer Research, Christie Hospital NHS Trust, Manchester, U.K.; Beatson Oncology Centre, Western Inrmary,
Glasgow, U.K.; Department of Medical Physics, Leicester Royal Inrmary, Leicester, U.K.
ABSTRACT:
Unscheduled interruption of a radiotherapy treatment can lead to signicant loss in local tumour control, particularly in tumours
that repopulate rapidly. General guidelines for dealing with such treatment gaps have been issued by the Royal College of
Radiologists and more specic advice on the use of compensation methods has been published previously [Hendry et al., Clin Oncol
1996;8:297307; Slevin et al., Radiother Oncol 1992;24:215220]. This article further elaborates on the practical application of these
methods. It sets out the main considerations arising in the especially critical case of head and neck treatments and simple
calculations are used to illustrate the approaches which may be adapted for particular situations. Radiobiological parameter values
are suggested for use in the calculations, but these may require modication in the light of further research in this important area.
Dale, R. G. et al. (2002). Clinical Oncology 14, 382393
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
Key words: Cancer, cell kinetics, fractionation, overall time, radiotherapy, time factors in radiotherapy, treatment interruptions
Received: 5 July 2001 Accepted: 2 May 2002
Introduction
Local tumour control can be adversely aected by
prolongation of overall treatment time in radiotherapy.
A number of studies have highlighted that tumour cell
repopulation can produce losses in local control which,
particularly for squamous cell cancers of the head and
neck region, may amount to 12% per day of treatment
prolongation [1,2]. Similarly, recent studies on non-
small cell lung cancer and cervix carcinoma have indi-
cated respectively 1.6% and 0.8% loss of local control
per day of treatment extension [3,4]. Adherence to
radiotherapy schedules is therefore important if individ-
ual treatments are not to be compromised. However,
there are occasions when unforeseen interruptions
occur, prime causes being equipment breakdown or
unwell patients and the Royal College of Radiologists
(RCR) in 1996 issued guidelines for dealing with
unscheduled treatment interruptions [5]. In parallel with
these guidelines a more detailed review of the evidence
for the deleterious eects of treatment prolongation was
published, together with a comparative assessment of
the methods available for the compensation of missed
treatment days [1].
Many U.K. departments have since implemented
measures for handling unscheduled treatment interrup-
tions and the evolving experience has highlighted that
some diculties remain, particularly with respect to
terminology and in relation to how to use the various
radiobiological parameter values. This article reiterates
some of the points previously discussed [1], but in
addition it specically elaborates on the practical issues
which arise when devising compensations for inter-
rupted treatments. Although some methods of treatment
compensation are clearly preferable to others, practical
factors (machine availability, ability of centres to work
extended hours and/or weekends, ability of an unwell
patient to undergo the full compensation, etc.) also
inuence the decision regarding which form of compen-
sation to adopt. It is therefore of some importance
(particularly in more dicult cases) to examine two or
three possible solutions in order to identify a compro-
mise scheme which helps the patient without causing
severe disruption to local service arrangements. The
methods described below are those to be considered
Author for correspondence: Dr R. G. Dale, Radiation, Physics &
Radiobiology, Charing Cross Hospital, London W6 8RF, U.K.
E-mail: r.dale@ic.ac.uk
09366555/02/040382+12 $35.00/0 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
when technical failures have caused the interruption.
For gaps resulting from adverse clinical reactions the
methodology is the same but the condition of the patient
may mean that it is not always possible to compensate to
the same extent. Although this paper concentrates on
head and neck squamous cell cancer, the methodology
is applicable to other sites provided appropriate
alternative parameter values are used.
Inuence of unscheduled treatment interruptions on tumour
repopulation
Figure 1 is a simplied diagram showing how the total
(physical) dose for a given tumour response (e.g. 50%
tumour control probability when the dose is delivered in
2 Gy fractions) is assumed to vary with treatment time.
If the treatment is completed before the initiation of
accelerated repopulation (denoted by the rising line
beginning at time T
delay
) then the dose required in this
region is xed and is independent of the treatment time
used. If, however, the treatment is of duration greater
than T
delay
days, the iso-eect dose increases in order to
compensate for the consequent tumour repopulation,
the dose in this region now being time-dependent. The
dose prescribed in schedules which extend beyond T
delay
days will inherently include extra dose to compensate for
the repopulation eect.
Figure 2 illustrates a prescribed treatment which is
scheduled to be completed at time T. If there occurs an
unscheduled interruption of duration t days during the
treatment, and no allowance is immediately made for
this, then the treatment will need to be extended by
t days at the end of the prescribed schedule. To maintain
the tumour iso-eect would require the addition of
extra dose, incurring an associated penalty (impaired
Therapeutic Index) in terms of a higher normal tissue
dose. To prevent overdosing of the normal tissue would
require that the supplementary tumour dose be reduced,
also with detrimental eect.
If, however, the unscheduled interruption could be
compensated for by delivering the missing dose (by
extra daily fractions, or weekend treatments), without
extending thetreatment duration, no such penalty would
be incurred. This demonstrates an important point: it is
the likelihood of extension to the treatment time, rather
than the gap per se, which is the main cause for concern
when interruptions occur. A further point is that
unscheduled gaps occurring early in treatment (before
the onset of tumour repopulation), if they lead to a
treatment extension, are assumed to be no less detrimen-
tal (on current evidence) than those occurring later in
treatment. The dierence between an early- and late-
interruption is practical rather than radiobiological:
with the former more time remains within the prescribed
schedule to eect a satisfactory compensation.
More detailed schematics illustrating the problems of
treatment interruptions have been published elsewhere
[68].
Equations
The biologically eective dose (BED) received by
a uniformly irradiated tissue which is concurrently
repopulating is calculated as:
where n is the number of fractions, d is the dose per
fraction, T is the overall treatment time. T
delay
is the
delay time (from the beginning of treatment) before the
onset of signicant repopulation [9]. / (in units of Gy)
is the fractionation factor and K (in units of Gy day
1
)
is the biological dose per day required to compensate for
Fig. 1 Schematic showing how the total dose required for a given tumour control probability (TCP) changes with increasing
treatment duration. The horizontal and sloped lines demonstrate how the dose rises steadily after an initial delay period.
coxirNs:1ioN ro xissrn 1r:1xrN1 n:xs iN :nio1nr:ix 383
on-going tumour cell repopulation. K is the BED-
equivalent of 1 days worth of repopulation [9]. The
expression in square brackets in Eqn (1) is termed the
Relative Eectiveness factor (RE).
Both / and K are tissue-specic and appropriate
values must be selected for each when calculating
tumour BEDs.
As applied to a tumour, Eqn (1) may be remembered
in words as:
BED=Total physical dose RERepopulation Factor
(RF)
For most late-responding normal tissues the prolifer-
ation rate is usually so small (except in cases where
consequential late reactions are dose-limiting [10])
that K can be neglected, i.e. K=0 and RF=0 in such
cases.
It has become conventional practice to place the /
value used in the BED calculation as a subscript to both,
the BED symbol and its associated numerical value. For
example, a stated BED
3
of 100 Gy
3
indicates that
/=3 Gy was used in calculating that particular biologi-
cal dose. The use of the subscript reinforces the point
that biological dose is conceptually dierent to physical
dose, even though both are in similar dimensions. Bio-
logical doses expressed in (for example) Gy
10
can be
added to other Gy
10
values to provide a measure
of resultant eect, but it is not permissible to add (say)
Gy
3
values to Gy
10
values.
Eqn (1) is valid in cases where the fractions are
relatively well-spaced. When two or more fractions are
delivered per day there may be incomplete repair of
sub-lethal damage between successive fractions, leading
to increased biological damage [11]. This is particularly
so withregard to late reactions. In such cases Eqn (1) is
changed to:
Factor h in Eqn (4) reects the increased damage caused
by incomplete repair. It is complex in form and is
dependent on the inter-fraction intervals (which are not
usually the same between all fractions) and the repair
kinetics. The derivation of the h factor is discussed in the
Appendix. There may be occasions when compensation
for unscheduled treatment gaps will involve the use of
many relatively close fractions (less than 8 h between
fractions) and, in such cases, the eects of incomplete
repair should be borne in mind. If there is to be more
than one day on which twice-or thrice daily fraction-
ation is required then, where possible, such days should
not be consecutive. It is recommended that allowances
for incomplete-repair should always be included when
the use of four or more closely-spaced fractions is
unavoidable. A later example (Example 5) will illustrate
some of the issues involved.
Eqns (1) and (2) provide the basis for devising com-
pensation for unscheduled treatment interruptions, but
there are many instances where they need to be utilized
in a slightly dierent form. Rather than list a family of
related equations, the methodology appropriate to par-
ticular circumstances will be explained in the worked
examples.
Fig. 2 Showing the eect of a treatment extension, caused by an earlier unscheduled gap. If the treatment extends into the time
period where steady tumour repopulation is occurring, extra dose (X) is required to compensate for this. It should be noted that this
will be the case even if, as here, the unscheduled gap occurred during the period prior to the initiation of tumour repopulation.
384 ciiNic:i oNcoiocx
Recommended values of /, K and T
delay
The range of / values usually considered for head and
neck cancers is around 1020 Gy [12]. A preliminary
analysis of the recently reported RTOG9003 head and
neck trial indicates a value just below the bottom end of
this range [13]. We therefore suggest that a generic /
value of 10 Gy be used for head and neck cancers, but
this gure should be kept under review.
For late-responding normal tissues a generic / of
3 Gy is generally recommended. The important excep-
tions to this are brain and spinal cord, for each of which
an / value of 2 Gy should be used, reduced further
to 1.5 Gy when fraction sizes greater than 2 Gy are
employed. A reduced / of 2.5 Gy may also be prefer-
able for normal tissues in cases where there are concerns
that tolerance may be clinically compromised [11]. A
comprehensive tabulation of / values for various nor-
mal tissue and tumours can be found in the chapter by
Joiner and van der Kogel in reference [14].
The data reviewed for the previous Clinical Oncology
article on gap compensation [1] indicated that head and
neck K factors were in the range 0.50.74 Gy day
1
. Since
then more sophisticated analyses of multi-centre data have
shown that K values are likely to be higher than originally
believed. Roberts and Hendry [15] have conducted a meta-
analysis of larynx treatment results from Edinburgh,
Glasgow, Manchester and Toronto, leading to an upwardly
revised K estimate of 1.2 (95% CL 0.82.2) Gy day
1
. The
results of the RTOG9003 head and neck trial [16] also
lend support to the likelihood of higher K values with
early analyses of those data suggesting K values of
0.940.99 Gy day
1
[13,17].
The head and neck tumour control data collated by
Withers et al. [12] demonstrated a dog-leg eect of
the type illustrated in Fig. 1 and have been analysed in
detail by Hendry and Roberts [18], who found the
repopulation delay time (T
delay
) to be 29 (95% CL
1731) days. For the shorter Manchester treatment
regimes the delay time was established as 26 (95% CL
1933) days.
On the basis of the above, and bearing in mind the
relatively large condence intervals and the fact that the
tted values of K and T
delay
must be used together, we
suggest that respective working values of 0.9 Gy day
1
and 28 days be adopted for head and neck cancers. It is
stressed that neither of these recommended values can
yet be considered as denitive and that they must be
reviewed in the light of continuing research.
The recommended K value of 0.9 Gy day
1
repre-
sents the BED required each day (after T
delay
has been
passed) to oset repopulation. If / for tumours is
taken as 10 Gy then, more specically, K is the BED-
equivalent of repopulation in units of Gy
10
per day. This
means that, when 2 Gy fractions are being used, the
daily physical dose required to oset the repopulation
after time T
delay
is K/[1+2/10]=0.75 Gy day
1
, i.e. for
each 2 Gy fraction delivered, (0.75/2)100=38% is
wasted in combating repopulation.
Values of K and T
delay
are derived on the basis that
there is an intrinsic pairing between them. This arises
because there is an a priori assumption that there is zero
population in the period up to T
delay
, meaning that the
paired parameter values provide the best t to the
observed increases in dose over the whole range of
treatment times studied.
The data relating to time factors and the eects of
gaps for head and neck treatments were reviewed up to
1996 in the previous article [1]. That review discussed the
fact that the time factor was approximately the same
during protracted treatments as in split-course treat-
ments and that there were contradictory suggestions
regarding the relative importance of gaps early or late in
the schedule. Since 1996 the importance of treatment
interruptions in radiotherapy for oropharyngeal carci-
nomas has been highlighted [19]. Evidence has also
emerged that the position of the gap is not important
and that the loss of tumour control following each day
of interruption of a head and neck treatment is about
the same as occurs when conventional schedules are
protracted [20,21]. The latter feature was conrmed in a
human xenograft tumour model in mice [22]. In con-
trast, in rat tumours it has been shown that the position
of the gap does matter [23]. Regarding the combination
of chemotherapy and radiotherapy, there are reports of
a lack of a time factor in alternating chemoradiotherapy
for advanced head and neck squamous cell carcinoma
[24]. Long gaps were found to be detrimental to local
control in anal canal carcinoma treated by split-course
radiotherapy and concomitant chemotherapy [25].
As discussed earlier, the assumptions in the head and
neck data tting exercises inherently excluded the possi-
bility of there being any repopulation in the period up to
the T
delay
time point, but that does not mean that
repopulation does not occur in that time. Indeed, other
analyses suggest that repopulation does occur from the
beginning of treatment [26]. There thus arises the ques-
tion of what K factor should be used in interrupted
treatments for which the nal overall time is less than
T
delay
. Withers et al. [12] suggested that the repopulation
rate during the early part of treatment reected the
pre-treatment tumour growth-rate. Examination of the
slopes before and after the delay time suggests they are
in the approximate ratio 1:10, i.e. that the K value to use
prior to T
delay
is one-tenth that used after the delay
point. For head and neck treatments we therefore rec-
ommend K=0.1 Gy day
1
and T
delay
=0 in cases where
the nal overall times are less that 28 days. It is
emphasized that these values are suggested on the basis
of the evidence currently available; they cannot be
regarded as being denitive.
Although the methodology described in this paper is
more widely applicable, there is at present very little data
relating to K and T
delay
factors for other tumour types.
For non-small-cell lung tumours there is evidence that
the loss of local control per day towards the end of
treatment is about the same as that for head and neck
cancers [3,27]. For cervix tumours the time factors are
coxirNs:1ioN ro xissrn 1r:1xrN1 n:xs iN :nio1nr:ix 385
probably around half those for head and neck tumours,
i.e. c0.5 Gy day
1
[1]. For breast tumours the K fac-
tors are likely to be around 0.3 Gy day
1
while for
prostate tumours they are likely to be in the region
0.10.3 Gy day
1
, or even lower [2830]. Little is
known about the corresponding values of T
delay
.
Calculation process
The table below (based on reference [1]) identies the
main methods for compensation and the associated
benets and diculties.
Interrupted treatments need to be evaluated on an
individual basis and there is no universal method for
tackling all problems. However, most examples will
involve a series of general steps which may be
summarized as follows:
Once an unscheduled gap has occurred, rst determine
the remaining treatment time and the number of frac-
tions still to be delivered. Determine if there are ways of
delivering these fractions to allow the originally pre-
scribed treatment time to be maintained, e.g. by treating
at weekends or by giving all or part of the remaining
treatment twice-daily. If this is possible then further
radiobiological calculations may not be necessary. (Ex-
amples 1 and 2 below relate to such a case). If this
option is not feasible (i.e. it is not possible to complete
treatment within the prescribed treatment time) then:
(1) First calculate the tumour and normal tissue
BEDs for the prescribed schedule. Both BEDs are
calculated via Eqn (1) but, for the late-reacting
normal tissue, K is set to zero.
(2) Determine the overall time until the beginning of
the unscheduled gap and, hence, the respective
pre-gap BEDs.
(3) Determine the late-normal BED still to give (the
post-gap BED).
(4) Review the various treatment options (e.g.
twice-daily fractionation and hyperfractionation,
increased fraction sizes, etc.) to ascertain which will
be likely to produce the minimum extension to the
treatment time, then calculate the required dose per
fraction to achieve the required late-normal BED
value. Calculate the resulting tumour BED for this
option, remembering to make allowance for the
extended time (Example 36 below demonstrate
various versions of this scenario).
(5) Review the nal tumour and normal tissue BEDs
which will result from the preferred compensation
option. If the tumour BED is signicantly smaller
than that originally prescribed a degree of clinical
judgement may be required in order to ne tune
the compensation in order to arrive at a reasonable
compromise. (Examples 46 illustrate the dilemmas
which may be involved in such cases).
It is stressed that these are general steps. For example, if
the favoured compensation option involves closely-
spaced fractions after the gap, the modied BED for-
mula [Eqn (2)] must be used to determine the possible
enhancement to normal tissue toxicity as a consequence
of incomplete-repair. It is suggested that if a total of four
Method Benet Diculty
(1a) Retain overall time and dose per fraction
by treating on weekend days as necessary.
Overall time, fraction size, inter-fraction
interval and Therapeutic Index maintained.
Unsocial hours and associated costs. May not
be appropriate for gaps occurring near the
end of a schedule.
(1b) Retain overall time and dose per fraction
by treating twice-daily as necessary.
Overall time and fraction size maintained. Possible loss of late-normal tissue tolerance
when several fractions have to be delivered at
68 h inter-fraction intervals. Scheduling
diculties.
(2a) Retain overall time by increasing dose
per fraction for same number of post-gap
days as there were gap days.
Overall time retained by accepting reduced
number of fractions. Still one fraction on each
treatment day.
Not suitable for schedules which already use
high dose per fraction. Therapeutic Index
adversely aected: Seeking equivalence for
tumour control gives increase in late
reactions. Seeking equivalence for
late-reactions leads to tumour under-dosage.
(2b) Retain overall time by using smaller
number of larger fractions after the gap.
Overall time retained. Still one fraction per
day.
As above.
(3a) Accept that treatment extension is
unavoidable and deliver extra fractions, using
increased dose per fraction to minimize the
extension duration.
Allows at least partial restoration of the
prescribed schedule.
Therapeutic Index adversely aected. Might
require acceptance of both reduced tumour
control and increased late-eects.
(3b) As for 3(a) but use twice-daily fractions
and a slightly reduced treatment extension.
As above. As for 3(a), but deterioration in Therapeutic
Index is not so marked.
386 ciiNic:i oNcoiocx
fractions or more are to be given at twice-daily intervals
(or more frequently) then the eects of incomplete repair
should always be considered.
Worked examples
Worked examples 13 each consider the handling of
5-day gaps. In practice the majority of unscheduled
interruptions involve interruptions of 5 days or less and
are relatively easy to deal with. With a gap of just 1 or
2 days dierent policies may apply in dierent centres.
Examples 15 involve a reference schedule of 70 Gy
delivered in 35 fractions over 46 days, typically used for
Category 1 head and neck tumours. The overall time of
46 days corresponds to a treatment beginning on a
Monday, continues with daily-fractionation for 7 weeks
with no treatment at weekends and nishes on a Friday.
For a similar 35 fraction schedule which begins mid-
week the treatment time will be longer (because the
treatment will extend into an eighth week) and specic
calculations should allow for this.
For other schedules, e.g. the commonly used 4-week
treatments, the principle involved in determining a
method of compensation is exactly the same as set out in
the 7-week treatments used here. In such cases, however,
there is more concern about b.i.d treatments if the dose
per fraction is already signicantly larger than 2 Gy,
because of the greater potential for incomplete repair.
Example 6 elaborates on this and also discusses a
treatment which does not begin on a Monday.
In all the examples requiring calculations, the process
here has been to devise a compensation scheme to
maintain the desired late-reacting BED and then, as
necessary, to consider alternatives in the light of how
much the resultant tumour BED is compromised. This is
done because late morbidity is often the most critical
concern in radiotherapy and some normal tissue para-
meter values are more reliably known than those for
tumours. Also, because late-responding tissues are
associated with less heterogeneity than tumours they
often exhibit steeper dose-response curves, i.e. any
deviations from the BEDs associated with the original
schedule will be more critical for the normal tissues.
Notwithstanding this view, however, there may be
instances where clinicians decide from the outset to
accept the risk of an elevated late-normal BED in order
to maintain a desired tumour eect.
Example 1. Loss of all of the third week (ve fractions) of a
treatment schedule of 70 Gy/35 fractions/46 days.
Assuming the treatment began on a Monday, the
intended overall treatment time is 46 days. After the gap,
treatment resumes on the Monday of the fourth week of
the schedule. Ten fractions have been delivered; 25
remain to be given. If treatment is to be completed on
the prescribed nishing date the available number of
days (including weekends) is 26. Thus the missed dose
in the gap can be compensated for by delivering the
remainder of the treatment on weekdays (20 fractions)
and on ve of the six remaining weekend days. This
does not involve changing the fraction size and, as
the treatment is not extended, constitutes a good
compensation.
If weekend treatments are not feasible a good com-
pensation is still possible if, on ve of the 20 remaining
treatment days, two fractions are delivered instead of
one. The important proviso is that the twice-daily frac-
tions must be delivered with a minimum time gap
between them of at least 6 h, preferably 8 h, in order to
minimize any potential problems with incomplete repair
[31]. It is further recommended that the days on which
twice-daily treatments are delivered are not consecutive,
but spaced throughout the available time period. In this
instance Fridays are a good choice for delivery of some
of the twice-daily fractions as there is a greater oppor-
tunity for completion of repair before treatment resumes
the following week.
Example 2. Loss of all of the sixth week (ve fractions) of a
treatment schedule of 70 Gy/35 fractions/46 days.
After the gap, treatment resumes on the Monday of the
seventh week of the schedule. Twenty-ve fractions have
been delivered; 10 remain to be given. Ideally these 10
fractions should be delivered over the ve remaining
treatment days. The missed dose can therefore be
compensated for by delivering the remainder of the
treatment as twice-daily fractions in each weekday
of the nal week. This does not involve changing the
fraction size and, as the treatment is not extended,
constitutes a good compensation. A better solution, if
feasible, would be also to make use of the weekend
before the nal week of treatment, thus providing 7 days
within which 10 fractions have to be delivered. Bi-daily
fractionation could be used (for example) on Monday,
Wednesday and Friday, single fractions on the other
4 days. The advantage of the latter scheme is that
it reduces the likelihood of creating excess biological
damage if there is incomplete repair between fractions.
Examples 1 and 2 represent sound solutions for
dealing with unscheduled interruptions; they do not
involve changing fraction size or overall time and,
provided there is reasonable spacing between treatment
days on which bi-daily treatment is given, do not invoke
any quantitative evaluations or serious radiobio-
logical dilemmas. The following examples illustrate the
compromises involved in more dicult cases.
Example 3. Loss of all of the seventh week (ve fractions)
of a treatment schedule of 70 Gy/35 fractions/46 days.
For the prescribed treatment the normal tissue BED
(BED
3
) is, from Eqn (1) with K=0:
coxirNs:1ioN ro xissrn 1r:1xrN1 n:xs iN :nio1nr:ix 387
The tumour BED (BED
10
), also from Eqn (1) but with
K=0.9 and T
delay
=28 days is:
In this example the unscheduled gap extends to the time
when treatment should have nished and any form of
compensation will therefore extend the treatment time
beyond the scheduled time.
We begin by assuming that the missing dose is
replaced by treating ve 2 Gy fractions over a full extra
(eighth) week, beginning on a Monday. On completion,
the overall time is 7 days longer than scheduled. With
a daily BED-equivalent of tumour repopulation of
0.9 Gy day
1
the tumour BED
10
will be lower than
intended by an amount 70.9=6.3 Gy
10
. The late-
normal BED
3
will be as prescribed.
If, instead, the outstanding daily treatments are given
in the period SaturdayWednesday, the net treatment
extension is 5 days, i.e. the tumour BED
10
is low by a
smaller factor of 50.9=4.5 Gy
10
. A further alternative
is to treat two fractions per day on Saturday and
Monday with one fraction on Sunday, thus extending
treatment by 3 days. In this case the tumour BED
10
will
be low by an even smaller amount of 30.9=2.7 Gy
10
.
In each of these instances the normal tissue BED
3
will be
as prescribed.
The dilemmas arise when attempts are made to
increase the total dose in order to restore the tumour
BED
10
to that originally prescribed; in this case it is
impossible to do that without increasing the normal
tissue BED
3
[8]. Delivering extra dose by treating with
extra fractions has the eect of further extending the
treatment time, which may compound the original prob-
lem. Increasing the dose per fraction helps minimize the
treatment extension but, because of the greater sensitiv-
ity of the late-responding critical tissue to changes in
dose per fractions, will increase the normal tissue bio-
logical dose proportionately more than that for the
tumour.
We next consider an instance where it is felt essential
to restore the tumour BED
10
to what it should be,
initially without regard for the eect on the normal
tissue. We assume the option of treating additionally
over the weekend is to be adopted, i.e. the overall time is
46+5=51 days.
The tumour BED
10
of 67.8 Gy
10
is to be maintained.
Therefore, for the whole schedule (pre-gap plus post-
gap):
BED
10
(pre-gap)+BED
10
(post-gap)Tumour
Repopulation Factor=Required BED
10
where d is the new value of dose per fraction to be
utilized over the ve fractions. The solution for d in
the above equation is d=2.62 Gy, i.e. 52.62 Gy will
restore the tumour BED
10
to that initially prescribed.
Again it should be noted that the required extra BED
10
of (50.9)=4.5 Gy
10
cannot be added simply pro-rata
across the ve 2 Gy fractions. The values of the biologi-
cal Gy
10
and the physical Gy units are dierent and they
cannot be added; to do so would lead to an even higher
fraction dose of 2.9 Gy. This and other subtleties associ-
ated with the use BED-equivalents has been discussed in
more depth elsewhere [9,11].
For the normal tissue, the compensated treatment
increases the BED
3
to:
BED
3
(pre-gap)+BED
3
(post-gap)
i.e.
Thus the revised treatment delivers a 6.7% excess in
normal tissue BED
3
. To evaluate what this compensated
scheme would mean in terms of the equivalent dose
in a schedule delivered with 2 Gy fractions we note
that, by re-arrangement of Eqn (1) and omitting the
repopulation factor:
i.e. the total dose in 2 Gy fractions would be 74.7 Gy.
Thus, the given normal tissue BED
3
is approximately
equivalent to 372 Gy fractions.
If the normal tissue dose is considered too high it is
possible to split the dierence, i.e. aim to achieve a
tumour BED
10
which is a little less than that prescribed
whilst accepting a small increase in normal tissue BED
3
.
Such a result may be arrived at by trial and error
processing of dierent values of dose per fraction. For
instance, in the above example an intermediate dose per
fraction of 2.3 Gy would deliver a total tumour BED
10
of:
BED
10
(pre-gap)+BED
10
(post-gap)Tumour
Repopulation Factor
i.e.
The normal tissue BED is:
BED
3
(pre-gap)+BED
3
(post-gap)
388 ciiNic:i oNcoiocx
i.e.
Thus, with 2.3 Gy fractions in the compensation, the
tumour and normal tissue BEDs are respectively 3.5%
lower and 3.1% higher than for the uninterrupted sched-
ule. The eects of higher or lower values of dose per
fraction could be tested, as appropriate, using the same
process. It is stressed that the process of hypofraction-
ating treatment after the gap is not necessarily the best
option: a better result is likely to be obtained if some
extra fractions can be used (via bi-daily fractionation) in
order to further reduce fraction size.
Worked examples for more complex cases
Unscheduled interruptions of longer than 5 days are
generally more dicult to deal with as there is less
chance of completing treatment without incurring a
signicant extension of the treatment time. The
following examples highlight such cases.
Example 4. Loss of all of the sixth and seventh weeks
(10 fractions) of a treatment schedule of 70 Gy/35 fractions/
46 days.
As in Example 3, the unscheduled gap runs right up to
the time when treatment should have nished. In this
case however, a very signicant part of the treatment has
yet to be delivered. In order to minimize the consequent
extension to treatment time it is inevitable that an
increased dose per fraction will need to be considered if
treatment is to be delivered in once-daily fractions.
We initially attempt to complete treatment in ve
fractions delivered during the eighth week, i.e. the
treatment time is extended by 7 days to 53 days. We rst
aim to match the prescribed late-normal tissue BED
3
(116.7 Gy
3
), i.e. the dose per fraction to use is d, where d
is solved from:
BED
3
(pre-gap)+BED
3
(post-gap)=Required BED
3
.
i.e.
for which d=3.22 Gy.
This same dose per fraction would produce a resultant
tumour BED
10
of:
BED
10
(pre-gap)+BED
10
(post-gap)Tumour
Repopulation Factor
i.e.
Thus, despite using a relatively large dose per fraction
for the last ve fractions, the resultant tumour BED
10
is
13.2% less than prescribed. If the weekend prior to the
eighth treatment week is used for treatment then seven
fractions may be delivered, leading to a fractional dose
of 2.57 Gy and a tumour BED
10
of 60.1 Gy
10
. If 11
fractions are distributed over the seven available treat-
ment days (by treating bi-daily on four of them) the
required fractional dose drops to 1.87 Gy, the tumour
BED
10
then being 61.9 Gy
10
. This latter value is still
8.7% short of the prescribed tumour BED
10
(67.8 Gy
10
),
thus some degree of compromise, achieved by increasing
dose per fraction as illustrated in the previous example,
might be considered. In extreme cases thrice-daily
fractionation could be considered, but only after care-
ful consideration of the potential for detriment from
incomplete repair.
If weekend or twice-daily fractionation cannot be
accommodated then it might be considered to treat the
remaining treatment over two full working weeks, i.e.
extend treatment into an eighth and ninth week, making
the overall treatment time 46+14=60 days. For this the
dose per fraction (d) ideally required to maintain the
tumour BED
10
is obtained from:
BED
10
(pre-gap)+BED
10
(post-gap)Tumour
Repopulation Factor
i.e.
for which d=2.85 Gy, leading to an associated BED
3
of
138.9 Gy
3
, which is 19% higher than prescribed. This
result demonstrates the alternative dilemma associated
with further extending the treatment in order to avoid
weekend and twice-daily treatments: the total dose to be
delivered is again increased by the extension into the
ninth week, with a consequently incurred penalty to
BED
3
.
Example 5. Loss of the nal 13 fractions of a treatment
schedule of 70 Gy/35 fractions/46 days.
This represents a very dicult case. As a compromise
between minimizing the extension whilst at the same
time ensuring that a reasonable number of fractions are
used we assume that 10 post-gap fractions will be given,
twice daily from Saturday to Wednesday, extending the
coxirNs:1ioN ro xissrn 1r:1xrN1 n:xs iN :nio1nr:ix 389
treatment to 46+5=51 days. We rst consider that the
eect of incomplete repair is negligible, i.e. that Eqn (1)
remains valid. The relevant equation to determine the
dose per fraction (d) to maintain the prescribed normal
tissue BED
3
(116.7 Gy
3
) is:
BED
3
(pre-gap)+BED
3
(post-gap)=Required BED
3
i.e.
For which d=2.41 Gy. The resultant tumour BED
10
would then be:
BED
10
(pre-gap)+BED
10
(post-gap)Tumour
Repopulation Factor
i.e.
To allow for the possibility of incomplete repair in the
critical normal tissue Eqn (2) is used for calculating
the post-gap BED
3
. Eqn (2) requires prior evaluation of
the h factor, which in turn requires an assumption to be
made about the nature of the repair kinetics. Mono-
exponential repair half-times for late-normal tissues are
often assumed to be of the order of 1.5 h, but there is
evidence that they may be longer for head and neck
morbidity. Bentzen et al. [31] investigated the repair
half-times of three normal tissue end-points from an
analysis of the CHART head and neck data and found
these to be in the range 3.84.9 h. Taking a mid-range
value of 4.5 h, this corresponds to an exponential repair
rate () of 0.15 h
1
. (The repair rate is related to repair
half-time via: =0.693/half-time). If the post-gap daily
fractions are 6 h apart and there is an 18-h overnight
gap, it is easier to calculate h only for the shorter time
interval between any two adjacent fractions. This is
because the incomplete repair after the longer (18 h)
gaps is relatively negligible compared with that following
each 6-h gap. Referring to the Appendix, and using Eqn
(A1) with N=2, =6 h and =0.15 h
1
, h is calculated
to be 0.407. The normal tissue BED
3
then becomes from
Eqns (1) and (2) with K=0:
BED
3
(pre-gap)+BED
3
(post-gap)
i.e.
This is 6.7% higher than the value calculated when
incomplete repair is ignored. If the twice-daily fractions
were to be spaced at 4-h intervals then the h factor is
0.549 and BED
3
increases further to 127.4 Gy
3
, 9.1%
higher than when incomplete repair is ignored. (Because
the h factors are based only on the shorter inter-fraction
intervals the consequent BED
3
values are slightly under-
estimated as there will be an additional amount of
incomplete repair following the longer, overnight, inter-
vals. This overnight contribution will become more
signicant as the number of successive days on which
multiple treatment is delivered is increased.)
It has been speculated [33,34] that the sub-lethal
damage repair may not be exponential in form (as
conventionally assumed) but may proceed at a slower
rate than is predicted by a single exponential function. A
reciprocal time model of repair, built on this supposi-
tion, has been found to give an excellent t a to a wide
range of experimental repair data and, unlike models
based on the mono-exponential repair mechanism, helps
explain the cases of radiation myelopathy observed in
the CHART trial [35]. The h factors in the reciprocal
time model may be calculated from Eqn (A2) in the
Appendix and used directly in Eqn (4). Bi-phasic and
other stretched functions have also been developed [36].
Example 6. A nominal 4-week schedule beginning on a
Wednesday is prescribed as 54 Gy/20 fractions/27days. As the
patient is too unwell for the last seven fractions to be treated
on schedule their deferment extends eventual completion of
treatment to 38 days.
This treatment began on a Wednesday and the expected
treatment time (with no treatment at weekends) is 27
days, rather than 25 days if it had began on a Monday.
The prescribed normal tissue BED
3
is:
Because the overall time is extended from 27 to 38 days
we assume for calculation purposes that K is zero in the
time up to 28 days and 0.9 Gy day
1
thereafter. The
prescribed tumour BED is therefore:
The interruption extends the overall time to 38 days. If
the seven outstanding fractions were treated at the
original fraction size (2.8 Gy) the late-reaction normal
tissue BED
3
would be unaltered. However, the tumour
BED
10
will be compromised because the treatment has
extended beyond the 28 days at which time faster
tumour repopulation is assumed to begin.
The tumour BED
10
would then be calculated from:
BED
10
(pre-gap)+BED
10
(post-gap)Tumour
Repopulation Factor
390 ciiNic:i oNcoiocx
i.e.
a reduction of 13.1%.
In short-duration treatments of this type the dose
per fraction is already relatively large and any further
increase (as may be required to strike a balance between
normal tissue and tumour BEDs) should be considered
with caution. As an example, to achieve a tumour
BED
10
with an intermediate value 65.0 Gy
10
requires a
dose per fraction (d) which is obtained from:
BED
10
(pre-gap)+BED
10
(post-gap)Tumour
Repopulation Factor=Required BED
10
i.e.
i.e. d=3.19 Gy per fraction.
Use of this fraction size for the deferred seven
treatments would increase the normal tissue BED
3
to:
BED
3
(pre-gap)+BED
3
(post-gap)
i.e.
which is still 10% more than that prescribed, even
though the tumour BED
10
has been deliberately
compromised.
A nal diculty with interrupted schedules which
already employ large fraction sizes is that the scope for
post-gap acceleration using twice-daily treatments is
limited on account of the large total daily doses which
would result. In this particular example, bi-daily frac-
tionation would deliver a total daily dose of 22.7 Gy,
corresponding to a BED
3
delivery rate of 10.3 Gy
3
per
day. This is over 50% higher than the BED
3
delivery rate
(6.8 Gy
3
per day) associated with the thrice-daily frac-
tionation of CHART, which itself is very similar to
22 Gy daily fractionation (6.7 Gy
3
per day). These
gures take no account of incomplete repair, which
would increment the BED
3
associated with 22.7 Gy
even further. Even with well-spaced fractions some
caution would be required when contemplating daily
biological doses of this magnitude and the possibility of
treating bi-daily with a signicantly reduced fractional
dose should be explored.
Conclusion
This paper sets out the practical considerations involved
in calculating compensations once a treatment interrup-
tion has occurred, but it is stressed that it is good
practice to aim to avoid interruptions wherever possible.
A wealth of radiobiological and clinical evidence con-
rms the seriousness of unnecessary treatment prolon-
gation and unscheduled gaps, particularly those near the
end of treatment, are especially problematic. Although
it is impossible to pre-empt some interruptions, e.g.
those resulting from machine breakdowns or bad clinical
response to treatment, those resulting form Public
Holidays and Statutory Days can be pre-planned. It is
not sucient to devise last-minute compensations for
such interruptions and departmental policies should
prohibit such practice. Rather, patients should be cat-
egorized in advance according to RCR guidelines and
their treatment schedules reviewed such that the pre-
dictable treatment gap is properly compensated by, if
necessary, revision to the whole schedule.
Extremely busy departments are clearly more likely to
be troubled by unscheduled gaps and will also nd it less
easy to timetable an eective compensation when such
gaps do occur. The permanent presence of spare treat-
ment capacity (e.g. by provision of enough treatment
machines within each department to allow the deliberate
under-usage of at least one of them) is an obvious
method for anticipating and coping with unscheduled
interruptions. Such a policy has resource implications,
but these need to be set against the fact that with
treatment interruptions, as in several other aspects of
radiotherapy treatment delivery, there exists a likely
inverse relationship between pressurized working
conditions and treatment quality.
Radiobiological methods of compensation, when they
have to be utilized, are better than none at all, but it is
nevertheless essential to be aware of the potential down-
side of invoking calculations which are themselves over-
simplications and which rely on parameter valueswhich
sometimes are not accurately known. Three particular
aspects of the calculation methods set out above should
be borne in mind.
Firstly (and as has been assumed in the calculations
here), although there is strong evidence for accelerated
repopulation following an initial period of slower
repopulation, it is not clear whether or not the K factor
varies during treatment. There is the possibility that
changing the dose per fraction, or the dose delivery rate,
(as occurs in devising some gap compensations) may
itself alter K or the lag period.
Secondly, the sub-lethal damage repair mechanisms
are not fully understood and there is a strong likeli-
hood that repair is slow in some normal tissues.
Hyperfractionated compensation schemes, involving
the delivery of many closely-spaced fractions after the
unscheduled gap, carry the risk of signicantly increas-
ing normal tissue morbidity, even in cases where the
consequences of incomplete repair potentially have been
coxirNs:1ioN ro xissrn 1r:1xrN1 n:xs iN :nio1nr:ix 391
allowed for by the inclusion of a seemingly appropriate
h factor in the calculations.
Finally, it should be remembered that BED calcula-
tions take no account of the physiological factors which
may inuence radiation response throughout an irradi-
ated volume. The response is essentially governed by the
integrated eect of the radiation, which in turn is related
to the degree of dose uniformity and to the functional
complexity of the tissue or organ. Where there are
unavoidable or deliberate dose gradients the response to
the gap compensation may dier throughout the treat-
ment volume. In such cases it is prudent to repeat the
biological assessments at the normal tissue hot spots
[37]. Where tumour shrinkage is known to have
occurred the clinician may feel that the use of reduced
eld size during gap compensation may partially oset
some of the potential problems. The possibilities of this
and other safeguards (increased shielding, revised treat-
ment plan, etc.) should always be considered alongside
the radiobiological aspects whenever the normal tissue
BED is likely to increase as a result of treatment
prolongation.
Ongoing elucidation of radiobiological processes and
parameters will inevitably mean that there will be a
requirement to review and, in some cases, modify, the
recommendations set out in this article. It is recom-
mended that each radiotherapy centre identies an indi-
vidual (local or remote) who is in a position to keep
abreast of unfolding developments and who can be the
prime source of advice to that centre on how to devise
treatment compensations.
Acknowledgements. The authors wish to express their apprecia-
tion to Drs Colligan (Inverness), Fowler (Wisconsin), Henk (London),
Morgan (Nottingham), Roberts (Manchester), Slevin (Manchester)
and Spittle (London), all of whom read the draft manuscript and made
a number of useful and constructive comments.
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APPENDIX
Calculation of h values for closely-spaced fractions
For mono-exponential recovery kinetics h is calculated
from:
In Eqn (A1), N is the number of fractions in a group of
closely spaced fractions and =exp(x), where is the
exponential repair constant of sub-lethal damage and x
is the average time interval (h) between these closely-
spaced fractions. For late-responding normal tissues is
often assumed to have a generic value of 0.5 h
1
; for
prediction of radiation myelopathy subsequent to head
and neck radiotherapy a smaller value of around
0.22 h
1
is more appropriate [31,32].
For reciprocal-time repair kinetics h is calculated
from:
In this model z is the reciprocal-time repair constant of
sub-lethal damage [34]. The myelopathies observed in
the CHART Trial [35] are consistent with a z value of
0.36 h
1
[34].
Provided there are only a few consecutive days on
which multiple daily fractions are delivered the calcula-
tion of h using either Eqn (A1) or Eqn (A2) may be
simplied by taking into account only the shortest
inter-fraction intervals. For example, if twice-daily frac-
tionation is being used with an interval of 6 h between
fractions, followed by an longer overnight interval of
18 h, the values used to calculate h are N=2 and x=6.
Allowance for the additional incomplete repair follow-
ing the longer overnight intervals may become necessary
if there are many successive days on which twice-daily
fractions is delivered. Reference [34] provides more
details on this.
coxirNs:1ioN ro xissrn 1r:1xrN1 n:xs iN :nio1nr:ix 393