Article Eeeeee

Review
Critical appraisal of the wait and see approach in rectal cancer

for clinical complete responders after chemoradiation
R. Glynne-Jones and R. Hughes
Centre for Cancer Treatment, Mount Vernon Hospital, Northwood HA6 2RN, UK
Correspondence to: Dr R. Glynne-Jones (e-mail: rob.glynnejones@nhs.net)
Background: Some 1020 per cent of patients with locally advanced rectal cancer achieve a pathological
complete response (pCR) at surgery following preoperative chemoradiation (CRT). Some demonstrate
a sustained clinical complete response (cCR), defined as absence of clinically detectable residual tumour
after CRT, and do not undergo resection. The aim of this review was to evaluate non-operative treatment
of rectal cancer after CRT, and the outcome of patients observed without radical surgery.
Methods: A systematic computerized search identified 30 publications (9 series, 650 patients) evaluating
a non-operative approach after CRT. Original data were extracted and tabulated, and study quality
evaluated. The primary outcome measure was cCR. Secondary outcome measures included locoregional
failure rate, disease-free survival and overall survival.
Results: The most recent Habr-Gama series reported a low locoregional failure rate of 46 per cent,
with 5-year overall and disease-free survival rates of 96 and 72 per cent respectively. These findings
were supported by a small prospective Dutch study. However, other retrospective series have described
higher recurrence rates. All studies were heterogeneous in staging, inclusion criteria, study design and
rigour of follow-up after CRT, which might explain the different outcomes. The definition of cCR
was inconsistent, with only partial concordance with pCR. The results suggested that patients who are
observed, but subsequently fail to sustain a cCR, may fare worse than those who undergo immediate
tumour resection.
Conclusion: The rationale of a wait and see policy relies mainly on retrospective observations from a
single series. Proof of principle in small low rectal cancers, where clinical assessment is easy, should not
be extrapolated uncritically to more advanced cancers where nodal involvement is common. Long-term
prospective observational studies with more uniform inclusion criteria are required to evaluate the risk
versus benefit.
Paper accepted 16 February 2012
Published online 27 April 2012 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.8732
Introduction
Preoperative radiotherapy and total mesorectal excision

(TME) have reduced the risk of local recurrence in
patients with resectable T2T3 rectal cancers1 3 . Similar
improvements have been achieved with preoperative
chemoradiation (CRT)4 7 . This improvement is partly
balanced by an increased risk of surgical complications,
including a postoperative death rate of 28 per cent8,9 ,
which may reach 30 per cent at 6 months in those aged over
85 years10 , and a long-term impact on anorectal, urinary
and sexual function11,12 . Deterioration in bowel function
is common following anterior resection, and patients with
2012 British Journal of Surgery Society Ltd
Published by John Wiley & Sons Ltd
low cancers may require a permanent stoma, which can be

associated with high psychological morbidity.
In patients with more locally advanced T3/T4 cancers,
preoperative CRT has been used to downstage tumours
that appear to encroach on the planned surgical resection
margin on magnetic resonance imaging (MRI). Curative
surgery after preoperative CRT is the current standard
of care. A trial in unresectable/locally recurrent disease
has conrmed an advantage in relapse-free survival for
5-uorouracil (5-FU)-based CRT over radiation alone13 .
Following preoperative CRT and an interval to allow a
response, a pathological complete response (pCR), dened
as no residual viable tumour cells, can be observed in
British Journal of Surgery 2012; 99: 897909
898
the resection specimen. One review of phase II and III

studies identied an overall pCR rate of 135 per cent14 .
Even higher rates of pCR were associated with doses of
radiotherapy exceeding 45 Gy and the use of a second
cytotoxic drug14 .
Although patients who proceed to radical surgery with
histological conrmation of a pCR have favourable longterm outcomes15 , intuitively it seems unlikely that patients
whose cancer has already been sterilized would benet
from subsequent radical surgery. Radiotherapy alone can
achieve long-term control of rectal cancer, but its use has
usually been conned to highly selected patients with small
early cancers16 using contact brachytherapy by specialists
with considerable expertise, and very high doses of over
100 Gy in a small number of fractions17 .
A series of retrospective studies from Brazil18 23 has
highlighted the rationale of a wait and see policy for
patients who achieve a complete clinical response (cCR),
dened as the absence of clinically detectable residual
tumour; their results suggest that observation of such
patients yields survival rates similar to those of patients
who undergo radical surgery with conrmation of a pCR20 .
More recently, the same authors have suggested additional
ways to optimize outcomes in this setting24,25 . Other recent
series appear to support the feasibility of this approach26,27 .
Adopting a non-operative strategy in patients who
achieve complete tumour regression avoids the risks of
surgical morbidity and mortality, and the sequelae of an
abdominoperineal resection (APR). However, because of
the lack of clarity regarding what constitutes a cCR, the fact
that this approach may fail in a fth of patients in the rst
year22 , and the uncertainty of the long-term efcacy of this
strategy, currently accepted standards of surgical followup are not appropriate. Consistent strategies are needed
for recognition of a cCR, along with reliable methods
to conrm that the tumour has been eradicated in the
pelvis, and a rational, systematic, consistent and meticulous
clinical, pathological and imaging follow-up programme.
Currently, there is still insufcient information on the
safety of this approach in clinically staged cT3T4 rectal
cancers to allow patient counselling in order to obtain
informed consent.
A review was therefore undertaken of the medical
literature regarding the non-operative management of
rectal cancer after 5-FU-based CRT, with emphasis on the
oncological outcome of a wait and see policy after CRT.
Methods
A literature search was performed using PubMed and

Embase databases from 1990 to 2011, supplemented by
hand-searching of abstracts from the American Society

of Clinical Oncology and other international meetings
(European Society of Medical Oncology, American Society
for Therapeutic Radiology and Oncology). The studies
qualied for this review if they met the following criteria:
inclusion of patients with primary rectal adenocarcinoma;
patients received neoadjuvant CRT; patients achieved a
cCR and were observed without proceeding to surgery;
and study endpoints included locoregional failure, diseasefree survival (DFS) and overall survival. Studies were
assessed for relevance by the authors; the review was
focused on studies in which a wait and see policy was
observed following CRT. Other randomized and nonrandomized CRT trials in rectal cancer identied from the
primary literature screen were searched for comparison
and discussion purposes.
The quality of studies was examined to assess the risk
of bias based on the following criteria: whether the study
reported inclusion and exclusion criteria; whether data
were collected prospectively or retrospectively; whether
the study selected appropriate patients; whether patients
were treated radically or palliatively; whether the dose of
radiotherapy was specied; whether the eld sizes were
described; the size of the study; clinical stage and imaging
modality; and follow-up time. These items were scored as
yes, no or uncertain. No and uncertain were interpreted as
quality item not met.
Phase II trials rarely report long-term outcome, so
cCR, dened as the inability to demonstrate any clinical
evidence of tumour within the rectal lumen according
to the methodology of Habr-Gama and colleagues28,29 ,
was used as the primary outcome measure of efcacy.
Secondary outcome measures included the feasibility of
salvage surgery, functional outcomes, local recurrence,
DFS and overall survival.
Results
Of 980 abstracts on CRT and rectal cancer, 450 were

selected. Of the 187 abstracts retrieved from searching
non-operative treatment, 68 that concerned tumours other
than rectal adenocarcinoma were excluded. Publications
retrieved in the PubMed search were reviewed to identify
those specically addressing the use of non-operative
treatments and a wait and see strategy in rectal cancer;
59 that appeared irrelevant or were not written in English
were omitted. This culminated in 60 abstracts for full-text
evaluation (Fig. 1).
Several papers describing a series of patients from Brazil
by Habr-Gama and colleagues18 25,28 37 and 12 other
publications/abstracts17,26,27,38 46 were selected for data
www.bjs.co.uk
Clinical complete response after chemoradiation
PubMed search
899
Embase search
Titles on rectal cancer

chemoradiation and response
n = 980
Relevant abstracts selected and
screened in more detail n = 450
Selected for full-text review n = 187
Excluded n = 127
Non-English language n = 2
Not rectal cancer n = 68
Excluded based on screening of titles
and/or abstracts/full texts n = 57
Potentially relevant articles

n = 60
Excluded after full-text review
Not relevant/insufficient data n = 30
Articles included in the review n = 30
Habr-Gama n = 18
Non-Habr-Gama n = 12
Fig. 1
Selection of articles for review
extraction and analysis (Fig. 1). To reduce publication bias,

both published and unpublished studies were included.
Full-text copies of all studies were obtained and relevant
data extracted independently by the two review authors.
All the Habr-Gama articles provided some information,

but only those tabulated (Table 1) provided either different
numbers or clearly gave different locoregional failure rates.
The majority were retrospective studies (two prospective)
and there were no randomized phase II or phase III trials.
In all there were nine series/studies, with 361 patients in
the Habr-Gama series and a further 289 patients in the
remaining eight studies.
There were no meta-analyses. Ten previous reviews
were identied, none of which appeared to be systematic
reviews25,32,47 54 .
The proportion of patients treated with CRT
who achieved a cCR varied from 109 per cent27 to
387 per cent25 (Tables 1 and 2). The largest experience
came from Habr-Gama and colleagues who recruited
patients between 1991 and 200918 23,25,28 . Their original series reported 118 patients with low rectal cancer,
who received preoperative CRT (504 Gy combined with
5-FU and folinic acid for 3 consecutive days on the rst
and last 3 days of radiotherapy)18 . A total of 305 per cent
(36 of 118) achieved a cCR, conrmed by clinical examination, radiological imaging and a negative biopsy. Of
the 30 patients who did not proceed to radical surgery,
eight eventually experienced local failure and required
salvage resection within 314 months. The outcome for
the rest in terms of local recurrence and survival was similar to that of patients found at surgery to have achieved
a pCR.
In a subsequent paper, 71 (268 per cent) of 265 patients
with a cCR at 8 weeks were observed rather than proceeding to radical surgery20 . Only two (3 per cent) suffered an
endoluminal recurrence, and three developed metastases.
Outcome of patients with clinical T2/T4 rectal tumours treated with radiotherapy/chemoradiation who did not proceed to
surgery in the Habr-Gama series
Table 1
5-year survival (%)
Reference
Habr-Gama
et al.18 1998
Habr-Gama
et al.20 2004
Habr-Gama
et al.21 2005
Habr-Gama
et al.22 2006
Habr-Gama23
2006
Habr-Gama
et al.25 2011
No. of
patients*
T2
Follow-up
(months)
Chemotherapy
118 (1991
1996)
265
Yes
36
FUFA
(15)
573
FUFA
260
(20)
57
FUFA
361 (1991
2005)
360 (1991
2005)
173 (1991
2009)
14 of 99 (14)
60
FUFA
14 of 99 (14)
NS
FUFA
(16)
65
5-FU-based
Locoregional
failure
Diseasefree
Cancerspecific
Overall
36 of 118 (305)
8 of 30 (27)
NS
NS
NS
71 of 265 (268) sustained

for 12 months
for 12 months
for 12 months
for 12 months
67 of 173 (387)
2 of 71 (3)
92
100
100
2 of 71 (3)
92
100
NS
5 of 99 (5)
85
93
93
6 of 99 (6)
NS
NS
NS
8 of 173 (46)
72
NS
96
cCR
Values in parentheses are *recruitment period and percentages. cCR, clinical complete response; FUFA, uorouracil with folinic acid; NS, not stated;
5-FU, 5-uorouracil.

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900
Table 2
Outcome of patients with rectal tumours treated with chemoradiation who did not proceed to surgery in other series
No. of
patients
T2*
Radiotherapy
Chemotherapy
Procedure
cCR*
Rossi et al.39 1998
16
NS
FUFA
No surgery
6 of 16 (38)
5 of 6 (83)
Nagakawa et al.41
2002
Lim et al.43 2007
52
No
FUFA
No surgery
(19)
NS fully
48
T1 and T2 (33)
PVI 5-FU 92%
No surgery
27 of 48 (56)
11 of 48 (23)
58
No (50 T4)
FUFA
No surgery
10 of 58 (17)
6 of 10 (60)
23
Yes
504 Gy, 28 fractions,

38 days + 30 Gy
brachytherapy
45504 Gy, 28
fractions, 38 days
Variable; mean 50 Gy,
25 fractions
45 Gy, 25 fractions, 33
days
days
days
?54 Gy (minimum 504
Gy), 28 fractions, 38
days
Minimum 504 Gy, 28
fractions, 38 days
5-FU/MMC
No surgery
NS
10 of 23 (43)
Capecitabine
850 mg/m2
Capecitabine
825 mg/m2
No surgery
12 of 49 (24)
6 of 12 (50)
No surgery; adjuvant
chemotherapy in
some
No surgery; adjuvant
XELOX routinely
Did not all

achieve cCR
9 of 22 (41)
21 of 192 (109)
1 of 21 (5)
Reference
Hughes et al.44
2010
Seshadri45 2011
Dalton et al.26
2012
Yu et al.46 2011
49
No
22
NS
Maas et al.27 2011
21
5 of 21 (24)
Total
Capecitabine
825 mg/m2
289
Locoregional
failure*
48 of 142 (338)
*Values in parentheses are percentages. cCR, clinical complete response; NS, not stated; FUFA, uorouracil with folinic acid; PVI, prolonged venous
infusion; 5-FU, 5-uorouracil; MMC, mitomycin; XELOX, capecitabine plus oxaliplatin.
Habr-Gama and colleagues21 later described a meticulous

monthly follow-up protocol for these 71 patients. The
presence of an obvious clinical tumour, a signicant ulcer
or a positive biopsy following CRT was considered an
incomplete response. Among patients who maintained a
cCR at 14 months, with a median follow-up of almost
5 years, there were no deaths from rectal cancer and
only two (3 per cent) of the 71 patients had a local
relapse.
In a further paper, 361 patients with cT2T4 tumours
treated with CRT, 99 (274 per cent) achieved a sustained
cCR, and 262 an incomplete response22 . Overall recurrence
rates for both groups were similar, at 11 per cent for the
cCR group and 125 per cent for incomplete responders.
Five-year survival rates were non-signicantly lower
for patients who underwent resection (P = 042). In
this report local recurrence was described in only ve
patients. Finally, Habr-Gama23 described 360 patients of
whom 122 were considered to have a cCR at the rst
assessment, but only 99 had a sustained cCR at 12 months
(275 per cent). Some attempt was made to capture the
outcome of the 23 patients whose disease progressed
under surveillance, and who had surgery between 12 weeks
and 1 year after CRT33 . These patients had a mean(s.d.)
interval to surgery of 48(104) weeks. Disease recurred
in eight (35 per cent) of 23, with a 5-year DFS rate
of 52 per cent and overall survival rate of 85 per cent.
Compared with patients who proceeded straight to surgery
within 12 weeks of CRT, those with delayed surgery had

signicantly earlier pathological disease and fewer lymph
node metastases, but no difference with regard to survival.
Initial reports described 36 months of follow-up18 , but
the most recent paper cited a mean follow-up time of
65 months25 .
Three other comparable small CRT series (two
prospective)26,27,46 have prescribed an assiduous formal
follow-up programme (Table 3), and reported local control
in the majority of patients. The Dutch series27 appeared to
reproduce the Habr-Gama data; with a mean(s.d.) followup of 25(19) months, and 18 of 21 patients being followed
for at least 1 year, only one of the 21 patients experienced
a local recurrence at 22 months; this recurrence was
endoluminal.

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Radiotherapy
The Habr-Gama series initially used a dose of 504 Gy
in 28 daily fractions over 56 weeks. More recently the
dose was increased to 54 Gy in 32 daily fractions30 .
Other studies used 4550 Gy. A prospective series from
the UK originally mandated a minimum of 50 Gy and
many patients received 54 Gy46 , but entry criteria were
subsequently relaxed to 45 Gy. Techniques and eld sizes
were not clearly described in these studies, so cannot be
compared, but are assumed to have a superior border at
L5/S1.
Table 3
901
Comparison of modern studies with systematic follow-up
Reference
No. of
patients
cCR*
Follow-up
(months)
Local
failure*
DRE
EUA
CEA
MRI
PET/CT
3 and 12 months
+ biopsy for
any suspicion
of residual
disease
Endoscopy
Yes
6 weeks then
every 6
months
Every 6
months
Mean 25
6 of 12 (50)
Yes, as for
DRE
4, 8, 12, 16
weeks; 6, 9,
12, 18, 24
months, etc.
8, 16
weeks +
12
months
Median
175
9 of 22 (41)
Endoscopy +
biopsy
4 times in
years 13,
twice in
years 4 and
5
4 times in
years 13,
twice in
years 4 and
5
No
Mean 25
1 of 21 (5)
Dalton et al.26
2012
49
12 of 49
(24)
NS
Yu et al.46
2011
22
Did not all

achieve
cCR
Maas et al.27
2011
21
21 of 192
(109)
4, 8, 12, 16
weeks; 6, 9,
12, 15, 18,
21, 24
months, etc.
4 times in year
1, twice in
years 25
Total
92
16 of 55
(29)
*Values in parentheses are percentages. cCR, clinical complete response; DRE, digital rectal examination; EUA, examination under anaesthesia; CEA,
carcinoembryonic antigen; MRI, magnetic resonance imaging; PET, positron emission tomography; CT, computed tomography; NS, not stated.
Chemotherapy
The chemotherapy regimens in the Habr-Gama series
and four other studies employed 5-FU with folinic acid
in the rst and fth weeks. Habr-Gama and colleagues30
increased the dose intensity to combine 5-FU and folinic
acid in the rst, third and fth weeks. Three studies
used oral capecitabine twice daily26,27,46 , one a prolonged
venous infusion of 5-FU43 , and one a combination of 5-FU
and mitomycin45 .
Timing of assessment of complete clinical response

The reports from Habr-Gama et al. were not entirely
consistent as regards the time points (such as 8 weeks,
12 months or 14 months) for dening a sustained cCR or
the number of patients subsequently failing to maintain
a cCR. More recently, the same authors recommended
a minimum of 6 weeks and an even longer interval to
assessment, with additional chemotherapy as consolidation
to increase cCR rates30 and other additional measures28,29 .
The Dutch series27 evaluated response at a mean(s.d.) of
65(3) weeks, and a UK retrospective series26 repeated
MRI at 6 weeks (more recently changed to 8 weeks) after
CRT coupled with an examination under anaesthesia and
biopsies of any residual scar tissue.
Assessment of complete clinical response

The original reports from Habr-Gama and colleagues
recommended assessment using careful digital rectal
examination (DRE), proctoscopy and excision of the

residual scar. Recently, clinical and endoscopic ndings
to identify a cCR have been rened29 to include whitening
of the mucosa, the presence of telangiectasia and a loss
of pliability in the rectal wall, in addition to tumours that
cannot be felt or seen. Habr-Gama and colleagues also
warned of features suggesting that a cCR has not been
achieved, such as deep or supercial ulceration, palpable
nodules and signicant stenosis. They emphasized the
importance of standardizing the denition of cCR.
A recent Dutch series27 dened cCR in terms of the
absence of residual palpable or visible tumour (with low
signal on high b-value diffusion weighted imaging, if
available); brosis and oedema were consistent with a cCR.
Patients were required to meet all of the following criteria
to be considered to have had a cCR: absence of suspicious
lymph nodes on MRI; no residual tumour at endoscopy or
only a small residual ulcer or scar; and negative biopsies
from the scar, ulcer or former tumour location.
Historically, the denition of cCR has been poorly
described and inconsistent. Over 70 different combinations
of investigations and imaging have been proposed to dene
a cCR55 . Most studies have dened a cCR as no detectable
tumour present on clinical examination56 or on DRE
and endoscopy57 . DRE is able to identify only a small
proportion of patients who actually achieve a pCR, and
only about 2550 per cent of patients achieving a cCR
determined by DRE are conrmed to have had a pCR
at surgery58 . In a pooled analysis, cCR was associated
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902
with pCR in approximately 30 per cent of patients49 . One

study suggested that patients with a low carcinoembryonic
antigen (CEA) level after CRT are more likely to achieve
a cCR and have better outcome34 .
Selection of patients
Habr-Gama herself selected patients in that the site of
tumour needed to be accessible to the surgeons nger28 .
She suggested that high tumours may be best treated
with an anterior resection. Because only patients with
tumours within 7 cm of the anal verge (requiring APR)
were selected, in the Habr-Gama series mean tumour size
was small 37 (range 17) cm20 compared with the
size of tumours usually treated with CRT. Low accessible
tumours may be easier to assess. Furthermore, only a small
percentage of tumours (22 per cent) described by HabrGama and colleagues20 were clinically node-positive. In
other series, tumours did not appear to be selected on the
basis of site or size26,39,41,44 46 , but an Australian study
included 33 per cent cT1 and cT2 tumours43 . Maas and
co-workers27 considered T3 and T4 rectal cancers eligible,
but six of 21 patients had cT1 or cT2 lesions.
Imaging of complete clinical response

Imaging of a patient with a cCR cannot robustly predict
a pCR. Recently, MRI has been employed successfully
with very careful documentation of appearances to identify
patients achieving and sustaining a cCR after CRT.
The appearances demonstrated a normalized rectal wall
(26 per cent) or brosis (74 per cent), with three patterns
of brosis (full-thickness, minimal or spicular brosis).
The appearance of normalized rectal wall or brosis
remained consistent during long-term follow-up in 18
of 19 patients59 .
Use of positron emission tomography (PET)/computed
tomography (CT) has been evaluated in a number of
small studies, which usually performed the PET/CT
assessment 6 weeks after CRT. Results were found to
be insufciently robust to conrm a cCR. However,
Habr-Gama and colleagues33 recommended PET/CT as
a promising method of conrming cCR, and reported that
in an ongoing study PET/CT was being carried out at 6
and 12 weeks, and then annually if a cCR was sustained.
PET/CT assessment of tumour response at 12 weeks after
completion of CRT may provide a better tool, with an
overall accuracy of 96 per cent35 .
Follow-up
Only four studies appeared to use a follow-up
protocol23,26,27,46 . Habr-Gamas group mandated an
exceptionally rigorous follow-up programme including

monthly clinical assessments with DRE, proctoscopy, serial
CEA measurement and CT. Patients were only considered to have achieved a sustained cCR at 12 months.
More recent studies have employed systematic follow-up
(Table 3)26,27,46 . Other authors have been more haphazard
in their approach.
Excision biopsy
It is unclear from the reports of Habr-Gama and colleagues
whether any residual suspicious areas were routinely
subjected to excision biopsy, which appeared to be the
pattern in other more recent studies26,27,46 . The efcacy
of a strategy of local excision following CRT was reviewed
in a pooled analysis by Borschitz and colleagues60 , which
showed that patients achieving pathological category after
CRT (yp) T0 or ypT1 consistently experienced low local
recurrence rates of less than 2 per cent. This was further
supported by a retrospective series from the MD Anderson
Institute61 , which claimed that this approach resulted in
similar outcomes to TME.
Early in the Habr-Gama series it appeared that local
excision was employed whenever feasible at the initial
assessment at 8 weeks and then subsequently over the rst
year20 . Positive biopsies obtained during proctoscopy were
considered to indicate an incomplete clinical response and
led to immediate radical surgical resection. A recent report
described 23 patients who underwent transanal endoscopic
microsurgery (TEM) after CRT with primary closure
of the rectal defect. It was claimed that TEM resulted
in signicant postoperative morbidity, wound dehiscence
and readmission rates of 30 per cent, often because of
rectal pain secondary to wound dehiscence36 . For this
reason, and because salvage resection for recurrence may
be prejudiced, TEM after CRT no longer appears to be
recommended25,28 . In a recent summary of their results,
Habr-Gama and co-workers25 described full-thickness
transanal excision of the residual scar as a diagnostic
procedure in only nine of 67 patients.
Locoregional recurrence
Relapse was rare in the Habr-Gama series. Initial studies
reported a higher relapse rate of 27 per cent (8 of 30)18 ,
but as denitions were tightened the local recurrence rate
decreased to 3 per cent21 . Locoregional relapse appeared
late (mean interval more than 50 months), and was
invariably endoluminal so could be surgically salvaged25 .
Only a single patient experienced a further local recurrence
after salvage surgery25 . This low level of local recurrence
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903
was reproduced in the Dutch series27 . In contrast,

relapse was more common in other series, with a local
recurrence rate ranging from 23 to 83 per cent (pooled
rate 338 per cent, 48 of 142) (Table 2).
The median time to endorectal recurrence reported
by Habr-Gama and colleagues25 was 39 months, and two
of ve endorectal recurrences developed after 5 years of
follow-up22 . In an ongoing UK prospective study, the
median time to tumour regrowth was 175 months after
CRT46 . Another study with mature follow-up described
late recurrences (after more than 5 years)44 .
long follow-up. Imaging modalities for staging evolved

with time, but MRI was not used consistently. It is not
clear how patients were selected and whether they were
consecutive. However, the quality of the study can be
criticized because only in the most recent analysis was there
any mention of patients lost to follow-up (3 per cent)25 .
No patients were documented who developed a local
recurrence, yet refused surgery on any account and could
not therefore be salvaged. More recent studies26,27,43 were
of better quality than earlier studies39,41,44 in terms of the
review authors predened details.
Surgical salvage
Studies in progress
To date, evidence regarding surgical salvage is sparse. In

the Habr-Gama series the patients were all amenable to
surgical salvage because recurrence was invariably endoluminal. Other series suggested that up to 25 per cent could
not be salvaged by anterior resection or APR39,41,43,44 ;
however, these studies did not appear to have such meticulous follow-up, so recurrence may have been detected
late.
Information gained from personal contacts and searching websites, such as http://www.clinicaltrials.gov, has
indicated the existence of several planned or ongoing
prospective studies and national registries. A study sponsored by the Royal Marsden (NCT01047969) has the
following primary outcome measures: to estimate the percentage of patients who can safely omit surgery, dened as
the percentage who have not had surgery and who had a
cCR (no detectable local disease) at 2 years after the end
of CRT; and to prove the safety of deferred surgery, as
measured by the percentage of patients with local failure
at 2 years, where local failure is dened as positive margin status of resected tumour or surgically unsalvageable
disease. A Danish Colorectal Cancer Group prospective
observational study (NCT00952926) is examining the frequency of local recurrence at 1, 3 and 5 years after CRT in
patients with low rectal cancer. Finally, the European Network for Watchful Waiting has been initiated in Denmark
(kfe.onk@slb.regionsyddanmark.dk).
Long-term outcomes: disease-free and overall

survival
The Brazilian series suggested that, if carefully watched,
patients with a cCR could safely avoid major surgery with
the same long-term outcome as a similar group treated with
radical surgery who had achieved a pCR20 . In a recent UK
series, of six patients initially achieving a good response in
whom surgery was delayed for 1236 weeks, four remained
disease-free but two developed metastatic disease26 . This
outcome was no different from the rate of subsequent
metastatic disease (30 per cent, 9 of 30) among the patients
who underwent immediate surgery following CRT.
Quality of life and functional outcomes

There was a striking lack of data on quality of life and
functional outcomes from all but one of the studies.
The most recent series reported better function among
patients who did not have surgery than in a comparable
group achieving a pCR at surgery, with a lower mean
Wexner incontinence score (08 versus 35) and defaecation
frequency (18 versus 28 times per day)27 .
Study quality
Two of the nine studies have been presented only in
abstract form45,46 . The Habr-Gama reports were of good
quality with regard to inclusion/exclusion criteria, and the
Discussion
The limitation of this review is that its conclusions are

based on only nine studies and 650 patients, the majority
from a single centre. There were no randomized phase II
or III trials, and no meta-analyses. These small studies had
considerable heterogeneity, as the selection of patients,
imaging modalities, initial method of staging, cytotoxic
drugs used in CRT, regimens, duration and dose intensity,
and radiotherapy dose and fractionation all varied. Some
series included elderly patients and it was unclear whether
they were suitable for surgery or just being treated with
palliative intent. There was also considerable heterogeneity
in terms of treatment strategy (CRT alone and CRT
followed by consolidation chemotherapy or boosted with
brachytherapy), the methods of assessment used to dene
a cCR (DRE, biopsy or imaging) and the rigour of
subsequent follow-up.
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904
Clinical assessment of cCR appears easier in the primary

tumour than in lymph nodes after CRT, as direct inspection
and palpation is possible, particularly in the low rectum.
The size of individual lymph nodes on radiological
assessment is not a good predictor of nodal metastases
and may lead to inaccurate radiological staging, because
50 per cent of positive lymph nodes are smaller than
3 mm37 . The appearances of a cCR may be different in
a small exophytic T2 tumour compared with a larger, more
inltrating, ulcerated lesion.
Habr-Gama and colleagues have demonstrated that, in
experienced hands, a non-operative strategy in selected
patients is safe and effective for a large proportion of
patients. A cCR may be easier to dene in patients with
low rectal cancers, and with experience in a single centre
treating large numbers of patients. The timing is important;
the present authors recommend that this should always be
documented and that assessment to dene cCR should not
be performed before 8 weeks after CRT. Yet it should
be emphasized that the data in the Habr-Gama series for
patients with low rectal cancer should not be extrapolated
to large bulky MRI-staged locally advanced cancers in
the mid-rectum threatening the circumferential resection
margin (and node-positive), typically treated by CRT in
UK practice.
Other authors have reported outcomes for unselected
patients (unt for, or refusing surgery) using lower doses
of radiotherapy, more advanced tumours and less rigorous
follow-up (Table 2). Outcome for the majority of patients
in other series was poorer than in the Habr-Gama series.
Recent prospective studies demonstrated a high risk of local
relapse after CRT, even after high doses of radiotherapy46 .
Studies that included patients with cT1 and cT2 tumours
fared better in terms of local control.
The strength of the data presented by Habr-Gama
and colleagues lies in the rigorous selection of patients
with low tumours; the meticulous methods of dening
cCR by clinical, endoscopic, radiological and metabolic
imaging conrmed histologically with local excision of
residual thickening; and the painstaking intensive followup over the rst year in order to conrm a sustained cCR.
The latter in particular may help to explain why all local
recurrences were endoluminal and amenable to surgery.
Questioning whether mutilating surgery can be avoided
for patients with rectal cancer has a long history62 ,
particularly in patients who have a cCR to external beam
radiotherapy and in those with early-stage tumours63,64 .
This conservative strategy is partly supported by early
studies of contact therapy and brachytherapy, and a
radiotherapy series from Canada42 . The strategy has been
examined recently in some detailed reviews49,50 .
Long-term outcomes in 250 patients from the

Habr-Gama series with clinically staged rectal tumours treated
with chemoradiation who proceeded to surgery within 12 weeks
or less, or after 12 weeks, and for patients with local recurrence
after an initial presumed complete clinical response31
Table 4
5-year survival (%)
Surgery 12 weeks
Surgery > 12 weeks
Suspected cCR but relapsed
Total no.
of patients
T2
121
129
23
12
9
NS
Disease-free Overall
56
59
52
86
82
85
cCR, clinical complete response; NS, not stated.
However, the ideal timing of clinical, radiological and

pathological assessment of response, and how to dene a
cCR following CRT remain uncertain. In a UK questionnaire, 69 per cent of surgeons stated that they would never
discuss non-operative management in patients with rectal
cancer who were t for curative surgery, but 30 per cent
were prepared to consider omitting surgery for those who
achieved a cCR after CRT55 . In contrast, in a similar
survey, 47 per cent of Brazilian surgeons believed that a
non-radical procedure would be the treatment of choice25 .
Patients selected as being unt for radical surgery may
receive CRT and a brachytherapy boost as part of the
treatment plan43 . In contrast, most series have included
unselected patients who serendipitously achieved a cCR
and then did not proceed to surgery because of subsequent
adverse events, co-morbidity or patient choice44 . Some
have supported this approach for selected patients65 .
Others have been more sceptical44,45,66 68 , arguing that
these series are more likely to reect selected early small
low tumours that are easily assessable, with accompanying
low rates (approximately 20 per cent) of clinically positive
nodes, and not deeply penetrating cT3/T4 as dened by
MRI, with a high risk of nodal metastases within the pelvis.
They have argued that even a pCR (ypT0) in the primary
tumour correlates only partially with sterilization within
the pelvic lymph nodes69 74 . If the mesorectum is not
removed, 1525 per cent of patients may still have positive
lymph nodes, potentially leading to future pelvic relapse.
Habr-Gama and colleagues31 attempted to provide
outcome data for patients who suffered disease relapse
within the rst year. In 23 patients the recurrence rate
was 34 per cent. The authors suggested that 5-year overall
survival and DFS rates were 85 per cent and 52 per cent
respectively, and not signicantly different from those
in the remaining patients undergoing surgery (Table 4).
Yet, this is not a suitable group for comparison as the
major downstaging achieved in dening a cCR (even if
www.bjs.co.uk
905
not sustained for 12 months) should select a group with an

excellent prognosis if resected immediately. For patients
treated with neoadjuvant CRT in the MERCURY study,
the 5-year overall survival rate for patients with good
MRI-assessed tumour regression grading (mrTRG) (good
clinical response) was 72 (95 per cent condence interval
56 to 88) per cent compared with 27 (8 to 47) per cent
for those showing a poor mrTRG (P = 0001). Similarly
5-year DFS rate was 64 and 31 per cent for patients with
good and poor mrTRG respectively75 .
Despite the apparent success of Habr-Gama and
colleagues in identifying endoluminal recurrence, locally
recurrent rectal cancer after radiotherapy or CRT may
not always be salvaged76 , although long-term survival can
be achieved in patients who undergo radical surgery with
negative resection margins. Data on salvage of recurrence
after a wait and see approach comes almost entirely from
the Habr-Gama series. There could be more difculties
in resecting diffusely recurrent disease potentially arising
from unresected lymph nodes. The potential for surgical
salvage for initial cT1/T2 tumours, which are very
likely to be node-negative, should not be extrapolated
to more locally advanced cT3/T4 tumours where phase III
trials suggest that up to 50 per cent are node-positive at
diagnosis4,7 .
Local recurrence develops later after CRT than in
patients who undergo radical surgery alone. In one recent
series, after neoadjuvant long-course CRT or radiotherapy,
24 (range 840) per cent of all local recurrences presented
later than 5 years after primary therapy77 . In a Canadian
study of 271 patients who were not t for surgery or
refused surgery despite achieving a cCR, the majority
of patients eventually developed local relapse42 . HabrGama and colleagues showed that recurrences occur late,
an observation supported by other small series44 . Small
studies with short follow-up do not add to knowledge of
the real risks of this approach47 .
A study of preoperative CRT, in which 95 per cent
of patients had T2/T3 tumours and the radiation eld
was placed at the L5/S1 border, showed positive nodes
above this level (superior to the superior rectal artery)
in 18 per cent78 . If not resected by radical surgery, these
nodes could progress and cause metastases. Habr-Gama
and co-workers28 have also suggested that high tumours
may be best treated with an anterior resection.
The optimal interval to surgery after CRT is unknown,
and is currently being investigated a UK trial comparing
6 versus 12 weeks after radiotherapy (NCT01037049).
Likewise, the best time to assess the response remains
unknown. Longer intervals may allow more time for
a response, and this strategy has been recommended
by Habr-Gama et al.18,24,31 . Retrospective data have

suggested that increasing the interval between CRT and
surgery can enhance the pCR rate in rectal cancer79 ;
however, if additional chemotherapy is administered
during the longer interval, it is unclear whether the interval
or the chemotherapy is responsible for the improved
response rate. A randomized study from Lyons (Lyons
R90-01) compared immediate and delayed surgery after
preoperative radiotherapy80 ; long-term outcomes in terms
of DFS and overall survival were no different.
Habr-Gama and colleagues30 also reported recently that
extending the duration of chemotherapy and hence the
interval to surgery after CRT increased the cCR rate of
48 per cent, achieving an overall complete response rate
(cCR and pCR) of 65 per cent. Others demonstrated an
increased pCR when CRT was followed by two courses of
FOLFOX chemotherapy (folinic acid, 5-FU, oxaliplatin)
and surgery was delayed, compared with standard surgery
at 6 weeks (pCR 25 versus 16 per cent)81 . However, the
increased pCR rates may simply reect a good early
response, and leaving a longer interval for this response to
be further expressed.
Many patients would trade some life expectancy to avoid
a permanent stoma82 , but patient preferences are difcult
to capture, and the balance between the risk of incontinence
and the inevitability of a permanent stoma appears more
uid. Patients appear comfortable to defer decision-making
regarding type of surgery to their surgeon, and long-term
views may validate the original decision to undergo APR83 .
It remains unclear whether the priority that surgeons
often place on avoiding a colostomy is always matched
by their patients preference84 . It is not known whether
avoidance of a colostomy should always trump the risk of
incontinence and late effects, including second malignancy.
More data are required on preferences as regards a wait
and see approach in patients who have not been selected
by expressing strong initial views regarding the avoidance
of a stoma. These data need to be interpreted in individual
patients in the context of overall life expectancy. To assist,
some have proposed a decision analytic model examining
the relative benets of radical surgery versus wait and see
in patients with rectal cancer who achieve a cCR after
neoadjuvant CRT85 .
Patients need to be informed clearly about all the surgical
options, the possibility of wait and see approaches, and
the potential outcomes of each. Patients should be included
in the decision-making process, so both a secure evidence
base and tailored information in an acceptable format are
required, aimed at supporting patients considering a wait
and see approach. At present the evidence supporting this
approach is insufcient.

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906
This review has claried the available data and will

aid decision-making in patients with rectal cancer who
show a cCR to CRT. The omission of surgery in patients
with a cCR has obvious short-term advantages, such as
less morbidity, fewer colostomies and fewer potential
surgical deaths. However, the majority of studies reporting
a watch and wait approach have limitations because
they are retrospective, mainly small, and with short and
insufciently rigorous follow-up. Functional and qualityof-life outcomes have been reported in only one study.
At present, for unselected patients with advanced disease
in whom a serendipitous cCR is observed following
neoadjuvant CRT, in whom surgery was originally planned
by the multidisciplinary team, the data are insufcient to
allow either the short- or long-term risks of omitting
surgery to be quantied. In such patients, the omission
of surgery raises further questions regarding the intensity
and duration of clinical and imaging follow-up, the need
for additional adjuvant chemotherapy in view of the initial
clinical staging, and the cost versus benet.
It seems unlikely that well designed non-inferiority
randomized controlled trials can be achieved. The present
authors therefore encourage careful observational studies,
providing denitive evidence about long-term (at least
7 years) oncological safety and functional outcomes. The
manner in which cCR has been conrmed (endoscopy,
imaging, biopsy or excision biopsy) should be made clear.
Outcomes in terms of distant relapse and overall survival
should be compared with those in patients who achieve a
good clinical response and proceed without delay to radical
surgery, and not an unselected surgical group including
poor responders.
Disclosure
10
11
12
The authors declare no conict of interest.

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910
G. L. Beets
Commentary
Critical appraisal of the wait and see approach in rectal cancer for clinical
complete responders after chemoradiation (Br J Surg 2012; 99: 897909)
Rectal cancer is generally considered to be moderately radioresistant compared with tumours of anal canal, head and neck
or prostate. Small tumours, however, have long been known to show a substantial complete response rate after a high dose
of radiotherapy, achieved with endocavitary with or without external beam radiotherapy1 . Surgery has always provided
a much more reliable method of local control for the more common larger tumours than radiotherapy. A randomized
trial comparing resection after neoadjuvant radiation showed a complete histological response in only 5 per cent after
radiotherapy alone, and in 14 per cent after chemoradiation2 . These low rates of complete remission precluded denitive
treatment as a valid option in patients who could tolerate a major operation. Yet, many a surgeon has felt a little uneasy
when no viable tumour was found after a major resection, sometimes leaving the patient with a permanent colostomy.
In retrospect, it is difcult to understand why surgeons have not tried earlier to identify responders before taking
them into the operating room. Dr Habr-Gama from Sao Paulo was the rst to do so systematically, and was initially
met with disbelief when she reported good results from just following the patient to see what happens. Slowly, however,
other reports are supporting this idea of wait and see, and its closely related cousin, a local excision. Yet there remain
many questions to be answered, so the critical review of Glynne-Jones and Hughes is well timed. I support their plea for
careful observational studies. With some of those questions resolved, with better methods to predict a high likelihood of
a complete response, and with radiotherapy methods that have higher response rates, I have no doubt that a substantial
minority of future patients with rectal cancer will be cured without surgery.
G. L. Beets
Department of Surgery, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands
(e-mail: g.beets@mumc.nl)
DOI: 10.1002/bjs.8793
Disclosure
The author declares no conict of interest.

References
1 Gerard JP, Romestaing P, Chapet O. Radiotherapy alone in the curative treatment of rectal carcinoma. Lancet Oncol 2003; 4:
158166.
2 Bosset JF, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A et al. Enhanced tumorocidal effect of chemotherapy with
preoperative radiotherapy for rectal cancer: preliminary results EORTC 22921. J Clin Oncol 2005; 23: 56205627.

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Review

Critical appraisal of the wait and see approach in rectal cancer

Preoperative radiotherapy and total mesorectal excision

low cancers may require a permanent stoma, which can be

the resection specimen. One review of phase II and III

A literature search was performed using PubMed and

R. Glynne-Jones and R. Hughes

hand-searching of abstracts from the American Society

Of 980 abstracts on CRT and rectal cancer, 450 were

British Journal of Surgery 2012; 99: 897909

Clinical complete response after chemoradiation

Titles on rectal cancer

Potentially relevant articles

Selection of articles for review

extraction and analysis (Fig. 1). To reduce publication bias,

All the Habr-Gama articles provided some information,

5-year survival (%)

71 of 265 (268) sustained

2012 British Journal of Surgery Society Ltd

British Journal of Surgery 2012; 99: 897909

R. Glynne-Jones and R. Hughes

Rossi et al.39 1998

PVI 5-FU 92%

504 Gy, 28 fractions,

Did not all

Maas et al.27 2011

Habr-Gama and colleagues21 later described a meticulous

within 12 weeks of CRT, those with delayed surgery had

2012 British Journal of Surgery Society Ltd

Clinical complete response after chemoradiation

Comparison of modern studies with systematic follow-up

Did not all

Timing of assessment of complete clinical response

Assessment of complete clinical response

examination (DRE), proctoscopy and excision of the

British Journal of Surgery 2012; 99: 897909

with pCR in approximately 30 per cent of patients49 . One

Imaging of complete clinical response

R. Glynne-Jones and R. Hughes

exceptionally rigorous follow-up programme including

British Journal of Surgery 2012; 99: 897909

Clinical complete response after chemoradiation

was reproduced in the Dutch series27 . In contrast,

long follow-up. Imaging modalities for staging evolved

To date, evidence regarding surgical salvage is sparse. In

Long-term outcomes: disease-free and overall

Quality of life and functional outcomes

The limitation of this review is that its conclusions are

British Journal of Surgery 2012; 99: 897909

Clinical assessment of cCR appears easier in the primary

R. Glynne-Jones and R. Hughes

Long-term outcomes in 250 patients from the

5-year survival (%)

cCR, clinical complete response; NS, not stated.

However, the ideal timing of clinical, radiological and

British Journal of Surgery 2012; 99: 897909

Clinical complete response after chemoradiation

not sustained for 12 months) should select a group with an

by Habr-Gama et al.18,24,31 . Retrospective data have

2012 British Journal of Surgery Society Ltd

British Journal of Surgery 2012; 99: 897909

This review has claried the available data and will

R. Glynne-Jones and R. Hughes

The authors declare no conict of interest.