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Series Title
Chapter Title What Are the Dose-Volume Constraints to Reduce Late Toxicity?
Chapter SubTitle
Copyright Year 2012
Copyright Holder Springer-Verlag Berlin Heidelberg
Corresponding Author Family Name Bujko
Particle
Given Name Krzysztokf
Suffix
Division Department of Radiotherapy
Organization Maria Sklodowska-Curie Memorial Cancer Centre
Address W.K. Roentgena 5, 02 781, Warsaw, Poland
Email bujko@coi.waw.pl

Abstract A reduction of the risk of late postradiation toxicity is a key issue in the current debate on the indications
for preoperative radiotherapy. The objective of this chapter is to provide readers with a proposal of
modifying currently recommended clinical target volume (CTV) boundaries in order to diminish the risk
of postradiation late side effects. Preoperative radiation increases slightly the risk of non-cancer death and
the risk of small bowel obstruction. Lowering cranial border of the CTV to the S2–S3 interface may reduce
this toxicity. Preoperative radiation increases the risk of anorectal and sexual function impairment in
patients undergoing anterior resection and the risk of perineal wound healing delay in patients undergoing
abdomino-perineal resection. Adequate location of the caudal border of the CTV may reduce this toxicity.
The sphincters’ complex, the caudal part of the vagina, the penile bulb and the perineal skin should be
avoided in CTV delineation, provided these regions are not invaded by a distal cancer extension. Examples
of CTV contouring are provided.
1

2
What Are the Dose-Volume
Constraints to Reduce Late Toxicity? 15
3 Krzysztokf Bujko

Contents 15.1 Introduction 4

15.1 Introduction.................................................. 000
Two recent randomized trials using modern 5
15.2 Preoperative Radiation Increases
surgery (total mesorectal excision [TME]) have 6
the Risk of Non-cancer Death
and the Risk of Small Bowel shown local recurrence risk reduction by approx- 7
Obstruction: Lowering Cranial Border imately 50% with preoperative radiation com- 8
of the CTV to the S2–S3 Interface pared to surgery alone [25, 28]. This benefit, 9
May Reduce This Toxicity........................... 000
however, has not translated into improvement of 10
15.3 Preoperative Radiation Increases the Risk of survivals. This lack of survival benefit and 11
Anorectal and Sexual Function significant late toxicity caused by radiation has 12
Impairment in Patients Undergoing
Anterior Resection and the Risk launched a debate on appropriate indications for 13
of Perineal Wound Healing Delay in preoperative radiation. There are two main stand- 14
Patients Undergoing Abdomino-Perineal points regarding this issue. Advocates of using 15
Resection: Adequate Location preoperative radiation claim that all patients who 16
of the Caudal Border of the CTV May
Reduce This Toxicity.................................... 000 have clinically diagnosed T3 cancer require this 17
treatment [16], whereas others limit indications 18
References................................................................ 000
for preoperative radiation for cT3 tumours with 19
deep infiltration into the mesorectum (>5 mm) [3]. 20
Some authors do not recommend preoperative 21
radiation even for patients with ‘good prognosis’ 22
nodal disease [27]. The latter authors point out 23
that with TME, the risk of local recurrence has 24
been diminished in specialized centres to less 25
than 10% and that postradiation toxicity is sub- 26
stantial which has a negative impact on the qual- 27
ity of life. This confers that only less than 5% of 28
irradiated patients (radiation reduces the pelvic 29
recurrence risk by half) benefit from this treat- 30
ment, and remaining 95% of patients are ‘unnec- 31
essarily’ exposed to the risk of radiation toxicity. 32
K. Bujko  Thus, a risk/benefit ratio analysis may favour 33
Department of Radiotherapy,
omitting preoperative radiation. On the other 34
Maria Sklodowska-Curie Memorial Cancer Centre,
W.K. Roentgena 5, 02 781 Warsaw, Poland hand, advocates of the preoperative radiation 35
e-mail: bujko@coi.waw.pl approach point out that in the total population, 36

V. Valentini et al. (eds.), Multidisciplinary Management of Rectal Cancer, 1

DOI 10.1007/978-3-642-25005-7_15, © Springer-Verlag Berlin Heidelberg 2012
 2 K. Bujko

37 the local recurrence rate after TME is higher surgery developed a second cancer as compared 79
38 than  observed in the specialized centres and to those treated with surgery alone; the relative 80
39 amounts 20% of pathologically staged T3 dis- risk was 1.85 with 95% confidence interval 81
40 ease [6]. In addition, with radiotherapy technique between 1.23 and 2.78. However, the favourable 82
41 modifications, the risk of late toxicity might be effect of radiation still dominated, as 20.3% of 83
42 reduced. Taking both of the above arguments into the irradiated patients got either local recurrence 84
43 account, a risk/benefit ratio analysis may favour or a secondary cancer, compared with 30.7% of 85
44 the use of preoperative radiation for all cT3 can- the patients treated with surgery alone (relative 86
45 cers. Thus, a reduction of the risk of late postra- risk, 0.55; 95% confidence interval 0.44–0.70). 87
46 diation toxicity is a key issue in the current debate The meta-analysis showed that the excess of 88
47 on the indications for preoperative radiotherapy. non-cancer deaths after preoperative radiation 89
48 In rectal cancer preoperative radiotherapy, two was also due to an increase in deaths attributed 90
49 guidelines showing anatomical borders of clini- to vascular and infective causes [5]. This meta- 91
50 cal target volume (CTV) are available [15, 22]. analysis also showed that the favourable effect of 92
51 The objective of the current article is to provide radiation still dominated, as at 5  years, there 93
52 readers with a proposal of modifying these guide- were 3.3% more of non-cancer deaths and 8.3% 94
53 lines in order to diminish the risk of postradiation fewer rectal cancer deaths in the irradiated 95
54 late side effects. It should be stressed that this patients compared to those treated with surgery 96
55 proposal is not accepted as a routine procedure alone. The above results suggest that preopera- 97
56 by all investigators and is still a matter of debate. tive radiation has a potential for improving over- 98
all survival which is counterbalanced by the 99
excess of non-cancer deaths. 100
57
[AU1] 15.2 Preoperative Radiation Small bowel late toxicity has been reduced 101
58 Increases the Risk of Non- after replacing postoperative radiation with pre- 102
59 cancer Death and the Risk operative radiation [8, 23]. This is because small 103
60 of Small Bowel Obstruction: bowel fills up the dead space left behind in a pos- 104
61 Lowering Cranial Border of terior pelvis after removal of mesorectum and 105
62 the CTV to the S2–S3 Interface rectum. Thus, in order to provide large dose to 106
63 May Reduce This Toxicity the tumour bed, irradiation of large volume of 107
small bowel cannot be avoided in the postopera- 108
64 The recent update of the Dutch TME trial, which tive setting. In contrast, in the preoperative set- 109
65 compared preoperative radiation and TME with ting, when the mesorectum and rectum are still in 110
66 TME alone, demonstrated no difference in over- situ, the amount of irradiated small bowel is much 111
67 all survival [28]. However, when patients were smaller. Despite this, in the Swedish randomized 112
68 operated with negative circumferential margin, trial, severe late small bowel side effect, namely, 113
69 higher cancer-specific survival and 10% gain in small bowel obstruction, has occurred more often 114
70 overall survival at 10  years in stage III cancer after preoperative radiation and surgery than sur- 115
71 were reported in the preoperative radiation gery alone – 13.9% versus 5.5% at 14 years [2]. 116
72 group. Of note, slightly more non-cancer deaths, It might be reasonable to assume that a reduc- 117
73 mostly due to secondary malignancy, were tion of irradiated volume may result both in a 118
74 reported in the radiotherapy group. Similar decreased risk of postradiation, second malig- 119
75 observations were recorded in Sweden. The data nancy and in the reduction of early and late small 120
76 from two trials demonstrated that, after a long bowel toxicity. Traditionally, the sacral promon- 121
77 follow-up, 7% of patients had second cancers tory has been the anatomical landmark for cranial 122
78 [1]. More patients treated with radiotherapy and border of CTV [15, 22]. The appropriateness of 123
 15  What Are the Dose-Volume Constraints to Reduce Late Toxicity? 3

124 this rule has been questioned by two recent arti- 15.3 Preoperative Radiation 169
125 cles on location of in-pelvic recurrences after Increases the Risk of Anorectal 170
126 TME. Syk et  al. [26] identified a total of 155 and Sexual Function 171
127 patients with local recurrence from a population- Impairment in Patients 172
128 based cohort of 2,315 patients. The site of recur- Undergoing Anterior Resection 173
129 rence was observed in the lower half of the pelvis and the Risk of Perineal Wound 174
130 in more than two-thirds of all patients. All recur- Healing Delay in Patients 175
131 rences were situated below S1–S2 interspace. Undergoing Abdomino- 176
[AU2]
132 Nijkamp et al. [18, 19] analysed the site of recur- Perineal Resection: Adequate 177
133 rence in 94 patients treated within the frame of Location of the Caudal Border 178
134 the Dutch TME trial. Only 3% of recurrences of the CTV May Reduce This 179
135 were situated above the S2–S3 interspace and Toxicity 180
136 additional 2% at the level of S2–S3 interspace.
137 However, if patients with negative circumferen- Anorectal and sexual function impairments 181
138 tial resection margin were considered, only in 2% caused by surgery and radiation are the most 182
139 of these patients, recurrence was observed above important adverse side effects as they affect large 183
140 or at S2–S3 interspace. The corresponding figure proportion of patients and are permanent as well 184
141 for the patients with positive circumferential as they interfere with patients’ daily activity. 185
142 resection margin was 12%. Interestingly, in the These adverse side effects have been reported in 186
143 patents with positive circumferential resection details on large number of patients treated within 187
144 margin, the recurrence did not always appear at the frame of the Dutch TME trial and the MRC 188
145 the same level as the primary tumour. With a cra- CR07 trial [14, 20, 24]. Faecal incontinence was 189
146 nially reduced CTV to the S2–S3 interspace, over reported in 62% of patients having preoperative 190
147 60% of reduction of absolute small bowel expo- radiation compared to 38% of those treated with 191
148 sure at dose levels of 15–35 Gy could be achieved surgery alone, p < 0.001 in the Dutch TME trial 192
149 with three-field conventional radiotherapy, [20] and 53.2% versus 37.3% in the MRC CR07 193
150 increasing to 80% when IMRT was used [18, 19]. trial, p = 0.007, respectively [24]. In the latter 194
151 Both of the above reports suggested that the cra- trial, the increase of incontinence in the irradiated 195
152 nial border of CTV can be lowered to the S2–S3 patients was observed only at low level of sever- 196
153 interspace in patients in whom pelvic MRI pre- ity; severe incontinence rate was similar in both 197
154 dicts negative circumferential resection margin treatment-assigned groups. In the Dutch TME 198
155 (Fig. 15.1). It should be stressed that this guide- trial, at 24 months post treatment, 67% of male 199
156 line should be used selectively. For patients with patients receiving preoperative irradiation and 200
157 the primary-tumour extension in the presacral who were previously sexually active, were still 201
158 region above the S2–S3 interspace or with active after treatment compared to 76% of patients 202
159 enlarged lymph nodes abutting mesorectal fascia from the surgery alone group, p = 0.06 [14]. For 203
160 at this level, CTV should be extended cranially. female patients, these figures were 72% and 90%, 204
161 Nijkamp et al. [18, 19] recommended CTV reduc- respectively, p = 0.01. It should be stressed that 205
162 tion to the S2–S3 interspace only in patients the main cause of faecal incontinence and male 206
163 without expected nodal or circumferential resec- sexual dysfunction is surgery, rather than radio- 207
164 tion margin involvement. therapy [24]. 208
165 Apart from lowering of caudal border of the Excluding the anal canal, or part of it, from the 209
166 CTV, belly-board and distended urinary bladder CTV is a strategy that prevents radiation-induced 210
167 result in a reduction of small bowel radiation faecal incontinence [12, 29]. Lange et  al. [12] 211
168 exposure [11, 18] (Fig. 15.1). reported incontinence in 93% of patients in whom 212
4 K. Bujko

sphincter was included in the preoperative radia- 213

tion fields compared to 65% of patients in whom 214
sphincter was not irradiated, p = 0.059. In addi- 215
tion, one can assume that the exclusion of inferior 216
part of the vagina may prevent vaginal dryness 217
and pain during intercourse. It is also worth to 218
note that scattered cumulative radiation dose at 219
the testicles was reported between 0.7 and 8.4 Gy, 220
with a mean of 3.56  Gy [10]. Such doses may 221
result in a permanent infertility and in a risk of 222
hypogonadism in substantial proportion of 223
patients [10, 30]. The increase of the distance 224
between lower field margin and testicles exponen- 225
tially decreased the amount of this dose [10]. 226
Another way of reducing sexual function impair- 227
ment is to avoid irradiation of the penile bulb. 228

Fig. 15.1  Clinical target volume (CTV) contoured at the

middle sagittal plane. White thick arrow; lower border of
mesorectum (level of the puborectal muscle) and upper
border of the anal canal. Black thick arrow; S2–S3 inter-
face. White thin arrow; lower border of tumour. In all
patients, there was no upwards tumour extension or threat-
ened circumferential resection margin. Thus, the upper
border of CTV terminates at S2–S3 interface sparing
small bowel. (Panel a) Lower border of tumour was
located 8 cm from the anal verge and 5 cm from the ano-
rectal ring. The lower border of CTV terminates 4 cm cau-
dally from the lower border of tumour and does not
include the distal part of mesorectum. The entire anal
canal and the distal part of vagina are spared. The black
line perpendicular to the surface of the sacral bone and the
thin black arrow shows the possibility of further reduction
of the CTV in order to spare small bowel. (Panel b) Lower
border of tumour was located 2.5 cm from the anal verge
and invaded 0.5 cm of the upper part of the anal canal. The
patient was scheduled for abdomino-perineal resection.
The lower border of CTV terminates at 1.5 cm caudally
from the lower border of tumour to account for distal
intramural spread. The perineal skin is spared in order to
avoid the acute skin toxicity and the perineal wound heal-
ing delay. Sparing of the perineum increases the distance
between lower border of fields and the testicles, diminish-
ing scatter dose at the testicles. Distended urinary bladder
reduces the amount of small bowel within radiation beams.
Belly-board is used in this patient, although, admittedly,
its value is unproven when CTV terminates at S2–S3
interface and the urinary bladder is distended. (Panel c)
Lower border of tumour was located 5 cm from the anal
verge and 2 cm from the anorectal ring. The lower border
of CTV terminates at the anorectal ring and includes the
entire mesorectum. Note that even if a margin for the
planning target volume would be added, still the distal
part of anal canal and the distal part of vagina are spared
 15  What Are the Dose-Volume Constraints to Reduce Late Toxicity? 5

229 Several studies reported that penile bulb dose- clearance is regarded as sufficient in patients 277
230 volume parameters correlated with the risk of undergoing anterior resection for low tumours 278
231 erectile dysfunction [21]. For example, erectile [17]. It should be pointed out that even in low- 279
232 dysfunction was observed in 0%, 80% or 100% of lying tumours, if levators and external sphincter 280
233 patients with a D70 (i.e. minimum dose received are not invaded, anterior resection is still possi- 281
234 by 70% volume of the penile bulb) of 0–40, 40–70 ble  as the ischiorectal fossa is not at risk of 282
235 and >70 Gy, respectively [7]. In addition, exclud- tumour recurrence. It seems that levators consti- 283
236 ing the perineal skin and distal part of ischiorectal tute an effective barrier against downwards can- 284
237 fossa is a strategy that prevents wound healing cer spread. There are no regional lymph nodes in 285
238 delay after abdomino-perineal resection and pain- the ischiorectal fossa. In the literature, recur- 286
239 ful acute perineal skin reaction. Marijnen et  al. rences in the ischiorectal fossa or in the perineum 287
240 [13] reported that 31% of 174 patients irradiated were reported only in the patients who have 288
241 preoperatively with perineum included into the undergone  abdomino-perineal resection. It can 289
242 fields had perineal wound complications in com- be assumed that these recurrences likely originate 290
243 parison with 18% of 40 patients in whom the from ­contamination of cancer cells during sur- 291
244 perineum was not irradiated. gery because no such cases were reported after 292
245 All of the above considerations suggest that anterior resection. 293
246 the sphincters’ complex, the caudal part of the The above surgical rules can be applied in the 294
247 vagina, the penile bulb and the perineal skin CTV construction. The examples are depicted in 295
248 should be avoided in CTV delineation (Fig. 15.1), the figure. It should be noted that the rules for [AU3]
296
249 provided these regions are not invaded by a distal CTV lower border location presented in this 297
250 cancer extension. figure are different to those recommended by 298
251 When considering the anatomical boundaries other investigators [22]. 299
252 of the CTV, it is worth to refer to the rules and to
253 the rationales for the boundaries of surgical resec-
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 Author Queries
Chapter No.: 15

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AU1 As per style, headings cannot be complete sentences. Please shorten the headings in this
chapter.
AU2 Nijkamp et al. (2011) has been changed to Refs. [18, 19], so please fix whether [18] or [19]
here and also in the following occurrences.
AU3 Please check if edit made to the sentence starting “It should be noted that...” is ok.