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Journal of Medical Imaging and Radiation Oncology 57 (2013) 733738

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R ADIATION O N C O L O G Y O R I G I N AL A R TICLE

Revised radiobiological modelling of the contribution of


synchronous chemotherapy to the rate of grades 34 mucositis
in head and neck cancer
Sara Meade,1 Chris McConkey,3 Paul Sanghera,1,2 Hisham Mehanna2 and Andrew Hartley1,2
1
Hall-Edwards Radiotherapy Research Group, Queen Elizabeth Hospital, 2Institute of Head and Neck Surgery and Education (InHANSE), University of
Birmingham, Birmingham, and 3Clinical Trials Unit, University of Warwick, Warwick, UK

S Meade MRCP; C McConkey MSc;


P Sanghera FRCR; H Mehanna FRCS, PhD;
A Hartley FRCR.
Correspondence
Dr Andrew Hartley, Hall-Edwards Radiotherapy
Research Group, Cancer Centre, Queen
Elizabeth Hospital, Birmingham B15 2TH, UK.
Email: andrew.hartley@uhb.nhs.uk
Conict of interest: None.
Submitted 22 March 2013; accepted 7 June
2013.
doi:10.1111/1754-9485.12096

Abstract
Introduction: Biological effective dose (BED) calculations modelled on reduced
accelerated repopulation when synchronous chemotherapy is delivered signicantly correlate with observed differences in local control in randomised
trials of platinum-based chemoradiation. The purpose of this study was to
examine whether a similar relationship existed in the context of grades 34
mucositis.
Methods: Biological effective dose from radiotherapy and synchronous
chemotherapy was calculated using three different models: AB using the
additional BED attributable to chemotherapy and standard repopulation
parameters; zero repopulation (ZRP) using zero correction for repopulation;
and variable tp (Vtp) using a variable doubling time for mucosal stem cell
repopulation. The correlation between the percentage change in biological
effective dose between trial arms, and the observed percentage change in
the rate of grades 34 mucositis was examined by using the Pearson
productmoment correlation.
Results: With the AB model, there were no signicant correlations with
observed differences in rates of grades 34 mucositis. With either the ZRP or
Vtp models, signicant correlations were observed. A value of 5 days for the
doubling time during repopulation (Tp) was associated with the most signicant correlation (P = 0.002).
Conclusion: Models where the dose lost due to accelerated repopulation is
reduced imply a therapeutic loss from the use of synchronous chemotherapy
when only local control and the rate of acute grades 34 mucositis are
considered.
Key words: head and neck; radiation oncology.

Introduction
When radiotherapy is administered as a sole modality,
biological effective dose (BED), calculated with appropriate parameters, correlates well with both local control
and acute grades 34 mucositis in squamous cell carcinoma of the head and neck.1 Attempts have been made
across tumour sites to express synchronous chemotherapy as a radiotherapy equivalent BED.29 This combined radiotherapy and chemotherapy BED can be used
to predict local control and toxicity end points in proposed randomised trials.
2013 The Royal Australian and New Zealand College of Radiologists

In squamous cell carcinoma of the head and neck,


there is a statistically signicant correlation between the
change in percentage tumour BED (tBED) calculated
using an additional BED from synchronous chemotherapy and the percentage change in local control.10
However, in a previous study that included trials combining platinum-based synchronous chemotherapy with
altered fractionation radiotherapy schedules, although
the percentage change in tBED calculated using this
additional BED method was signicantly associated with
the percentage change in local control (P = 0.02), more
signicant correlations were achieved when the BED was
733

S Meade et al.

calculated using alternative methods. If the combined


tBED was calculated by ignoring the effects of accelerated repopulation, there was a strong correlation
between the percentage change in tBED and the percentage change in local control (P = 0.0002). Similarly, if
the effect of accelerated repopulation was reduced by
increasing the value of Tp (the cell doubling time during
accelerated repopulation), more signicant results than
those obtained with the additional BED were again seen.
A value of 10 days for Tp gave the most signicant result
for this variable Tp method (P = 0.0005).
This previous study did not consider whether similar
ndings were obtained if the biological effective dose
when considering acute grades 34 mucositis (amBED)
were modelled in the same way. This is relevant as there
have been several studies that have attempted to model
the effect of synchronous chemotherapy on the therapeutic ratio of local control versus the rate of acute
grades 34 mucositis.2,11 It is the purpose of this study,
therefore, to examine the relationship between the percentage change in amBED calculated using these alternative models and the percentage change in the rate of
grades 34 mucositis. In addition, the effect of such
modelling on the therapeutic ratio as dened above will
be discussed.

Calculation of BED for acute mucosa (amBED):


a/b = 10 Gy; a = 0.3 Gy-1; Tk = 7 days, Tp = 2.5 days.
In radiotherapy alone arms of studies, the BED in
respect of acute grades 34 mucositis (amBED), was
calculated using standard parameters as outlined above.
In chemoradiation arms, three methods were used to
calculate amBED; additional BED (AB), zero repopulation
(ZRP) and variable tp (Vtp).
The AB method used the addition of 6.4 Gy10, a value
derived from a previous study to the radiotherapy
amBED.2 Standard parameters for repopulation were
used in calculating the radiotherapy amBED.
The ZRP method calculated the amBED with no correction for repopulation.
Finally, the Vtp method used integer Tp values between
3 and 10 days to examine a partial suppression of
repopulation.
For each method, the percentage difference between
the two different treatment arms of each trial for the
calculated amBED was then determined. The correlation
between the percentage difference in amBED and the
percentage difference in the rate of acute grades 34
mucositis was assessed using the Pearson product
moment correlation weighted by the number of patients
in each study.

Methods

Results

For the purposes of this study, the methods described by


Meade et al. were employed but with substitution of
appropriate parameters into the linear quadratic equation to take account of the end point being the rate of
grades 34 mucositis as opposed to local control.10
Briey, trials of synchronous chemoradiation with
platinum-based regimes in head and neck tumours were
identied using a Medline search of trials in addition to
meeting abstract databases. Studies that compared
radiotherapy alone with platinum-based chemoradiation
or those that compared different radiotherapy fractionation schedules with concurrent platinum-based chemotherapy were selected. Of these, trials were included if it
was possible to derive the dose, fractionation and overall
treatment time of the radiotherapy delivered together
with the rate of acute grades 34 mucositis.
Biological effective dose was calculated using the
standard linear quadratic equation:12

Twelve trials of platinum-based chemoradiation with


sufcient information to permit calculation were
identied.1324 Patient numbers, details of study arm,
total dose, number of fractions, overall treatment time
and the observed difference in the rate of grades 3 or 4
mucositis are documented for each trial in Table 1. If
arms within trials employed different radiotherapy
schedules, rows of the table are split to give the differing
parameters. In addition, for each trial arm, the amBED is
given calculated by each of the three methods. For each
trial, the percentage difference in amBED between treatment arms is given for each of the three models. In the
case of the Vtp method, a value of 5 days is used in the
table for the purpose of illustration.
Using the AB model, there was no signicant correlation (P = 0.35) between percentage change in amBED
and percentage change in the rate of grades 3 mucositis.
The ZRP method was associated with a signicant correlation (P = 0.002). Using the Vtp model, the strongest
correlation was identied for a tp value of 5 days
(P = 0.002).

BED = D(1 + (d /( / ))) ((In(2)/ Tp )(T Tk ))

(1)

where D = total dose (Gy); d = dose per fraction (Gy);


a/b = linear (a (Gy-1)) and quadratic (b (Gy-2)) components of the linear quadratic model (Gy); T = overall
treatment time (days); Tk = kick-off or onset of accelerated repopulation time (days); Tp = average doubling
time during accelerated repopulation (days).
The following standard parameters derived from previous radiobiological studies were used for the purposes
of this study:12
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Discussion
In line with recently published results for local control,
the use of methods to calculate amBED, which either
reduce accelerated repopulation or abolish it from the
calculation, results in strong correlations with observed
difference in the rates of acute grades 34 mucositis in
2013 The Royal Australian and New Zealand College of Radiologists

2013 The Royal Australian and New Zealand College of Radiologists

100

518

192

222

130

116

721

124

271

240

224

163

Adelstein13

Forastiere14

Olmi15

Denis16

Jeremic17

Brizel18

Ang19

Fountzillas20

Adelstein21

Staar22

Huguenin23

Bensadoun24

RT
RT + cisplatin
RT
RT + cisplatin
RT
RT + carboplatin/5FU
RT
RT + carboplatin/5FU
RT
RT + cisplatin
RT
RT + cisplatin/5FU
RT + cisplatin
RT + cisplatin
RT
RT + cisplatin
RT
RT + cisplatin
RT
RT + carboplatin/5FU
RT
RT + cisplatin
RT
RT + cisplatin/5FU

Study
arms

78.8
77.8

74.4

69.9

70

75
70
70
72
70.2

77

70

68

70

68

Total
dose (Gy)

65
65

62

41

35

60
56
35
42
39

70

35

34

35

34

Number of
fractions

44
43
49
50

38

46

30
28
51
43
50

50
52
46

45

46

58

OTT
(days)

13

-2

16

11

-7

32

33

19

58

Observed D
in rate of grades
34 mucositis (%)
34.5
40.9
48.0
54.4
46.5
52.9
44.5
49.2
49.4
55.8
63.1
65.8
43.3
51.2
43.1
49.5
48.0
54.4
53.3
59.7
49.1
56.5
49.5
53.8

AB
amBED
(Gy10)

8.8

14.9

12.0

13.3

14.9

18.0

4.2

13.0

10.7

13.8

13.3

18.6

D AB
amBED (%)

34.5
81.6
48.0
84.0
46.5
81.6
44.5
84.0
49.4
85.5
63.1
84.4
84.0
72.4
43.1
82.8
48.0
84.0
53.3
81.9
49.1
83.3
49.5
88.3

ZRP
amBED
(Gy10)

78.5

69.6

53.8

75.1

92.2

-13.8

33.7

72.9

89.0

75.5

75.1

136.7

D ZRP
amBED
(%)

34.5
58.0
48.0
66.0
46.5
64.0
44.5
64.2
49.4
67.5
63.1
73.8
64.1
61.8
43.1
63.0
48.0
66.0
53.3
67.6
49.1
66.2
49.5
68.9

tp 5
amBED
(Gy10)

39.2

34.8

26.9

37.6

46.1

-3.7

16.8

36.5

44.5

37.8

37.6

68.3

D tp 5
amBED
(%)

5FU, 5 urouracil; AB, additional BED method; amBED, acute mucosal biological effective dose; BED, biological effective dose; Gy, Gray; Gy10, gray calculated with alpha beta ratio of 10 Gy D = difference;
OTT, overall treatment time; RT, radiotherapy; tp, average doubling time during accelerated repopulation; ZRP, zero repopulation method.

Number of
patients

First author
(reference)

Table 1. Derivation of acute mucosal biologically effective dose (amBED) by additional BED method, zero repopulation method and variable Tp method

Radiobiological modelling of mucositis

735

S Meade et al.

randomised trials of chemoradiation.10 As discussed


above, when radiotherapy is used as sole modality, there
is a strong correlation between percentage changes in
amBED calculated using standard repopulation parameters and percentage differences in the rates of grades
34 mucositis.1 One hypothesis for the mode of action of
synchronous chemotherapy might therefore be that it
works by suppressing accelerated repopulation both in
tumour and in normal mucosa.
The additional BED method where synchronous
chemotherapy is converted to a BED and added to the
radiotherapy BED calculated with standard repopulation
parameters has been used in several attempts to quantify the effect on the therapeutic ratio of synchronous
chemotherapy.2,11 Such attempts are now called into
question by the current study as no correlation was seen
between the percentage change in amBED calculated
using the additional BED method and the percentage
change in the rates of grades 34 mucositis.
To more accurately calculate the therapeutic ratio
between tumour control probability and severe acute
mucositis, it is necessary to use a model such as Vtp
that has been shown to be signicantly associated with
outcomes in the synchronous chemoradiotherapy
setting. For example, using a tumour tp of 10, the tBED
of 70 Gy in 35# with chemotherapy is 78.5 Gy10. By
the methods described in the appendix, this can be
shown to be equivalent to administering 79.1 Gy10 of
radiotherapy alone for which the acute mucosal BED
would be 60.9 Gy10. Using a tp of 5 for mucosa and the
Vtp method described in this paper, the acute mucosal
BED for 70 Gy/35# administered with chemotherapy
is 66.0 Gy10, giving an apparent therapeutic loss of
5.1 Gy10. If the ZRP model is employed, this therapeutic
loss rises to 17.6 Gy10. However, complete abolition of
accelerated repopulation in mucosa and tumour is very
unlikely.10
Therefore, this study, together with the previous work
of Meade et al., challenges not only previous methods for
accounting for synchronous chemotherapy in radiobiological models but the assumption that when considering
only local control and the rate of grades 3 or 4 mucositis,
synchronous chemotherapy has a benecial effect on the
therapeutic ratio. There are clearly many other factors to
consider in this therapeutic trade-off, not least the late
effects on mucosa and swallowing function of administering higher doses of radiotherapy as sole modality
instead of synchronous chemotherapy, which have not
been considered in the current study. In addition, the
derivation of optimal parameters for repopulation in the
synchronous chemotherapy setting is hampered by the
lack of randomised trials with a planned overall treatment time of greater than 7 weeks. Further, the current
study is largely based on trials carried out in the conformal radiotherapy era. The widespread use of intensitymodulated radiation therapy and the associated, but
as yet incompletely dened, volume relationship for
736

mucosal tolerance will have a signicant effect on such


modelling in the future.25
In addition to these limitations, this study has only
examined changes in one repopulation variable, Tp.
Values for other parameters have been assumed from a
previous study that showed strong correlations between
BED calculated both for tumour and mucosa with
changes in outcomes in randomised trials of altered
fractionation.1 Alterations of other factors in the linear
quadratic equation, particularly a, are possible solutions.26 Increasing a in the context of synchronous
chemotherapy would model both decreased repopulation
and decreased fraction sensitivity. BEDs calculated in
this way may be useful when comparing different radiotherapy schedules with the same synchronous chemotherapy. However, it would be more difcult to compare
BEDs between radiotherapy alone arms and chemoradiation arms as the BED thus calculated will be in different units, for example, Gy10 versus Gy12. Further, an
increase in a does not model the improved local control
seen when chemotherapy is added to hypofractionated
accelerated schedules delivered over 34 weeks.27,28 For
all these reasons, further work is still required to dene
the optimum model for predicting the effects of synchronous chemotherapy on both local control and acute
mucositis.

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Appendix
The BED for tumour (tBED) of 70 Gy in 35# with synchronous chemotherapy can be calculated to be 78.46 Gy10 using
the Vtp method and Equation 1 with the following parameters: a/b = 10 Gy; a = 0.3 Gy-1; Tk = 22 days, Tp = 10 days.
To calculate what dose in 35 fractions would be needed to be given as radiotherapy alone to be equivalent to the
combined chemotherapy and radiotherapy tBED of 78.46 Gy10:

tBED = 78.46 = D(1 + (d / / )) ((In(2)/ Tp )(T Tk ))


where a/b = 10 Gy; a = 0.3 Gy-1; Tk = 22 days but Tp = 3 days rather than 10 days as radiotherapy alone rather than
with synchronous chemotherapy is being considered.
Therefore:

78.46 = 35d (1 + (d /10)) 18.48


0 = 3.5d2 + 35d 96.94
Solving the quadratic gives a practical value for d of 2.26 giving 35d = D = 79.07 Gy10.
The amBED of 79.07 Gy in 35 fractions is calculated using Equation 1 and the radiotherapy alone mucosal
parameters of a/b = 10 Gy; a = 0.3 Gy-1; Tk = 7 days, Tp = 2.5 days.
The amBED of 70 Gy in 35 fractions with synchronous chemotherapy is calculated using the same parameters other
than a Tp of 5 as suggested by the current study.

738

2013 The Royal Australian and New Zealand College of Radiologists

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