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1
Articles
Lancet Gastroenterol Hepatol
2020
Published Online
December 10, 2020
https://doi.org/10.1016/
S2468-1253(20)30333-2
See Online/Comment
https://doi.org/10.1016/
S2468-1253(20)30390-3
*TREC Collaborators are listed in
the appendix
Cancer Research UK Clinical
Trials Unit (S P Bach FRCS,
K Brock PhD) and Birmingham
Clinical Trials Unit
(K Handley PhD, M Kaur BSc,
N Marchevsky MSc,
L Magill PhD), University of
Birmingham, Birmingham, UK;
Department of Colorectal
Surgery (S P Bach,
S Korsgen FRCS), Department of
Radiation Oncology
(I Geh FRCR), University
Hospitals Birmingham NHS
Foundation Trust,
Birmingham, UK; Leeds
Institute of Medical Research,
University of Leeds, Leeds
Cancer Centre, Leeds, UK
(A Gilbert FRCR, Prof D Sebag-
Montefiore FRCR); Department
of Colorectal Surgery, Central
Manchester University
Hospitals NHS Foundation
Trust, Manchester, UK
(Prof J Hill FRCS); Department of
Colorectal Surgery, North Tees
and Hartlepool NHS
Foundation Trust, University
Hospital of North Tees,
Stockton-on-Tees, UK
(T Gill FRCS); Department of
Colorectal Surgery, Newcastle
upon Tyne Hospitals NHS
Foundation Trust, Newcastle
upon Tyne, UK
(P Hainsworth FRCS);
Department of Colorectal
Surgery, East Suffolk and North
Essex NHS Foundation Trust,
Colchester Hospital, Colchester,
Essex, UK (M G Tutton FRCS);
Department of Colorectal
Radical surgery versus organ preservation via short-course
radiotherapy followed by transanal endoscopic microsurgery
for early-stage rectal cancer (TREC): a randomised,
open-label feasibility study
Simon P Bach, Alexandra Gilbert, Kristian Brock, Stephan Korsgen, Ian Geh, James Hill, Talvinder Gill, Paul Hainsworth, Matthew G Tutton,
Jim Khan, Jonathan Robinson, Mark Steward, Christopher Cunningham, Bruce Levy, Alan Beveridge, Kelly Handley, Manjinder Kaur,
Natalie Marchevsky, Laura Magill, Ann Russell, Philip Quirke, Nicholas P West, David Sebag-Montefiore, on behalf of the TREC collaborators*
Summary
Background Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage
rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse eects of
treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting
patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision.
Methods TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible
participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of
30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly
allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course
radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the
transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of
local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised
prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong
clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and
24 months. Secondary outcomes evaluated safety, ecacy, and health-related quality of life assessed with the European
Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population.
This trial is registered with the ISRCTN Registry, ISRCTN14422743.
Findings Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation
and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and
39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ
preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage.
Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious
adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of
28 randomly assigned to total mesorectal excision (p=0·04, χ² test). Serious adverse events associated with organ
preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported
in three cases). Radical total mesorectal excision was associated with medical and surgical complications including
anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia
(two patients). Histopathological features that would be considered to be associated with increased risk of tumour
recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly
assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ² test).
Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who
were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of
life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision,
which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent
organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ
preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse
events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%)
of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ
preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ
preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients.
Interpretation Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ
preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of
Articles
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Introduction
Radical surgical resection adhering to the principles of
total mesorectal excision is the standard of care for
localised rectal cancer, with selective use of pre-operative
chemoradiotherapy reserved for patients with locally
advanced disease.1 Although total mesorectal excision
provides eective local tumour control, patients must
accept a 2% mortality risk and the prospect of
considerable short-term morbidity.2 Cancer survivors
report long-term bowel, bladder, and sexual dysfunction
following total mesorectal excision that impairs quality
of life (QOL).3,4
Surgery, Portsmouth Hospital
NHS Trust, Portsmouth, UK
(J Khan FRCS); Department of
Colorectal Surgery, Bradford
Teaching Hospitals NHS
Foundation Trust, Bradford, UK
(J Robinson FRCS,
M Steward FRCS); Department
of Colorectal Surgery, Oxford
University Hospitals NHS
Foundation Trust, Oxford, UK
(C Cunningham FRCS);
Department of Colorectal
Surgery, Western Sussex
Hospitals NHS Foundation
Trust, West Sussex, UK
(B Levy FRCS); Department of
Colorectal Surgery, Lancashire
Teaching Hospitals NHS
Foundation Trust, Lancashire,
UK (A Beveridge FRCS); Patient
representative, National
Cancer Research Institute,
London, UK (A Russell); Division
of Pathology and Data
Analytics, School of Medicine,
Leeds University, Leeds, UK
(Prof P Quirke FRCPath,
N P West PhD)
Correspondence to:
Mr Simon P Bach, Drugs, Devices,
Diagnostics and Biomarkers
(D3B) Clinical Trial Team, Cancer
Research UK Clinical Trials Unit,
Institute of Translational
Medicine, Birmingham B15 2TH,
UK
s.p.bach@bham.ac.uk
See Online for appendix
organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term
risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ
preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing
STAR-TREC study, are needed to more precisely determine oncological outcomes following dierent organ
preservation treatment schedules.
Funding Cancer Research UK.
Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
Research in context
Evidence before this study
Radical surgery to remove the rectum, adhering to the principles
of total mesorectal excision, without pre-operative
radiotherapy, is the standard of care for early-stage rectal
cancer. However, radical surgery has measurable mortality,
substantial morbidity, and a considerable impact on patients’
quality of life (QOL). Patient groups and health-care
professionals both recognise the potential benefits of an organ
preservation approach for the treatment of early-stage rectal
cancer to reduce the morbidity associated with radical surgery
without compromising oncological outcomes, but there is
currently a lack of high-quality, prospective, randomised
evidence to justify adoption of this approach. Organ
preservation strategies commonly use a combination of
radiotherapy and local excision. The feasibility of primary organ
preservation with chemoradiotherapy is not in doubt, but the
cumulative toxicity arising from multiple treatments is
problematic, particularly for patients who do not achieve organ
preservation, and adversely affects patients’ health-related QOL
(HRQOL). Furthermore, to the best of our knowledge, no
randomised study has compared an organ preservation strategy
with total mesorectal excision alone. The GRECCAR 2 trial
enrolled patients with small T2 and T3 rectal cancer following a
good clinical response to chemoradiotherapy, randomly
assigning patients to undergo either radical surgery or transanal
local excision (transanal endoscopic microsurgery). Conversion
to radical surgery was advised for patients with ypT2 or more
advanced stage cancer. A composite endpoint of death, cancer
recurrence, and treatment-related morbidity at 2 years
concluded that organ preservation was not superior to
chemoradiotherapy plus radical surgery due to the cumulative
toxicities of multiple treatments. Further exploratory analysis
by treatment received suggested lower rates of faecal
incontinence in patients who achieved organ preservation at
2 years. Notably, few studies have reported longer-term toxicity
rates or patient-reported outcomes including HRQOL following
organ preservation, particularly in a randomised setting against
total mesorectal excision surgery alone. This limits our ability to
extrapolate available data on HRQOL to guide patient choices.
Added value of this study
The TREC study demonstrates the feasibility of randomly
assigning patients with early-stage rectal cancer to a
multimodality organ preservation strategy (incorporating
short-course radiotherapy and transanal endoscopic
microsurgery) versus radical surgery without radiotherapy.
The comparison of organ preservation with radical surgery
showed some benefits of organ preservation with respect to
fewer serious surgical complications, low acute patient-
reported toxicity, and little impact on QOL and function at
3 months. Sustained benefits for up to 3 years in overall QOL,
social function, body image, and decreased embarrassment
about bowel function were also observed with organ
preservation. The risk of unsalvageable local recurrence was low
in TREC.
Implications of all the available evidence
The findings of the TREC study suggest that short-course
radiotherapy and transanal endoscopic microsurgery is
associated with lower acute and late patient-reported side-
effects than total mesorectal excision (the standard of care),
and consequently has a minimal impact on patients’ QOL.
The high levels of compliance, low toxicity, significant
downstaging, and high rates of organ preservation achieved in
the TREC study support further evaluation of short-course
radiotherapy to achieve primary organ preservation in patients
with early-stage rectal cancer alongside other measures that
could reduce the adverse effects of treatment, such as smaller
risk-adapted radiotherapy fields, non-operative management of
complete response, and a biomarker-driven approach to
initiating surgical intervention. Such measures should be
implemented in the context of well conducted clinical research,
such as the ongoing STAR-TREC study, as larger randomised trials
are required to establish the oncological safety of organ
preservation.
Articles
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3
25% of total mesorectal excision operations done in
the UK are for non-irradiated T1 and T2 rectal tumours.2
Interest in primary organ preservation for early-stage
rectal cancer is gathering momentum but there is a lack of
high quality, prospective, randomised evidence to justify
its adoption.5,6 Primary organ preservation in early-stage
rectal cancer aims to preserve the rectum and its function.
This approach can involve radiotherapy, local excision, or
a combination of treatment approaches. Local transanal
surgical excision of early-stage rectal cancer can achieve
organ preservation, but overall oncological outcomes are
compromised.1,7,8 The risk of local recurrence following
transanal excision is associated with the presence of
specific high-risk histopathological features that are only
evaluable, and thereby appreciated, once the tumour is
removed.8 Chemoradiotherapy followed by transanal local
excision is an experimental approach to improve outcomes
for primary organ preservation in early-stage rectal
tumours, but multiple treatments can give rise to
cumulative toxicities that detract from the benefits of
organ preservation.9–11 The ecacy of pre-operative short-
course radiotherapy compared with chemoradiotherapy
for prevention of local relapse is supported by two phase 3
trials in patients with radically excised rectal cancer, where
short-course radiotherapy showed benefits in terms of
reduced toxicity.12,13 Short-course radiotherapy with delayed
local excision provided safe and eective primary organ
preservation in a cohort of frail, elderly patients with T1
and T2 N0 rectal cancer,14 but excessive surgical morbidity
was reported in another study.15
To our knowledge, TREC is the first study to randomly
assign patients with early-stage rectal cancer to organ
preservation (via short-course radiotherapy and delayed
transanal endoscopic microsurgery) or radical surgery
(total mesorectal excision) without preoperative chemo-
radiotherapy. TREC was designed to assess the feasibility
of recruiting patients to a larger randomised phase 3 trial
comparing these dierent treatment approaches.16 This
study was designed to address the lack of randomised
evidence describing the trajectory of symptomatic toxicity
and health-related quality of life (HRQOL) following
organ preservation and total mesorectal excision. The
aim of the TREC study was to determine the feasibility of
randomisation between two markedly dierent treatment
options. We also aimed to explore the impact of the novel
organ preservation intervention to inform the design of a
larger phase 3 study comparing radical surgery with
organ preservation.
Methods
Study design and participants
TREC was a randomised, open-label, feasibility study done
in the UK, at 21 tertiary referral centres specialising in the
treatment of early-stage rectal cancer. TREC assessed the
feasibility of randomly assigning eligible patients with
early-stage rectal cancer to either total mesorectal excision,
without pre-operative radiotherapy in accordance with
NICE guidance,6 or a novel organ preservation strategy.
A non-randomised registry was included to capture
treatment outcomes in patients for whom randomisation
was considered inappropriate, due to a strong clinical
indication for one of the treatment options (eg, individuals
considered unsuitable for total mesorectal excision due to
frailty, comorbidity, or older age).
Eligible patients were aged 18 years or older with rectal
adenocarcinoma staged T2 or lower, no lymph node
involvement (ie, N0), with a maximum diameter of 30 mm
or less, and no metastasis. Patients with a previous history
of pelvic radiotherapy were excluded. Participants provided
written informed consent and the study was done in
accordance with the Declaration of Helsinki and Good
Clinical Practice Guidelines. The trial was approved by the
West Midlands, Black Country Research Ethics Committee
(10/H1202/81).
Randomisation and masking
All patients were reviewed by a colorectal cancer multi-
disciplinary team at each centre, and eligible patients who
were considered equally suitable for total mesorectal
excision or organ preservation were invited to enrol in the
study and randomly assigned in a 1:1 ratio. Treatment
allocation was done with a computer-based randomisation
service accessed by telephone or web link. Patients and
investigators were not masked to treatment allocation.
Where the multidisciplinary team strongly preferred one
of the two treatment groups the patients were invited to
participate in the study via a non-randomised registry.
Entry to the registry was by online or telephone registration
before any treatment was initiated. At the outset of the
study, eligible patients who declined randomisation were
excluded from the study and oered standard treatment,
but a protocol amend ment on May 8, 2013, allowed
patients who were particularly reluctant to undergo radical
surgery or formation of a stoma to choose organ
preservation through the non-randomised registry.
Procedures
Baseline investigations included colonoscopy, tumour
biopsy, high-resolution pelvic MRI, endorectal ultrasound
(optional) and CT scan of the thorax, abdomen, and pelvis.
Organ preservation consisted of three-dimensional pelvic
conformal short-course radiotherapy followed by local
excision. 25 Gy in five fractions was given over a period of
5–7 days with photon energies of at least 6 MV and a three
or four field technique. The clinical radiotherapy target
volume included the tumour, mesorectum, and internal
iliac, obturator and presacral nodes, up to the level of
S2/3 junction. Radiotherapy quality assurance was
coordinated by the UK National Cancer Research Institute
Radiotherapy Trials Quality Assurance team.
After an interval of 8–10 weeks following completion of
short-course radiotherapy the area of the rectal wall
aected by cancer was removed, with a 10 mm margin of
normal mucosa, via transanal endoscopic microsurgery.
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Figure 1: Trial profile
*23 patients were randomly assigned to organ preservation while three crossed over from total mesorectal excision to organ preservation.
68 patients recruited to non-
randomised registry
(treatment determined by
multidisciplinary team or
patient choice)
61 non-randomised
patients underwent
organ preservation
7 non-randomised
patients underwent
radical surgery (total
mesorectal excision)
35 underwent radical
surgery (total
mesorectal
excision)
19 patients allocated to
organ preservation
included in intention-
to-treat analysis and
20 in per-protocol
analysis
310 patients assessed by multidisciplinary team
159 not enrolled
139 ineligible
1 study closed
19 unknown
152 eligible patients identified
55 patients randomly assigned29 patients did not enter study
27 allocated to organ
preservation
28 allocated to radical
surgery (total
mesorectal excision)
Protocol deviation: three patients
crossed over from total mesorectal
excision to organ preservation
group
30 received short-course
radiotherapy
25 received primary
radical surgery
(total mesorectal
excision)
Protocol deviation: three patients
crossed over to total mesorectal
excision group (ie, did not undergo
transanal endoscopic microsurgery)
26 received transanal
endoscopic
microsurgery*
1 received chemotherapy
for liver metastasis
2 patients initially assigned to
radical surgery but who received
organ preservation underwent
total mesorectal excision
5 patients underwent early
per-protocol conversion to total
mesorectal excision
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5
The surgeon performed full thickness local disc excision of
the tumour site, incorporating the muscularis propria with
a small amount of mesorectal fat. Transanal endoscopic
microsurgery specimens were pinned out, mucosal
surface upwards, to identify the rim of surround ing
normal tissue, before fixing intact. Standard radical
surgery adhered to the principles of total mesorectal
excision by low anterior resection or abdomino perineal
excision where the primary tumour encroached upon the
anal canal. Surgery comprised a minimally invasive, open,
or hybrid approach. Specimens were classified according
to TNM5, and pT1 cancers were substaged by the depth of
the submucosal invasion. Central histopathological review
was done for quality assurance and to score radiotherapy
regression grade. Pathological complete response (ypT0)
was designated by no visible tumour cells, despite
embedding the entirety of the tumour and sectioning all
blocks at three levels. Histopathological features con-
sidered high risk for local relapse following organ preser-
vation were a maximum tumour diameter greater than
30 mm, cancer within 1 mm of the circumferential or deep
resection margin, predominantly poor dieren tiation,
presence of lymphatic or venous invasion (intramural or
extramural), and tumour depth of invasion of submucosal
tumour stage 3 (sm3) or greater.8 Patients with one or
more of these high-risk features were considered for
planned early conversion from organ preservation to total
mesorectal excision surgery within 8 weeks.
Patients were followed up in the clinic at 3, 6, 12, 24,
and 36 months; with carcinoembryonic antigen testing
at 12, 24, and 36 months; and CT scan of the thorax,
abdomen, and pelvis at 12 and 24 months. Additionally,
patients undergoing organ preservation had white light
endoscopy and MRI scans every 3 months for 2 years,
then every 6 months for up to 3 years.
Outcomes
The primary endpoint was cumulative recruitment of
randomised patients, reported 12, 18, and 24 months from
the date of first randomisation. Secondary endpoints
comprised measures of safety, including 30-day and
6-month mortality, clinician-reported morbidity (Common
Terminology Criteria for Adverse Events [CTCAE], version
4·0, reported 3 weeks after short-course radiotherapy and
incidence of serious adverse events), patient-reported
toxicity, and HRQOL assessed with validated European
Organisation for Research and Treatment of Cancer
(EORTC) QLQ C29 and C30 questionnaires measured at
baseline, and at 3, 6, 12, 24, and 36 months in the intention-
to-treat population.17,18 Serious adverse events were defined
as those that caused death, threat to life, prolonged hospital
stay, readmission to hospital, or persistent disability.
Secondary ecacy endpoints were tumour downstaging
(including the incidence of histopathological features
considered high risk for local recurrence following
transanal excision alone), organ preservation rate, stoma
rates, tumour recurrence, disease-free survival, overall
survival, and HRQOL. Overall survival was calculated from
the date of randomisation or registration to the date of
death, and disease-free survival was calculated from the
date of randomisation or registration to the date of death
Randomised patients Non-randomised patients
Organ
preservation
(n=27)
Radical
surgery
(n=28)
Organ
preservation
(n=61)
Radical
surgery
(n=7)
Age, years 65 (52–79) 65 (49–83) 74 (53–89) 69 (53–73)
Sex
Male 19 (70%) 17 (61%) 39 (64%) 4 (57%)
Female 8 (30%) 11 (39%) 22 (36%) 3 (43%)
ASA physical status classification
I 11 (41%) 13 (47%) 24 (39%) 4 (57%)
II 14 (52%) 11 (39%) 23 (38%) 2 (29%)
III 2 (7%) 4 (14%) 13 (21%) 0
Missing ·· ·· 1 (2%) 1 (4%)
Distance from lower border of tumour to anal
verge, mm
60 (40–80) 60 (50–70) 60 (40–70) 55 (35–75)
Tumour position
Anterior 7 (27%) 10 (35%) 8 (15%) 1 (14%)
Lateral 14 (54%) 5 (18%) 20 (36%) 3 (43%)
Posterior 5 (19%) 12 (43%) 23 42%) 3 (43%)
Not known 0 1 (4%) 4 (7%) 0
MRI T stage
Tx 1 (4%) 2 (7%) 6 (10%) 0
T1 10 (37%) 5 (18%) 10 (16%) 0
T2 16 (59%) 21 (75%) 45 (74%) 7 (100%)
Ultrasound stage
Tx 0 0 1 (2%) 0
T1 9 (33%) 10 (36%) 16 (26%) 1 (14%)
T2 10 (37%) 9 (32%) 31 (51%) 4 (57%)
Not done 8 (30%) 9 (32%) 13 (21%) 2 (29%)
Sphincter preservation considered feasible
Yes 23 (85%) 25 (89%) ·· ··
No 4 (15%) 3 (11%) ·· ··
Compliance with treatment allocation 23 (85%) 25 (89%) 55 (90%) 7 (100%)
SCRT commenced 27 (100%) 3 (11%) 60 (98%) ··
SCRT completed 27 (100%) 3 (11%) 60 (98%) ··
Primary surgery
TEM 23 (85%) 3 (11%) 55 (92%) 0
Low anterior resection 3 (11%) 23 (82%) 0 7 (100%)
Abdominoperineal excision 0 2 (7%) 0 0
No surgery* 1 (4%) 0 5 (8%) 0
Temporary stoma 2 (7%) 20 (71%) 0 5 (71%)
Stoma for complications 1 (4%) 3 (11%) 2 1 (14%)
Planned early conversion to TME following
organ preservation
5 (19%) 2 (7%) 4 (7%) ··
Second surgery (planned early conversion following TEM)
Low anterior resection 3 0 1 ··
Abdominoperineal excision 1 2 3 ··
Hartmann’s 1 0 0 ··
Temporary stoma 3 0 1 ··
(Table 1 continues on next page)
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or disease recurrence, whichever occurred first. The site of
recurrence at first relapse was grouped as isolated local
(pelvic), local plus distant, or isolated distant, to determine
recurrence-free survival.
Statistical analysis
Statistical analysis was done at Birmingham Cancer
Research UK Clinical Trials Unit and Birmingham
Clinical Trials Unit with R software (version 3.5.2). TREC
assessed the feasibility of developing multidisciplinary
organ preservation teams, opening sites, and recruiting
patients to a randomised trial design. The study was not
formally powered for a cancer outcome and no a-priori
recruitment target was set. The secondary endpoint of
tumour downstaging was selected to show the eect size
needed to produce a significant dierence between
randomised groups in the intention-to-treat population.
As preoperative short-course radiotherapy reduces local
recurrence after total mesorectal excision by 50%,19 we
hypothesised that short-course radiotherapy with an
interval of 8–10 weeks to transanal endoscopic micro-
surgery would reduce the incidence of high-risk histo-
pathological features by 50% or more compared with
non-irradiated, radical surgery. Histopathological features
that were considered high risk for local recurrence were
derived from previous studies in patients treated with
transanal endoscopic microsurgery alone, as were
estimates of prevalence.8 46 randomised patients were
required to show that short-course radiotherapy reduced
the incidence of high-risk features from 75% to 35%
(α=0·05, 80% power, one-tailed). Binary proportions were
compared across randomised groups by χ² test. Survival
outcomes were estimated with the Kaplan-Meier method
and randomised groups were compared with the log-rank
test. Patients without the event in each outcome were
censored at the last known event-free time. Outcomes for
the non-randomised population are provided for hypoth-
esis generation. Completion of patient-reported outcomes,
and item and scale compliance were determined.
EORTC-QLQ guidelines were used for analyses and
management of missing data.20 All item responses were
converted from a four-point Likert-type scale with linear
transformation onto a 0–100 scale.20 Dierences in mean
scores were classified as a small change for 5–10 points, a
moderate change for 10–20 points, or a large change for
more than 20 points.21 Exploratory item-level probabilities
of the reported benefit or detriment of an organ-sparing
approach compared to radical surgery were calculated for
each patient-reported outcome assessment point with a
Bayesian model-based analysis, adjusting for assessment
time, treatment allocation, and baseline patient-reported
outcome score. Trial oversight was main tained by a
combined trial steering committee and data monitoring
committee.
This trial is registered with the ISRCTN Registry,
ISRCTN14422743.
Role of the funding source
Cancer Research UK reviewed, approved, and funded the
study design (CRUK/09/032). The funder played no part
in study design, data analysis, or writing of this report.
SPB, KB, AG, NM, MK, LM, KH, DSM, PQ, and NPW
accessed and verified the data. All authors had full access
to all trial data and had final responsibility for the decision
to submit for publication.
Randomised patients Non-randomised patients
Organ
preservation
(n=27)
Radical
surgery
(n=28)
Organ
preservation
(n=61)
Radical
surgery
(n=7)
(Continued from previous page)
Overall stoma rate
Permanent 2 (7%) 4 (14%) 3 (5%) 0
Temporary 6 (22%) 23 (82%) 3 (5%) 6 (86%)
Organ preservation rate 19 (70%) 1 (3%) 56 (92%) 0 (0%)
ASA=American Society of Anesthesiologists. SCRT=short-course radiotherapy. TEM=transanal endoscopic microsurgery.
TME=total mesorectal excision. *No TEM done following complete clinical response of the primary tumour.
Table 1: Baseline characteristics and treatment of intention-to-treat population
Randomised patients Non-randomised patients
Organ
preservation
(n=27)
Radical
surgery
(n=28)
Organ
preservation
(n=61)
Radical
surgery
(n=7)
30-day mortality 0 0 0 0
6-month mortality 1* 0 0 0
All serious adverse events 5 15 15 1
Number of patients with a serious adverse event† 4 (15%) 11 (39%) 10 (16%) 1 (14%)
Cause of serious adverse events reported
Abdominal pain 0 0 1 0
Acute kidney injury 0 2 0 0
Anastomotic leak 1* 2 2 1
Anastomotic stricture 0 1 0 0
Cardiac arrest 0 1 0 0
Cardiac failure 0 0 1 0
Diarrhoea 1 1 2 0
Deep venous thrombosis 0 1 0 0
Fever 0 0 1 0
Fistula 0 0 1 0
Incisional hernia 0 1 0 0
Pancreatitis 0 1 0 0
Paralytic ileus 0 1 1 0
Pneumonia 0 2 2 0
Rectal bleed 2 1 2 0
Rectal pain 1 0 0 0
Stoma oedema 0 1 0 0
Stroke 0 0 2 0
Serious adverse events are classified as complications leading to either death, threat to life, prolonged hospital stay,
readmission to hospital, or persistent disability. *Primary surgery was low anterior resection. †Comparison of
proportion of randomised patients with one or more serious adverse events (p=0·04, χ² test).
Table 2: Serious adverse events in the intention-to-treat population
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Results
152 eligible patients with early-stage rectal cancer were
identified at 21 UK sites; 14 recruiting sites opened during
year 1, and seven sites joined during year 2. 123 (81%)
patients entered the TREC study, whereas 29 declined
(figure 1). Between Feb 22, 2012, and Dec 19, 2014,
55 patients consented to randomisation at 15 sites
(appendix p 8); 27 patients were allocated to organ preser-
vation and 28 to radical surgery (figure 1). Cumulative
recruitment to the ran domised study was as follows:
18 patients at 12 months, 31 at 18 months, 39 at 24 months,
and 55 at 36 months. The date for final follow-up was
April 19, 2018. Randomised patients were generally well
matched in terms of age, sex, American Society of
Anesthesiologists (ASA) physical status classification, and
tumour stage (table 1). 68 patients were recruited to the
non-randomised registry at 17 sites, with organ preser-
vation preferred in 61 patients and radical total mesorectal
excision surgery in seven (figure 1). Non-randomised
patients who underwent organ preser vation were
generally older than randomised patients, more likely to
have life-limiting comorbidities, and more often had
T2 tumours (table 1). Six of 21 sites contributed non-
randomised patients only. All sites that recruited more
than three patients to TREC included patients for
randomisation (appendix p 8).
Compliance with the organ preservation treatment
strategy was high for both randomised (23 [85%] of
27 patients) and non-randomised groups (55 [90%] of 61;
table 1). Short-course radiotherapy was well tolerated, with
four (15%) of 27 patients having one or more grade 3
adverse event, of which diarrhoea was the most common
(appendix p 1). Three patients who were randomly
assigned to total mesorectal excision refused this
treatment allocation and instead received the organ
preservation treatment (protocol deviation); two of these
three patients reverted back to total mesorectal excision
following transanal endoscopic microsurgery due to the
presence of histopathological features con sidered high
risk for local recurrence (figure 1). Patients randomly
assigned to undergo primary total mesorectal excision
were most frequently reconstructed by low anterior
resection (23 [82%] of 28), with a temporary diverting
stoma (20 [71%] of 28; table 1). The rate of abdomino-
perineal excision with total mesorectal excision was 14%
(four of 28 patients) in the intention-to-treat population.
Serious adverse events were reported in four (15%) of
27 patients randomly assigned to organ preservation
versus 11 (39%) of 28 randomly assigned to radical surgery
(table 2; p=0·04, χ² test). One patient allocated to organ
preservation who had total mesorectal excision as the first
surgery (no transanal endoscopic microsurgery) died
following anastomotic leakage (ypT2N0). Serious adverse
events were reported for ten (16%) of 61 non-randomised
patients allocated to undergo organ preservation and
one (14%) of seven allocated to undergo total mesorectal
excision (table 2).
Organ preservation was achieved in 19 (70%) of
27 randomised patients and 56 (92%) of 61 non-randomised
patients (table 1). Three patients (staged ypT1sm2N0,
ypT1sm3N0, and ypT2N0) randomly assigned to organ
Randomised patients Non-randomised patients
Organ
preservation
(n=27)
Radical
surgery
(n=28)
Organ
preservation
(n=61)
Radical
surgery
(n=7)
TNM (y)pT stage
0 7 (26%) 0 20 (33%) 0
1 6 (22%) 14 (50%) 18 (30%) 1 (14%)
2 8 (30%) 13 (46%) 12 (20%) 6 (86%)
3 5 (19%) 1 (4%) 4 (7%) 0
x 0 0 1 (2%) 0
Clinical complete response with no surgery 1 (4%) 0 5 (8%) 0
All cases with a complete response 8 (30%) 0 25 (41%) 0
Kikuchi substaging of pT1 tumours
Submucosal tumour stage 1 2 (33%) 2 (14%) 7 (39%) 0
Submucosal tumour stage 2 1 (17%) 3 (21%) 6 (33%) 0
Submucosal tumour stage 3 3 (50%) 9 (64%) 5 (38%) 1 (100%)
TNM pN stage
0 3 (11%) 23 (82%) 0 7 (100%)
1 0 3 (10%) 0 0
2 0 1 (4%) 0 0
x 24 (89%) 1 (4%) 60 (100%) 0
Surgical resection margin <1 mm
Clear 23 (85%) 26 (93%) 49 (82%) 7 (100%)
Involved adenoma 0 1 (4%) 1 (2%) 0
Involved carcinoma (deep) 3 (11%) 1 (4%) 1 (2%) 0
Involved carcinoma (mucosal) 0 0 0 0
No surgery 1 (4%) 0 5 (8%) 0
Missing 0 0 4 (6%) 0
Positive lymphatic invasion 0 5 (18%) 1 (2%) 1 (14%)
Positive vascular invasion 2 (8%) 7 (25%) 4 (7%) 0
Tumour differentiation
Well or moderately differentiated 17 (63%) 26 (93%) 31 (51%) 7 (100%)
Poorly differentiated 2 (7%) 2 (7%) 3 (5%) 0
Pathological complete response 7 (26%) 0 19 (31%) 0
Complete response* 1 (4%) 0 5 (8%) 0
Tumour diameter, mm 3 (0–17) 10 (0–30) 4 (0–45) 8 (2–30)
Radiotherapy response (Dworak 5-point system)
Complete 7 (26%) 0 19 (31%) ··
Good 5 (19%) 2 (67%) 15 (25%) ··
Moderate 6 (22%) 0 7 (11%) ··
Mild 4 (15%) 0 4 (7%) ··
No surgery 1 (4%) 0 5 (8%) ··
Missing 3 (11%) 1 (33%) 5 (8%) ··
High-risk histopathological feature
present†
16/27 (59%) 24/28 (86%) 24/61 (39%) 7/7 (100%)
*Including pathological and clinical complete response. †Comparison of proportion of randomised patients with
one or more histopathological feature considered high risk for relapse following local excision (maximum tumour
diameter >30 mm, R1 resection, predominantly poor differentiation, presence of lymphatic or venous invasion and
depth of invasion ≥submucosal tumour stage 3; p=0·03, χ² test).
Table 3: Histopathological tumour characteristics
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preservation underwent total mesorectal excision by low
anterior resection following short-course radiotherapy
without undergoing transanal endoscopic microsurgery
(protocol deviations); in one, the transanal endoscopic
microsurgery equipment could not reach the tumour,
while in the other two the tumour was considered too large
for transanal endoscopic microsurgery. Early per-protocol
conversion from organ preservation to total mesorectal
excision followed histopathological evaluation of the
transanal endoscopic microsurgery specimen in five (19%)
of 27 patients (table 1); there was no evidence of residual
tumour in three patients, while two were staged ypT2N0.
Histopathological evaluation of randomised transanal
endoscopic microsurgery specimens revealed that
seven (26%) of 27 patients achieved a pathological
complete response, and one achieved a clinical complete
response (without transanal endoscopic microsurgery);
therefore, eight (30%) of 27 patients randomly assigned
to organ preservation achieved a complete response
(table 3). The remaining patients were staged pT1
(six [22%] of 27), pT2 (eight [30%] of 27), and pT3
(five [19%] of 27). Of the 26 patients who underwent
resection, resection margins were clear of cancer in
23 (88%) cases; three (12%) demonstrated adeno car-
cinoma up to 1 mm of the deep margin. Histopatho-
logical examination revealed that 14 (50%) of 28 patients
randomly assigned to total mesorectal excision (ie, who
did not undergo radiotherapy) were pT1, 13 (46%)
of 28 were pT2, and one (4%) of 28 was pT3 (table 3).
Microscopic lymph node metastasis was detected in
four (14%) of 28 patients. Resection margins were clear
of cancer (≥1 mm) in 26 (96%) of 27 patients who had
total mesorectal excision; an abdominoperineal excision
was R1 at the circumferential margin. Histopathological
features that would be considered high risk for local
tumour recurrence if present following transanal
endoscopic microsurgery alone were present in 24 (86%)
of 28 patients randomly assigned to radical surgery
Figure 2: Overall survival and disease-free survival for randomised and non-randomised populations
(A) Overall survival in the randomised population. (B) Overall survival in the non-randomised population. (C) Disease-free survival in the randomised population.
(D) Disease-free survival in the non-randomised population. SCRT=short-course radiotherapy. TEM=transanal endoscopic microsurgery.
Number at risk
(number censored)
Radical surgery
SCRT followed by TEM
28 (0)
26 (0)
28 (0)
25 (0)
27 (1)
24 (0)
25 (1)
19 (4)
19 (6)
15 (7)
10 (15)
6 (16)
AB
01 2 3 4 5
0
25
50
75
7 (0)
60 (0)
7 (0)
58 (1)
7 (0)
52 (2)
7 (0)
46 (6)
5 (2)
29 (22)
2 (5)
13 (37)
01 2 3 4 5
100
Overall survival (%)
Number at risk
(number censored)
Radical surgery
SCRT followed by TEM
28 (0)
26 (0)
27 (0)
25 (0)
26 (1)
22 (0)
23 (1)
17 (3)
17 (6)
13 (6)
10 (13)
4 (13)
C
01 2 3 4 5
0
25
50
75
100
Disease-free survival (%)
Kaplan-Meier overall survival estimates at 3 years:
Radical surgery 93% (95% CI 83–100)
Organ preservation 88% (95% CI 77–100)
p=0·35
Kaplan-Meier disease-free survival estimates at 3 years:
Radical surgery 85% (95% CI 73–100)
Organ preservation 76% (95% CI 60–95)
p=0·12
Kaplan-Meier disease-free survival estimates at 3 years:
Radical surgery 100%
Organ preservation 76% (95% CI 66–88)
p=0·12
+
++ ++ ++++++++++++++++++
++++ ++ +++++++++ +
+
Radical surgery
SCRT followed by TEM
Kaplan-Meier overall survival estimates at 3 years:
Radical surgery 100%
Organ preservation 86% (95% CI 76–96)
p=0·24
++ +++++
+++ ++
++
+
++++++++ +++++++++++++++++++++++++
Years
7 (0)
60 (0)
7 (0)
56 (1)
7 (0)
48 (1)
7 (0)
43 (3)
5 (2)
28 (17)
2 (5)
11 (32)
D
01 2 3 4 5
Years
+
++
++ ++++++++++++++++
+++
++ +++++
++
++
++ +++++
++
++
+
++++++++++++++++++++++++++
+++++
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9
(ie, who did not undergo radiotherapy), versus 16 (59%)
of 27 randomly assigned to organ preservation (p=0·03,
χ² test; table 3). 25 (41%) of 61 non-randomised patients
who underwent organ preservation achieved a complete
response, while high-risk histopathological features were
present in 24 (39%) of 61 (table 3).
Median follow-up of randomised patients was
4·28 years (IQR 3·27–5·02). There was no significant
dierence between randomised groups with respect to
either overall survival (hazard ratio [HR] 1·95 [95% CI
0·47–8·16]; p=0·35) or disease-free survival (2·32
[0·77–6·95]; p=0·12; figure 2). Local recurrence occurred
in three (11%) of 27 patients randomly assigned to organ
preservation and was isolated and technically salvageable
in two (7%) of 27 patients; however, severe cardiovascular
comorbidity prohibited surgical salvage in one individual
(appendix p 2). All three patients who developed local
recurrence had previously declined planned conversion
to total mesorectal excision despite having high-risk
transanal endoscopic microsurgery features: ypT3 in two
patients and R1 in one patient (appendix p 2). No
instances of local recurrence were recorded following
primary total mesorectal excision. Isolated systemic
metastasis developed in three (11%) of 27 patients
allocated to organ preservation versus two (7%) of 28
allocated to total mesorectal excision (appendix p 2).
Median follow-up of non-randomised patients was
4·07 years (IQR 3·19–4·69). Local recurrence occurred in
six (10%) of 60 non-randomised patients allocated
to organ preservation; recurrence was isolated in
three patients (appendix p 3). Systemic recurrence
developed in six (10%) of 60 non-randomised patients
allocated to organ preservation. The proportion of patients
free from local recurrence at 3 years following organ
preservation was 91% (95% CI 79–100) in the randomised
population and 91% (84–99) in the non-randomised
population (figure 3).
Patient allocation and patient-reported outcome com-
pletion rates for randomised patients are provided in the
appendix (p 9). Compliance with patient-reported out-
comes was good (78·5% median completion rate;
64·0% 36-month response rate), with no dierence in
response rates or missing items between groups. Key
patient-reported outcome data are presented for ran-
domised patients in figure 4. A full summary of each
patient-reported outcome item at each timepoint for
randomised patients is provided in the appendix (pp 4–5),
including a Bayesian model-based analysis (appendix p 6).
Baseline questionnaires were completed following ran-
domi sation and patients had knowledge of their treatment
allocation. Dierences at baseline favoured organ
preservation, for emotional (dierence of 11·6 points)
and role function (dierence of 10·3 points), body image
(dierence of 18·5 points), and health anxiety (dierence
of 21·3 points).
During follow-up, patients randomly assigned to total
mesorectal excision reported a deterioration in function
scores at 3 months, with moderate dierences between
the two randomised groups favouring organ preservation
for overall QOL, health anxiety, and physical, social, and
role function (figure 4A–D). Patients randomly assigned
to total mesorectal excision also demonstrated persistent
moderate or large deteriorations in overall QOL, health
anxiety, and role and social function, compared to
baseline. The low body image scores noted preoperatively
in the total mesorectal excision group at randomisation
deteriorated further at 3 months and subsequently did
not demonstrate recovery up to 36 months (figure 4E).
Patients randomly assigned to organ preservation did not
have any significant deterioration in pre-treatment QOL,
health anxiety, and function (physical, role, social,
emotional, and cognitive) over the 36-month study
Figure 3: Cumulative risk of any local recurrence compared to risk of any recurrence (local or distant) with
organ preservation therapy in intention-to-treat population
(A) Randomised population. (B) Non-randomised population.
Number at risk
(number censored)
Local recurrence
Any recurrence
26 (0)
26 (0)
25 (1)
25 (1)
23 (2)
22 (2)
18 (6)
17 (5)
14 (10)
13 (9)
4 (19)
4 (16)
A
01234 5
0
25
50
75
100
Recurrence-free survival (%)
Kaplan-Meier estimates at 3 years:
Local recurrence: 91% (95% CI 79–100)
Any (local plus distant) recurrence: 82% (95% CI 68–100)
Local recurrence
Any recurrence
+++++
++ ++ +
++++++ ++++ ++++++
++++ ++++
++
+++
Number at risk
(number censored)
Local recurrence
Any recurrence
60 (0)
60 (0)
58 (2)
56 (2)
50 (6)
48 (5)
45 (10)
43 (9)
29 (26)
28 (24)
12 (42)
11 (40)
B
01234 5
0
25
50
75
100
Recurrence-free survival (%)
Years
Kaplan-Meier estimates at 3 years:
Local recurrence: 91% (95% CI 84–99)
Any (local plus distant) recurrence: 86% (95% CI 77–95)
+++++ ++ ++++++++++++++++++++++++++++++
+++++
+++++
+
++
+
+++++ ++ +++++++++++++++++++++++++++++
+++++
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Figure 4: Change in EORTC
QLQ C30 and CR29 over time
for randomised patients
Data are mean (95% CI).
(A) Quality of life. (B) Physical
functioning. (C) Role
functioning. (D) Social
functioning. (E) Body image.
(F) Impotence. (G) Sexual
interest (female). (H) Sexual
interest (male). (I) Diarrhoea.
(J) Embarrassment about
bowel function. (K) Faecal
incontinence. (L) Stool
frequency. EORTC=European
Organisation for Research and
Treatment of Cancer.
A
Very poor: 0
10
20
Poor: 30
40
50
60
Moderate: 70
80
90
Very high: 100
Quality of life
B
Very poor: 0
10
20
Poor: 30
40
50
60
Moderate: 70
80
90
Very high: 100
Physical functioningSocial functioning
D
Very poor: 0
10
20
Poor: 30
40
50
60
Moderate: 70
80
90
Very high: 100
F
None: 0
10
20
Mild: 30
40
50
60
Moderate: 70
80
90
Severe: 100
Impotence
H
Very poor: 0
10
20
Poor: 30
40
50
60
Moderate: 70
80
90
Very high: 100
Sexual interest (male)
J
Embarrassment about bowel
function
C
Very poor: 0
10
20
Poor: 30
40
50
60
Moderate: 70
80
90
Very high: 100
Role functioning
E
Very poor: 0
10
20
Poor: 30
40
50
60
Moderate: 70
80
90
Very high: 100
Body image
G
Very poor: 0
10
20
Poor: 30
40
50
60
Moderate: 70
80
90
Very high: 100
Sexual interest (female)
I
None: 0
10
20
Mild: 30
40
50
60
Moderate: 70
80
90
Severe: 100
None: 0
10
20
Mild: 30
40
50
60
Moderate: 70
80
90
Severe: 100
None: 0
10
20
Mild: 30
40
50
60
Moderate: 70
80
90
Severe: 100
None: 0
10
20
Mild: 30
40
50
60
Moderate: 70
80
90
Severe: 100
Diarrhoea
K
Randomisation
3 months
6 months
12 months
24 months
36 months
Faecal incontinence
Visit
L
Randomisation
3 months
6 months
12 months
24 months
36 months
Stool frequency
Visit
Radical surgery
Short-course radiotherapy followed by transanal
endoscopic microsurgery
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11
period. Minimal change in body image scores occurred
in the organ preservation group and a large dierence
persisted compared with total mesorectal excision at
36 months (dierence of 25·7 points).
For symptom items, there were no baseline dierences
in score (figure 4F, I–L). Compared with the organ
preservation group, patients randomly assigned to total
mesorectal excision showed a deterioration at 6 months in
stool frequency, flatulence, incontinence, abdominal pain,
and embarrassment about bowel function. Dierences
persisted at 36 months for overall stool frequency
(dierence of 16·3 points; figure 4L), stool frequency at
night (dierence of 25·4 points), and embarrassment
about bowel function (dierence of 31·7 points; figure 4J)
in favour of organ preservation. There was also a moderate
increase from baseline diarrhoea scores at 36 months for
patients randomly assigned to total mesorectal excision
(increase of 13·4 points) in comparison with those
assigned to organ preservation (decrease of 6·8 points;
figure 4I). Notably, the scores in the total mesorectal
excision and organ preservation groups for faecal
incontinence and flatulence were relatively similar at
36 months, with both groups reporting relatively mild
symptoms (figure 4K). Urinary symptoms, including
frequency and incontinence, remained stable during
follow-up. Impotence scores deteriorated from baseline to
36 months (figure 4F) in both the randomised total
mesorectal excision group (increase of 32·1 points) and
the randomised organ preservation group (increase of
17·1 points). No marked changes occurred in female
sexual items (figure 4G). The benefit of organ preservation
in patient-reported outcome scores was supported by an
exploratory Bayesian model-based analysis (appendix p 6).
Higher probabilities towards benefit for organ preservation
were observed with organ preservation in many items at
baseline, as noted previously. Inferences were adjusted for
baseline values. At 36 months there was a 90% or greater
probability of superiority for organ preservation in many
patient-reported outcome items, including overall QOL;
role, social, and emotional function; body image; health
anxiety; diarrhoea; stool frequency; embarrassment about
bowel function; and urinary incontinence.
Discussion
The TREC study demonstrates that it is feasible to
randomly assign patients with early-stage rectal cancer to
two markedly dierent treatment options: multimodality
organ preservation treatment or total mesorectal excision
with no preoperative radiotherapy. 81% of eligible patients
approached for TREC took part and 36% were randomly
assigned, highlighting the acceptability of an organ
preservation approach if it is oered. All sites that
included more than three patients were able to randomly
assign patients, suggesting that clinical teams eectively
adapted conventional clinical consultations to randomly
assign patients to a study comparing two substantially
dierent treatment approaches. The high proportion of
non-randomised patients allocated to organ preservation
indicates that referral patterns to specialist organ
preservation practices were well established for frail,
elderly, comorbid, and stoma-averse individuals with
early-stage rectal cancer but underdeveloped in the wider
patient population considered suitable for total mesorectal
excision. Importantly, TREC was designed as a feasibility
study, to introduce and evaluate a protocolised, multi-
modality organ preservation approach. The primary aim
was to determine whether patients and clinicians would
support randomisation between radical surgery and
organ preservation, with secondary aims relating to
safety, ecacy, and acceptability—key elements to inform
the design of a future phase 3 trial.
Recent systematic reviews do not support adoption of
an organ preservation approach for treatment of early-
stage rectal cancer in fit patients because of insucient
high quality evidence.22,23 In comparison with previous
studies of chemoradiotherapy, the organ preservation
approach followed in the TREC study has a number of
strengths; we reported higher radiotherapy compliance
(99% in randomised and non-randomised patients) than
with chemo radiotherapy in previous studies (72–89%)
and low acute toxicity (grade 3 adverse events:
15% vs 10–42%), alongside favourable organ preservation
and complete response rates.10,11,24 The low acute toxicity
rate is not only reflected by clinician-reported monitoring
of serious adverse events, but importantly also by
prospective assess ment of patient-reported outcomes. As
a feasibility study, TREC was not powered to undertake
formal comparisons of specific long-term cancer outc-
omes, but the sample size allowed exploratory evaluation
of downstaging of histopathological features that would
be considered high risk for local recurrence if present
following transanal endoscopic micro surgery alone.8
Introduction of short-course radio therapy with an interval
of 8–10 weeks to transanal endoscopic microsurgery was
associated with significant tumour downstaging, corrobo-
rating an earlier report.25
To the best of our knowledge, we have, for the first
time, shown consistent indications of benefit in multiple
aspects of HRQOL and patient-reported toxicity with an
organ preservation approach compared with total
mesorectal excision alone, for up to 3 years. The risk of
serious adverse events was lower with an organ preser-
vation approach (15%) than with total mesorectal
excision (39%), which is the current standard of care.
The organ preservation rates observed with short-course
radiotherapy are equivalent to those observed in other
studies evaluating chemoradiotherapy and transanal
endo scopic microsurgery.10,24,26 Results from non-
randomised patients who underwent organ preservation,
who were a decade older with increased comorbidities,
were consistent with those obtained from the randomised
patient population and also in accordance with our
previous experience of using short-course radiotherapy
and transanal endoscopic microsurgery to achieve organ
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preservation in elderly and frail patients.14 Several studies
of organ preservation have recorded severe treatment-
related toxicities that might be poorly tolerated in an
older, frail patient population and so it was reassuring
that in our study the tolerability and toxicity of short-
course radiotherapy and transanal endoscopic micro-
surgery did not seem to be any worse for this group.24,27
The high rates of organ preservation for non-randomised
patients might reflect a clear reticence for total mesorectal
excision to be either oered or accepted. It is likely that
the threshold for converting patients to total mesorectal
excision in the non-randomised organ preservation
group was higher than in the randomised group as non-
randomised patients were generally older, with comor-
bidities. Notably, this discrepancy in conversion rates did
not lead to a marked increase in local recurrence. Future
studies need to address the best approach to manage the
decision to convert patients to total mesorectal excision.
Short-course radiotherapy and transanal endoscopic
microsurgery, after an interval of 8–10 weeks, led to
30% of randomised patients and 41% of non-randomised
patients achieving a complete response, which is similar
to studies of chemoradiotherapy where 40–45% of
patients achieved a complete response.26,27 A 10-week
interval from short-course radiotherapy to transanal
endoscopic microsurgery was chosen to balance the
potential benefits of waiting longer for optimal tumour
regression with the risk of disease progression through
treatment delay in a small proportion of patients who
might be resistant to radiotherapy. At the inception of the
TREC study the benefits of a good histopathological
tumour response were appreciated,28 and the available
evidence suggested that short-course radiotherapy
produced downstaging after an interval to surgery of
10 days or more;25 however, the optimal timing for
assessment of radiotherapy response was unknown.
TREC used transanal endoscopic micro surgery routinely,
as did other contemporary studies following reports of
extremely poor correlation between clinical and histo-
pathological staging in the context of a relatively short
interval between radiotherapy and radical surgery.29
Emerging data on the oncological safety of non-operative
approaches to rectal cancer treatment,30,31 combined with
the high complete response rates observed in this study
and others,10,24,26 suggest that the adoption of a watch-and-
wait strategy with selective use of transanal endoscopic
microsurgery is feasible with the aim of further reducing
treatment-related toxicity and improving HRQOL.16
However, the small sample size of TREC and the low
number of events preclude meaningful analysis of
oncological outcomes. We found no significant dierence
in either overall survival or disease-free survival between
patients randomly assigned to organ preservation versus
those randomly assigned to total mesorectal excision, in
line with the GRECCAR 2 study,11 with very wide
confidence intervals for the hazard ratios, reflecting the
small sample size and relatively small number of events.
A consistent proportion of patients relapse with distant
metastasis regardless of primary therapy.11,32 Isolated and
technically salvageable local recurrence was detected in
two (7%) of 27 patients randomly assigned to organ
preservation, each associated with strong histological
indicators for early conversion to total mesorectal excision
(ypT3R0 and ypT2R1), but the patients had declined early
conversion to total mesorectal excision and opted for
close observation. Local recurrence might have been
avoided with early conversion. These data emphasise the
need for a phase 3 trial to more precisely define the risks
and benefits associated with adopting an organ preser-
vation approach.
Despite the small patient numbers, the patient-reported
outcomes data reveal that an organ preservation approach
is associated with consistent improvements in multiple
symptom and function items 3 months after treatment,
with longer-term benefits for overall QOL, social function,
body image, and less embarrassment about bowel
function. We found no evidence of acute deterioration
in HRQOL or patient-reported toxicity with organ
preservation versus total mesorectal excision.10,15,24 This
exploratory analysis supports favourable longer-term
patient-reported outcome scores seen at 1-year, 2-year,
and 5-year follow-ups after organ preservation in various
trials.10,33 Our data provide an important contribution to
the literature due to the absence of published randomised
studies comparing patient-reported outcomes following
total mesorectal excision and organ preservation.
Although an unexpected finding, the lower baseline
mean scores in a number of function items for the radical
surgery group (completed after knowledge of randomi-
sation status) might reflect our impression that the
perceived risks of surgery in early-stage rectal cancer are
higher than patients desire.
As a feasibility study, TREC provides the justification
to further evaluate short-course radiotherapy and
transanal endoscopic microsurgery versus radical
surgery in a randomised setting. Although randomisation
was feasible, our recruitment rate across centres
indicated that recruitment to a future phase 3 trial
should be international. Around the same time as the
TREC study, a single-arm phase 2 trial done in the
Netherlands (CARTS) had evaluated chemoradiotherapy
followed by transanal endoscopic microsurgery.9 These
studies provided the basis for the design of an inter-
national phase 2/3 trial (STAR-TREC) designed to
randomly assign patients to radical surgery, organ
preservation with short-course radiotherapy, and organ
preservation with chemo radiotherapy.16 The external
pilot (phase 2) demonstrated that it was possible to
accelerate recruitment and the study progressed to
phase 3 in 2020. The adoption of a more selective use of
transanal endoscopic microsurgery, and a longer time
interval to assess response in STAR-TREC were based
on new data that became available after the completion
of recruitment to TREC.
Articles
www.thelancet.com/gastrohep Published online December 10, 2020 https://doi.org/10.1016/S2468-1253(20)30333-2
13
Our findings have some limitations: in a feasibility
study the overall numbers of randomised patients are
low and individual centres contributed relatively few
patients. However, recruitment of a randomised patient
population has considerable strengths and reduces many
sources of bias. This dataset will help inform the choices
of patients who would normally receive standard total
mesorectal excision and are considering the option to
undergo organ preservation instead. The non-randomised
registry primarily set out to describe the tolerability of
treatment and early outcomes for older individuals
considered to be at high risk for total mesorectal excision
as this population is generally under-represented in
rectal cancer trials. Although eligibility for inclusion was
identical to the randomised group, the results should not
be directly extrapolated to patients considered fit for total
mesorectal excision. It is nonetheless reassuring that
consistent trends were demonstrated across both ran-
domised and non-randomised populations following
novel organ preservation therapy with short-course
radiotherapy and transanal endoscopic microsurgery.
Although the use of routine transanal endoscopic micro-
surgery might now be considered over-treatment, at the
time of the design of TREC, there were little data to
support the long-term oncological safety of a watch-and-
wait strategy, and there were concerns that short-course
radiotherapy and treatment delay without transanal
endoscopic micro surgery represented significant under-
treatment.
We conclude that TREC provides evidence to support
further evaluation of organ preservation strategies that
incorporate short-course radiotherapy as an alternative to
radical surgery for early-stage rectal cancer. This is a
feasible and acceptable approach for patients. Further
evaluation of short-course radiotherapy is justified
because of the excellent compliance, low toxicity, benefits
in HRQOL, and high organ preservation rates observed in
TREC. It is important that organ preservation con tinues to
be evaluated in the context of well-conducted clinical
research to establish the oncological safety of this
approach.16
Contributors
SPB, DS-M, SK, IG, JH, PQ, and NPW made substantial contributions
to the conception and design of the trial. KB, KH, and NM contributed
to data analysis. AG contributed to data interpretation and data analysis.
All authors contributed to data collection. MK and LM provided
acquisition of data. SPB, DS-M, KH, MK, LM, PQ, NPW, AG, and KB
had full access to all trial data, vouch for the integrity of the data and
adherence to the study protocol, and had final responsibility for the
decision to submit the manuscript for publication.
Declaration of interests
SPB and DS-M report grants from Cancer Research UK, during the
conduct of the study. SPB reports personal fees from Intuitive Surgical,
outside the submitted work. KB reports equity ownership for
AstraZeneca and GlaxoSmithKline, personal fees from Eli Lilly and Invex
Therapeutics, reimbursement of costs from Merck, and employment by
UCB Pharma, outside the submitted work. JK reports grants from
Intuitive Surgical, outside the submitted work. PQ reports grants from
Cancer Research UK and Yorkshire Cancer Research, during the conduct
of the study. NPW reports grants from Yorkshire Cancer Research,
during the conduct of the study and personal fees from Eisai, outside the
submitted work. All other authors declare no competing interests.
Data sharing
Data sharing requests will be considered by the trial management group
on written request to trec@trials.bham.ac.uk. De-identified participant
data or other pre-specified data will be available, subject to a written
proposal and an agreed data sharing agreement.
Acknowledgments
The study was supported by a grant from Cancer Research UK
(CRUK/09/032) to SPB and DS-M. PQ and NPW were funded by a
programme grant from Yorkshire Cancer Research. PQ is a National
Institute for Health Research (NIHR) senior investigator. AG is funded
by a Cancer Research UK clinical trials fellowship (CRUK/28301).
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