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Pathological response following long-course neoadjuvant chemoradiotherapy

for locally advanced rectal cancer

Article  in  Histopathology · September 2005

DOI: 10.1111/j.1365-2559.2005.02176.x · Source: PubMed

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Histopathology 2005, 47, 141–146. DOI: 10.1111/j.1365-2559.2005.02176.x

Pathological response following long-course neoadjuvant

chemoradiotherapy for locally advanced rectal cancer
R Ryan, D Gibbons, J M P Hyland, D Treanor, A White, H E Mulcahy, D P O’Donoghue,
M Moriarty, D Fennelly & K Sheahan
Centre for Colorectal Disease, St Vincent’s University Hospital, Dublin, Ireland

Date of submission 28 November 2004

Accepted for publication 18 February 2005

Ryan R, Gibbons D, Hyland J M P, Treanor D, White A, Mulcahy H E, O’Donoghue D P, Moriarty M, Fennelly D

& Sheahan K
(2005) Histopathology 47, 141–146
Pathological response following long-course neoadjuvant chemoradiotherapy for locally
advanced rectal cancer

Aims: To standardize the pathological analysis of total 10 patients (17%). Using the 5-point TRG, there was
mesorectal excision specimens of rectal cancer following good agreement between both pathologists (j ¼ 0.64).
neoadjuvant chemoradiotherapy for locally advanced Using the 3-point grade, agreement was excellent (j ¼
disease (T3 ⁄ T4), including tumour regression. 0.84). No disease recurrence has been reported in
Methods and results: Standardized dissection and repor- patients with a complete, or near complete pathological
ting was used for 60 patients who underwent total response (3-point TRG 1), after a mean follow-up of
mesorectal excision following long-course chemoradi- 22 months.
otherapy. Tumour regression was scored by two Conclusion: Tumour regression grade is a useful
pathologists (K.S., D.G.) using both an established method of scoring tumour response to chemoradio-
5-point tumour regression grade (TRG), and a novel therapy in rectal cancer. TRG 1 and 2 can be regarded
3-point grade. Both scores were evaluated for inter- as a complete pathological response (ypT0). A modified
observer variability. A complete or near-complete 3-point grade has the advantage of better reproduci-
pathological response (3-point TRG 1) was found in bility, with similar prognostic significance.
Keywords: chemoradiotherapy, pathological response, rectal cancer, tumour regression grade
Abbreviations: CT, computed tomography; ERUS, endorectal ultrasound; MRI, magnetic resonance imaging;
TME, total mesorectal excision; TRG, tumour regression grade

and a potential survival advantage associated with

Introduction
In the USA, there were 148 300 cases of colorectal
carcinoma in 2002, of which rectal cancer accounted
for 41 000 cases and 8500 deaths.1,2 The number of
true rectal cancers, excluding rectosigmoid cancers, is
less.3 In an effort to reduce further the incidence of
margin positivity, local recurrence and improve survi-
val, preoperative neoadjuvant radiotherapy with or
without chemotherapy has been introduced as an
adjunct to total mesorectal excision (TME). A number
of trials have reported reduced local recurrence rates
Address for correspondence: Dr K Sheahan, Consultant Histopathol-
ogist, Centre for Colorectal Disease, St Vincent’s University Hospital,
Elm Park, Dublin 4, Ireland. e-mail: k.sheahan@st-vincents.ie

2005 Blackwell Publishing Limited.
preoperative radiotherapy.4–6 Long-course chemoradi-
otherapy, in contrast to short-course radiotherapy, is
associated with a significant tumour response and
downstaging.7–9
Accurate pathological assessment of these specimens
is essential both to stage the cancer, and to quantify the
response to treatment. The pathological description of
these specimens with particular reference to tumour
response has not been adequately described.
Materials and methods
This was a prospective cohort study of all patients
with locally advanced rectal cancer in a single unit
142 R Ryan et al.

n = 247
Biopsy-proved rectal cancer

n = 40 n = 43 n = 42

Rectosigmoid Early stage Distant Locally advanced

rectal cancer • rT3/4N0/1/2M0
cancers cancers metastases

n = 122

n = 72
n = 50
Unsuitable for Pre-operative chemoradiotherapy
chemoradiotherapy

n = 60

Treatment not completed Surgery – TME

Disease progression
n = 12 Unfit for resection

Liver Residual ‘Curative’

Surgery metastases disease Resection

• Curative resection n=5 n=5 n = 50

or palliation

Figure 1. Patient stratification.

diagnosed between May 1997 and March 2003. fractions with a total tumour dose of 45–50 Gy, which
Patients with histologically confirmed carcinoma of was combined with chemotherapy during the first and
the rectum were staged radiologically using a combi- final weeks of therapy.
nation of chest X-ray, spiral computed tomography
Table 1. Tumour regression grade
(CT), external pelvic phased array magnetic resonance
imaging (MRI) and endorectal ultrasound (ERUS). MRI Five-point Three-point
and ERUS were used to determine local disease extent10 TRG Description TRG
and CT and plain chest radiography for extrapelvic
1 No viable cancer cells 1
disease. Patients with clinical and radiological evidence
of locally advanced disease (T3 ⁄ 4 or N1 ⁄ 2), but 2 Single cells or small groups
without distant metastases, were selected for chemo- of cancer cells
radiotherapy. This excluded patients with localized
3 Residual cancer outgrown by 2
disease (T1 ⁄ 2 N0), those with extrapelvic disease (M1)
fibrosis
at diagnosis, and those unfit for chemoradiotherapy
(see Figure 1). 4 Significant fibrosis outgrown 3
Preoperative therapy was administered in the form of by cancer
external beam radiation therapy in combination with
5 No fibrosis with extensive
infusional 5-flourouracil (625 mg ⁄ m2) over a 5-week residual cancer
period. The radiotherapy was administered in 25 equal

2005 Blackwell Publishing Ltd, Histopathology, 47, 141–146.
 Neoadjuvant chemoradiotherapy for locally advanced rectal cancer 143

Figure 2. a, Tumour regression grade 1 of 5; b, Tumour regression grade 2 of 5, a and b together form Tumour regression grade 1 of 3.
c, Tumour regression grade 3 of 5, also Tumour regression grade 2 of 3. d, Tumour regression grade 4 of 5; e, Tumour regression grade 5 of 5,
d and e together form Tumour regression grade 3 of 3.

On completion of the treatment, patients were
re-staged to assess both local and distant disease using
similar imaging modalities. Subsequently, all patients
underwent TME, in the form of either anterior resection
or abdominoperineal resection.
The fresh surgical specimens were examined and
photographed. The mesorectal margin was inked and,
following a minimum of 24 h of fixation in formalin,
the specimens were serially sectioned in 10-mm slices,

2005 Blackwell Publishing Ltd, Histopathology, 47, 141–146.
as described by Quirke et al.,11 before being photo-
graphed and digitally archived.
All lesional tissue and mesorectal lymph nodes were
submitted for microscopic analysis. Haematoxylin and
eosin sections were reported using a minimum dataset
and a standardized reporting system including criteria
such as tumour type, grade, assessment of tumour
margin (infiltrative or expansile), lymphovascular and
perineural invasion, proximal, distal and radial mar-
144 R Ryan et al.

gins, lymph node status, ypTNM stage, and tumour Table 2. Tumour stage (ypTNM)
regression grade (TRG) as described by Mandard R0 R1 ⁄ 2 M1
et al.12,13 This grades tumour response on a 5-point
scale according to the degree of radiation-induced T0N0 9 – –
fibrosis and regressive changes in the tumour
T1N0 4 – –
(Table 1). The modified 3-point grade was devised by
combining TRG1 and 2 to form one category, and T2N0 8 – –
combining TRG4 and 5 into another, giving rise to
three distinct grades (Table 1 and Figure 2). The T3N0 15 2 –
reproducibility of both the 5-point and 3-point TRG T4N0 2 – 1
scoring systems was assessed by two pathologists (K.S.,
D.G.), who scored each specimen independently. Any T2N1 4 – –
specimen where a difference in scores existed was then T3N1 5 – 2
scored by consensus using a double-headed micro-
scope. We cross-tabulated results for both pathologists, T3N2 4 1 1
using both scoring systems, and analysed interobserver
T4N0 – 1
variability, expressed as the j statistic.
Two hundred and forty-seven patients were diag- T4N1 – – 1
nosed with carcinoma of the rectum during this period.
T4N2 – 1 –
After exclusion of early-stage cancers, cancers of the
rectosigmoid junction, those with distant metastases
and patients unfit for chemoradiotherapy, 60 patients Table 3. Consensus TRG scores for 5-point and 3-point TRG
underwent a TME with curative intent following scores
neoadjuvant chemoradiotherapy (Figure 1). A detailed
histopathological assessment was made of all speci- Five-point Three-point
TRG Number TRG Number
mens from this group.
1 9 1 10
Results 2 1
Sixty patients’ tumours were evaluated. There were 39 3 17 2 19
males and 21 females, with a mean age of 63 years
(range 20–84). Two patients had histologically verified 4 20 3 31
liver metastases which had not been detected on 5 13
preoperative, post-treatment imaging.
Thirty-three anterior resections and 27 abdomino-
perineal resections were performed. A median of 11 (j statistic ¼ 0.64). For the 3-point score, a difference
(range 2–32) blocks of tumour were examined. For existed in six specimens (j statistic ¼ 0.84).
TRG 1 and 2 specimens, this figure was 14. The The mean duration of follow-up for the entire group
median number of tissue blocks containing tumour was 22 months. During this time, three patients had
was five (range 1–21). A median of six (range 0–53) local disease recurrence and five developed liver meta-
nodes were retrieved per specimen, with a median stases. There were six cancer-related deaths. There
of four (range 1–21) nodes involved by tumour were no local or distant recurrences and no cancer-
per node-positive case. Five had peritoneal involve- related deaths in TRG 1 or 2 patients. While a trend
ment, 13 had lymphovascular invasion and six had towards a relationship between tumour response and
perineural invasion. Tumour stage is outlined in cancer-specific survival existed, it did not reach statis-
Table 2. tical significance.
Nine patients had a TRG score of 1, corresponding
to a complete pathological response. Thirteen patients
Discussion
demonstrated no regressive changes (Table 3). For TRG
1 and 2 there was, as expected, full agreement between Over the last 5–10 years, preoperative neoadjuvant
both pathologists. For TRGs 3, 4 and 5 disagreement radiotherapy, with or without chemotherapy has come
was found in 16 specimens, and where a difference into routine clinical practice. The two most common
existed it was just one point in all but one specimen regimens used are the short-course regimen, consisting

2005 Blackwell Publishing Ltd, Histopathology, 47, 141–146.
 Neoadjuvant chemoradiotherapy for locally advanced rectal cancer
of 25 Gy administered over 5 days with surgery in the
subsequent 5 days, and the long-course regimen,
consisting of 45–50 Gy over 5 weeks, frequently com-
bined with chemotherapy. The major landmark trials
which have proven a benefit from neoadjuvant radio-
therapy have used the short-course regimen.4,6 In
general, the short-course regimen is offered to all
patients, irrespective of disease stage, whereas the long-
course regimen is reserved for those with cancers that
have invaded the perirectal fat or regional lymph
nodes. The long-course regimen, particularly when
combined with chemotherapy, has a number of poten-
tial advantages. These include a downstaging effect,14
which decreases tumour bulk with a greater potential
for curative resection.
Many pathological changes differentiate specimens
excised after long-course and short-course therapy and
between those treated with combined chemoradiother-
apy and just radiotherapy alone.15,16 These include
downstaging, reduced tumour bulk, tumour regression,
node shrinkage, node sterilization and radiation-
induced fibrosis.
We use the ypTNM17 (y denotes post-treatment)
staging system because the traditional Dukes stage does
not lend itself to analysis of these specimens. The TNM
staging system is more informative than the Dukes
stage and allows the inclusion of additional informa-
tion on peritoneal involvement (T4) and margin
involvement (R1 ⁄ 2), which is of particular interest in
the setting of neoadjuvant chemoradiotherapy, where
a major aim is sterilization of the specimen margins.
The lymph node yield was low with a median of six
nodes per specimen. This is in contrast to previously
published data in rectal cancer from this unit, which
reported a median node yield of 19 per specimen for
patients not treated with neoadjuvant therapy.18 This
observation is in keeping with previously published
evidence that radiation therapy causes shrinkage and
regression of lymph nodes.19,20 Novel methods of
improving yield using fat-clearing techniques and
marker dyes may be necessary in order to increase
node yield.21
Using the 5-point score, a different TRG score was
reported by each pathologist in 16 specimens. In all but
one case the difference between the two scores was
just one point and the discrepancy was between TRGs
3 and 4, and 4 and 5, as expected. There was no
difference between the two pathologists with respect to
TRG scores 1 and 2. The distinction between TRGs 3, 4
and 5 is based on the degree of fibrosis in response to
the therapy. Even in the absence of chemoradio-
therapy, significant fibrosis may be seen in response
to cancer, so that it may be difficult to decide how

2005 Blackwell Publishing Ltd, Histopathology, 47, 141–146.
145
much fibrosis is caused by the cancer and how much
by neoadjuvant therapy.
In an attempt to improve reproducibility while still
stratifying patients into prognostically significant
groups, we re-evaluated the tumours using a modified
3-point grade (Table 2). All specimens were then
re-evaluated by both pathologists, blinded to the
original 5-point TRG score. Using a 3-point score, the
majority of patients were reproducibly stratified to
the correct categories (j ¼ 0.84), with no disagreement
about the complete responders, and disagreement in
just six patients with partial or no response.
A similar approach to scoring tumour response using
a 3-point rectal cancer regression grade has been
suggested by Wheeler et al.22 This grading system also
grades the tumour response based on the degree of
fibrosis in response to therapy. A major distinction,
however, between this score and our proposed 3-point
score is that Wheeler et al. use the presence or absence
of macroscopic disease to distinguish between grades 1
and 2. In our experience, the quantification of macro-
scopic disease following chemoradiotherapy can be
inaccurate. We found that the distinction between
tumour and fibrosis is very difficult to demonstrate on
gross examination. This is one of the reasons why a
greater number of blocks of tumour were sampled in
patients with a complete or near-complete response.
Concerning the tumour response, nine (15%) pati-
ents had a complete pathological response, defined as
having no tumour cells on detailed pathological
examination. Twenty-seven patients (45%) had a
partial response, which is defined as a 5-point TRG
score of 3 or better. The complete response rate is in
keeping with similar series reported in the literature,
with rates in the region of 10–30%.8,14,16,20,22 An
accurate description of tumour response necessitates
extensive tumour sampling. This is especially true for
those with a complete or near-complete response,
reflected in the higher number of tumour blocks
examined in TRG 1 and 2 specimens compared with
the average (14 versus 11). Where a heterogeneous
response was seen within a tumour, we scored the
tumour based on the least responsive area.
With respect to survival, no significant association
was found between tumour response and cancer-
specific survival; however, no recurrence, either local
or distant, has occurred in the complete or near-
complete responders (3-point TRG 1). This may be
attributed to the short duration of follow-up and the
small number of patients and events. Shia et al.
recently reported a similar cohort of patients with
longer follow-up and found that a significant survival
relationship was found only for patients with a
 146 R Ryan et al.
complete or near-complete pathological response.16
This cohort of patients included those treated with both
chemoradiotherapy and radiotherapy alone, in con-
trast to our study, in which all patients were treated
with combined modality therapy.
Preoperative long-course chemoradiotherapy pre-
sents a particular challenge to the pathologist, repre-
senting a subset of the total number of rectal cancers. It is
important that these specimens are dissected and repor-
ted in a standardized manner. The assessment of tumour
response is integral to the description and prognosis for
these cases, and a robust and reproducible method of
grading this response must be used. A 3-point grade
yields similar quality prognostic information, while
being more easily implemented, and more reproducible.
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