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R ADIATION O N C O L O G Y O R I G I N AL A R TICLE
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
S Meade et al.
Methods
Results
(1)
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
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
735
S Meade et al.
References
1. Hartley A, Sanghera P, Kazi W et al. Correlation of
currently used radiobiological parameters with local
control and acute and late mucosal toxicity in
randomised studies of altered fractionation for locally
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Radiol) 2011; 23: 2933.
2. Hartley A, Sanghera P, Glaholm J et al.
Radiobiological modelling of the therapeutic ratio for
the addition of synchronous chemotherapy to
radiotherapy in locally advanced squamous cell
carcinoma of the head and neck. Clin Oncol (R Coll
Radiol) 2010; 22: 12530.
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radiation is the chemotherapy worth in advanced
head and neck cancer? Int J Radiat Oncol Biol Phys
2007; 68: 14915.
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radiation is the chemotherapy worth in advanced
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to provide quantitative evaluation of contribution
of chemotherapy to local tumour control in
chemoradiotherapy cervical cancer trials. Int J Radiat
Oncol Biol Phys 2007; 72: 153843.
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overview of preoperative (neoadjuvant)
2013 The Royal Australian and New Zealand College of Radiologists
7.
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15.
16.
17.
737
S Meade et al.
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:
738
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