ACPGBI CRC Part 4

Guidelines doi:10.1111/codi.
13705
Association of Coloproctology of Great Britain & Ireland

(ACPGBI): Guidelines for the Management of Cancer of the
Colon, Rectum and Anus (2017) – Multidisciplinary
Management
Simon Gollins*, Brendan Moran†, Richard Adams‡, Chris Cunningham§, Simon Bach¶,
Arthur Sun Myint**, Andrew Renehan††, Sharad Karandikar¶¶, Vicky Goh‡‡, Davide Prezzi§§,
Gerald Langman¶¶, Sam Ahmedzai*** and Ian Geh†††
*North Wales Cancer Treatment Centre, Glan Clwyd, UK, †Basingstoke & North Hampshire Hospital, Basingstoke,UK, ‡Cardiff University and Velindre
Cancer Centre, Cardiff, UK, §John Radcliffe Hospital, Oxford, UK, ¶University of Birmingham and Queen Elizabeth Hospital,Birmingham, UK,
**Clatterbridge Hospital, Wirral, UK, ††University of Manchester and Christie Hospital, Manchester, UK, ‡‡King’s College and Guy’s & St Thomas’
Hospital, London, UK, §§Guy’s & St Thomas’ Hospital, London, UK, ¶¶Birmingham Heartlands Hospital, Birmingham, UK, ***University of Sheffield,
Sheffield, UK, and †††Queen Elizabeth Hospital, Birmingham, UK
4.1 Multidisciplinary Management of Rectal Cancer 4.1.7 Future directions in the management of rectal cancer
4.1.1 Definition of rectal cancer 4.1.7.1 Improving the efficacy of CRT
4.1.2 Introduction 4.1.7.2 Neoadjuvant chemotherapy
4.1.3 Early rectal cancer (cT1-2 N0 M0, MRF ve) 4.1.7.3 Watch and wait
4.1.3.1 Clinical assessment of rectal SPECC lesions
4.2 Systemic Chemotherapy for Colorectal Cancer
4.1.3.2 Excised pT1 rectal cancer polyps
4.2.1 Adjuvant chemotherapy
4.1.3.3 Standard TME for early rectal cancer
4.2.1.1 General recommendations
4.1.3.4 Local excision of early rectal cancer
4.2.1.2 Lymph node positive (stage III) disease
4.1.3.5 Subsequent management after local excision
4.2.1.3 Lymph node negative (stage I and II) disease
4.1.3.6 Preoperative radiotherapy for early rectal cancer
4.2.1.4 Adjuvant chemotherapy in rectal cancer
4.1.3.7 Contact x-ray brachytherapy (Papillon) and high
4.2.2 Systemic chemotherapy for advanced disease
dose-rate brachytherapy
4.2.2.1 Locoregional recurrence
4.1.4 Resectable rectal cancer not involving the mesorectal
4.2.2.2 Unresectable primary disease
fascia (cT2-4[peritoneum] N0-2 M0, MRF ve)
4.2.2.3 Operable metastatic disease
4.1.4.1 Introduction
4.2.2.4 Inoperable metastatic disease
4.1.4.2 Efficacy of SCPRT and long course CRT
4.2.2.5 Addition of biological therapies
4.1.4.3 Efficacy of SCPRT vs long course CRT
4.1.4.4 Preoperative vs postoperative CRT 4.3 Supportive and Palliative Care
4.1.4.5 Early toxicity of SCPRT and long course CRT 4.3.1 Definitions
4.1.4.6 Late toxicity and quality of life following SCPRT or 4.3.2 Supportive care in the oncology setting
long course CRT and surgery 4.3.3 Supportive care after cancer treatment
4.1.4.7 Selection of patients for preoperative radiotherapy 4.3.4 Palliative care in advanced disease and end of life care
4.1.5 Rectal cancer threatening, involving or beyond the 4.3.5 Provision of specialist palliative care services and hospices
mesorectal fascia (cT3-4 N0-2 M0, MRF +ve) 4.3.6 Last days of life
4.1.6 Low rectal cancer
adenocarcinoma with a distal margin at or below 15 cm

4 Multidisciplinary Management
from the anal verge, measured by rigid sigmoidoscopy.
Standard anatomical texts put this at the level of the
4.1 Multidisciplinary Management of Rectal Cancer
third sacral vertebra (Williams & Warwick, 1980) but it
4.1.1 Definition of rectal cancer is generally agreed by surgeons that the rectum starts at
A definition of rectal cancer is important for optimal the sacral promontory (UKCCCR, 1989).
planning of neoadjuvant therapy and surgical strategy. Whilst there remains debate about the proximal limit
Anatomically the rectum is distal to the sigmoid colon of the rectum, there is increasing recognition of the
and its upper limit is the termination of the sigmoid complexity of management of low rectal cancers. The
mesocolon. A commonly used definition is an Low Rectal Cancer Development Program (LOREC)
has defined a ‘low’ rectal cancer as an MRI-based
Correspondence to: Dr Ian Geh, Queen Elizabeth Hospital, Birmingham, UK.
E-mail: [email protected] anatomical definition of an adenocarcinoma with its
Colorectal Disease ª 2017 The Association of Coloproctology of Great Britain and Ireland. 19 (Suppl. 1), 37–66 37
Guidelines S. Gollins et al.
lower edge, at or below the origin of the levators at the (Mawdsley et al., 2005) and poorer overall survival
pelvic side-wall. This usually corresponds to a measure- (OS) (Wibe et al., 2002), even after TME (Marijnen
ment of within 6 cm of the anal verge (PELICAN Can- et al., 2003). The CRM can be involved by direct or
cer Foundation; Salerno et al., 2006a,b). discontinuous tumour spread, lymph node spread, lym-
phovascular spread and perineural spread (Nagtegaal &
A low rectal cancer should be defined as an MRI- Quirke, 2008). The risk of CRM involvement is also
based anatomical definition of an adenocarcinoma related to the quality of TME surgery (Nagtegaal et al.,
with its lower edge, at or below the origin of the 2002; Quirke et al., 2009). Local recurrence can also
levators at the pelvic side-wall. This usually corre- occur despite a clear CRM, possibly from lymphatic
sponds to a measurement of within 6 cm of the anal spread to pelvic side-wall nodes (Ueno et al., 2007). In
verge. patients undergoing surgery, with or without preopera-
Recommendation grade D tive radiotherapy (RT), the combination of CRM and
lymph node status may be a more effective discriminator
4.1.2 Introduction of prognosis than TNM staging (Nagtegaal et al.,
The Clinical Guidelines published by NICE (CG 131) in 2007).
November 2011 defined three broad categories of rectal Magnetic resonance imaging (MRI) is the current
cancer, relating to the risk of pelvic local recurrence (LR) gold standard imaging modality for pre-treatment
following treatment (Table 1) and represent a useful assessment of CRM involvement (MERCURY Study
starting point for considering treatment strategy Group, 2006; The Royal College of Radiologists,
(National Institute for Health and Clinical Excellence, 2014). High resolution MRI is essential for optimal
2011). The increasingly widespread use of total mesorec- staging and to guide management decisions (Al-Sukhni
tal excision (TME), involving meticulous dissection of et al., 2012; Battersby et al., 2015). A well-performed
the mesorectal fascia (MRF) (Heald et al., 1982) has had MRI can identify the extent of extramural spread (T3a-
a major impact in reducing LR of rectal cancer. The ‘low’ d), which has a greater predictive value for nodal
and ‘moderate’ LR groups can be considered as ‘re- involvement than assessment of lymph node size per se.
sectable’ or ‘operable’, because the surgical MRF resec- Lymph node status remains difficult to assess pre-treat-
tion margin is not threatened. The ‘high’ LR risk group ment with poor sensitivity and specificity, although sen-
is at significant risk of surgical MRF resection margin sitivity may be increased by the addition of diffusion
being involved, unless some form of tumour downstag- weighted MRI sequences (Heijnen et al., 2013). Assess-
ing can be achieved preoperatively. ment of extramural vascular invasion (EMVI) by MRI
In addition, both the ‘moderate’ and the ‘high’ LR risk may define a subgroup at high risk of local and distant
groups are at significant risk of developing distant meta- recurrence (Al-Sukhni et al., 2012; Battersby et al.,
static disease, which is the main cause of death. These con- 2015; Chand et al., 2015). This has been highlighted
siderations drive the current treatment and clinical by the MERCURY study; independent MRI-defined
research strategies described below (Table 4.1). risk factors were EMVI, tumours <4.0 cm from the anal
An involved circumferential resection margin verge and anterior tumours. A systematic review and
(CRM), defined as tumour ≤1 mm from the surgical meta-analysis (Al-Sukhni et al., 2012) concluded that
resection margin is an important, independent predictor MRI specificity was significantly higher for prediction of
of LR (historically up to 85%) (Nagtegaal et al., 2002; CRM involvement (94%, 95% CI 88–97) than for T
Quirke et al., 1986), distant metastases (DM) (75%, 95% CI 68–80) and N stage (71%, 95% CI 59–
Table 4.1 Risk assessment for local pelvic recurrence according to MRI findings (National Institute for Health and Care Excel-
lence, 2011)
Risk of pelvic local recurrence Characteristics of rectal tumours predicted by MRI
Low (resectable) cT1 or cT2 or cT3a and

no lymph node involvement
Moderate (resectable) any cT3b or greater, in which the potential surgical margin is not threatened or
any suspicious lymph node not threatening the surgical resection margin or
the presence of extramural vascular invasion
High (borderline resectable a threatened (<1 mm) or breached resection margin or
or unresectable i.e. threatened low tumours encroaching onto the inter-sphincteric plane or with levator involvement
or involved CRM)
38 Colorectal Disease ª 2017 The Association of Coloproctology of Great Britain and Ireland. 19 (Suppl. 1), 37–66
S. Gollins et al. Guidelines
81). Standardized proforma based reporting (Taylor after local excision’ (Morino et al., 2015). ‘Conserva-
et al., 2010) may improve staging consistency nationally tive’ definitions such as this limit the application of rec-
and increase minimum dataset collection to 100% as tal sparing treatment, whereas broader definitions
shown in the Royal College of Radiologists/NCIN increase the likelihood of under-treating patients. New
CASPAR project (Tait, 2015). multimodal treatment strategies may allow safe expan-
sion of the application of rectal preserving therapy,
All patients with rectal cancer being considered while stratification through molecular profiling may per-
for curative surgery should have locoregional staging sonalize care and reduce risk of under-treatment.
by high resolution MRI pelvis, unless there are con- Rectal neoplasms present as a spectrum, ranging
traindications. from benign to malignant. The ‘Significant Polyp Early
Recommendation grade B Colorectal Cancer’ (SPECC) programme, supported by
ACPGBI aims to improve outcomes by reducing over
MRI should be reported as per Royal College of treatment of benign lesions and under treatment of can-
Radiologists’ guidance [BFCR(14)2]. Proforma cer. A significant rectal neoplasm is defined as a sessile
based reporting can standardize and improve com- polyp >20 mm in diameter, which is morphologically
pleteness of minimum staging data. aberrant, where polypectomy may be unsafe or result in
Recommendation grade C incomplete excision (Moran & Dattani, 2016).
Staging investigations should be reviewed by the Explain to patients and their family members or
Colorectal MDT in the context of the patients’ clini- carers (as appropriate) that due to insufficient good
cal history and findings, histology and results of quality clinical evidence, the optimal treatment for
other investigations to decide on the subsequent early rectal cancer is uncertain.
management of the patient. Recommendation grade D
Recommendation grade D
Offer patients with early rectal cancer the opportu-
Colorectal MDTs should correlate pre-treatment nity to participate in clinical trials (if eligible) that
radiological staging with post-surgical pathological evaluate the treatment options for early rectal cancer.
stage. Recommendation grade D
4.1.3.1 Clinical assessment of rectal SPECC lesions
Radiotherapy and chemotherapy for rectal cancer There are particular pitfalls associated with the evalua-
should only be given after discussion and agreement tion of rectal SPECC lesions and it is important that
by the Colorectal MDT, within facilities conforming MDT’s demonstrate appropriate expertise in the clinical,
to national guidelines. radiological and histopathological assessment of these
Recommendation grade C cases. Evaluation should optimally include:
1 Detailed visualization of the lesion using magnified
4.1.3 Early rectal cancer endoscopy, washing the tumour to characterize its
(cT1-2 N0 M0, MRF ve) dimensions, morphology, margins and pit patterns.
Introduction of population-based bowel screening, com- Biopsies should be targeted at the most suspicious part
bined with improved access to diagnostic services has of the lesion for malignancy.
resulted in a downward shift in rectal cancer stage at pre- 2 Documentation of the location of the rectal SPECC
sentation. The term early rectal cancer (ERC) encom- lesion in relation to the upper border of the anal
passes a set of macroscopic and microscopic features that canal (anorectal ring) and quadrant of the bowel wall
characterize tumours with an excellent prognosis follow- (anterior, posterior left lateral, right lateral) using a
ing standard surgery. Such tumours may also be amen- combination of digital rectal examination and either
able to local techniques that aim to preserve the rectum flexible or rigid proctoscopy. Placement of a tattoo
and reduce treatment-related morbidity. in the rectum is generally not recommended.
Optimal management of ERC is yet to be deter- 3 Imaging of the lesion including MRI pelvis, en-
mined; in fact there is no consensus as to the definition dorectal ultrasound (ERUS). MRI will locate the rec-
of ERC. A recent EAES/ESCP consensus conference tal lesion, in relation to the pelvic floor, anterior
stated that ‘ERC is a rectal cancer with good prognostic organs, peritoneum and MRF, and characterize any
features that might be safely removed preserving the T3 extension, EMVI or lymph nodes seen within the
rectum, and that will have a very limited risk of relapse mesorectum.
4 ERUS is the most accurate modality to discriminate excellent prognosis. With no further treatment, the risks
between T1 and T2 rectal cancer, but is highly oper- are of luminal recurrence and progression of involved
ator dependent and is not universally available (Ash- undetected mesorectal lymph nodes. Current guidelines
raf et al., 2012). consider carcinoma within 1 mm of the resection mar-
5 It should be appreciated that obtaining definitive his- gin as being involved but recent evidence suggests that
tological diagnosis through biopsy may be con- the risk of recurrence is highest only when tumour is
founded by either sampling error (superficial biopsies present at the resection margin or within diathermized
or sampling of an adenomatous component) or tissue (Brown et al., 2016). Risk factors for lymph node
inter-observer variation in histopathological interpre- involvement include extent of submucosal invasion,
tation. Where malignancy is clinically suspected or intramural lymphovascular invasion (LVI) and poor dif-
biopsies report diffuse high-grade dysplastic changes, ferentiation. However, these features are often difficult
then specialist evaluation should be considered. to assess due to destruction of important anatomical
An MRI performed prior to local excision of all rec- landmarks by the tumour and surgical factors such as
tal SPECC lesions is recommended. A significant pro- piecemeal resection and diathermy artefact. Evidence of
portion (20–40%) of SPECC lesions with ‘benign’ complete macroscopic removal by endoscopic assess-
histology on initial biopsy are subsequently found to ment is important as pathological assessment of piece-
contain cancer within the lesion on complete lesion meal specimens may be equivocal.
excision, and interpretation of MRI performed immedi- Patients found to have pT1 rectal cancer polyps fol-
ately after full thickness local excision is often hampered lowing local excision should be routinely staged with
by surgical artefact and the presence of reactive lymph pelvic MRI, unless this was performed prior to the pro-
nodes. A pre-treatment MRI also serves as an important cedure. Staging for distant metastases by CT should be
reference, for comparison with follow up imaging, to routinely performed as for all colorectal cancers.
enable early detection of luminal or lymph node recur-
rence. Piecemeal resection of significant rectal neoplasms
In summary, the assessment, decision-making and (SPECC lesions) should be avoided, as this can pre-
treatment of rectal SPECC lesions are complex and clude comment on the completeness of excision and
continue to evolve. Expertise in imaging, pathology complicates assessment of prognostic features.
and surgery are essential to deliver a safe and effective Recommendation grade C
ERC service and concentration of specialist services will
facilitate this. For these reasons, NICE (CG 131) rec- 4.1.3.3 Standard TME for early rectal cancer
ommended formation of early rectal cancer MDTs. Standard primary radical TME is an oncologically effec-
tive treatment for early stage rectal cancer; only 2% and
Patients with significant rectal neoplasms (SPECC 12% of patients experience local or distant failure
lesions) should be adequately assessed prior to any respectively (Peeters et al., 2007). However, radical
definitive treatment. resection of a rectal tumour requires a permanent stoma
Recommendation grade C in approximately 25% of cases while many more patients
have a temporary stoma, many of which are not
Patients with significant rectal neoplasms (SPECC reversed (Healthcare Quality Improvement Partnership,
lesions), which may be suitable for rectal preserving 2015). Six-month mortality following radical curative
treatment, should have access to an early rectal can- surgery for rectal cancer is 4.6% for patients aged 65–
cer MDT for further assessment and management. 74 years rising to 13.4% for patients aged 75–84 years
Recommendation grade D (Kapiteijn et al., 2001; Rutten et al., 2008). Recog-
nized long-term morbidities of radical TME include
4.1.3.2 Excised pT1 rectal cancer polyps impaired anal sphincter function, pelvic nerve damage
A pT1 malignant rectal polyp is an adenocarcinoma aris- (male and female urinary and sexual dysfunction) and
ing within a pre-existing adenoma in which tumour cells small bowel adhesion formation.
have breached the muscularis mucosa, extending into
the submucosa but not the muscularis propria (Williams 4.1.3.4 Local excision of early rectal cancer
et al., 2013). This is often an unexpected finding fol- Early rectal tumours may be locally excised through the
lowing snare polypectomy or endoscopic mucosal resec- anus with low morbidity and mortality using Transanal
tion on lesions presumed to be benign. Endoscopic Microsurgery (TEM) (Bach et al., 2009;
Almost all locally removed malignant rectal polyps Cataldo et al., 2005) allowing for preservation of the
are stage I cancers and generally associated with an rectum and its function. Full thickness excision offers
accurate pathological assessment and potential cure for factors, with significantly higher LR rates of 15–30%
many pT1 and pT2 cancers. Morbidity and mortality following TEM alone.
after local excision are lower than after radical resection, The risk of LR following local excision has to be
with a reported 30-day mortality of 0.5% compared with considered within the context of alternative treatment
2.4% in a study of 5305 patients (You et al., 2007). by radical surgery and its morbidity and mortality risks.
However, several case series have reported LR rates For most patients, a risk of LR <10% is acceptable but
ranging from 5% to 28% for pT1 cancers and 11% to 45% many will accept a risk of 30% to avoid the conse-
for pT2 cancers following transanal excision (Endreseth quences of radical surgery (Johnston et al., 2013).
et al., 2005; Garcia-Aguilar et al., 2000). These series Patient co-morbidity and life expectancy are important
predate accurate pre-treatment MRI staging, which may considerations in decision-making and there is no clear
identify and exclude a proportion of high-risk patients. answer, although data are emerging on the efficacy of
These series also predate widespread adoption of ‘op- multimodal treatment of frail patients with ERC (Smart
timized’ endoscopically-assisted TEM or transanal mini- et al., 2016). Decisions need to be tailored to individ-
mally invasive surgery (TAMIS) and include patients ual patients, although clinicians should leave patients in
treated using per-anal excision. Per-anal excision is asso- no doubt what is the standard of care for this stage of
ciated with higher recurrence rates, whilst endoscopi- disease, offering the optimum chance of cure.
cally-assisted techniques are broadly similar in efficacy The Association of Coloproctology of Great Britain
(Barendse et al., 2012; Moore et al., 2008). and Ireland introduced guidance for the use of local
Presence of untreated involved mesorectal lymph excision for ERC (Williams et al., 2013). These include:
nodes is another cause of local disease failure following • T1 cancer
local excision. The risk of lymph node involvement • Maximum diameter <3 cm
increases with depth of bowel wall penetration; for pT1 • No lymphatic or vascular invasion
tumours the risk ranges from 1% to 3% for Kikuchi • Well or moderately differentiated
sm1, 8% for sm2 and 23% for sm3 (Tytherleigh et al., When these criteria are adhered to, lymph-node
2008). Overall incidence of lymph node metastasis involvement and LR rates of less that 10% can be
ranges from 6% to 14% for pT1 tumours, 17% to 23% expected in this population. For similar stage of cancer,
for pT2 tumours, and 49% to 66% for pT3 tumours radical surgery is associated with mortality in 3–5%, major
(Ricciardi et al., 2006). morbidity in 20–40% and likelihood of stoma of 40%
Tumour implantation is another potential source of (Marijnen et al., 2005). The impact of radical surgery for
luminal recurrence and may explain why LR rates are early stage disease on long-term quality of life is well
often higher following local excision, than implied by established (Doornebosch et al., 2007). This introduces
the risk of lymph node metastasis. Prospectively col- the concept of trade-off in ERC where improved func-
lected data from the UK ACPGBI TEM Collaboration tional outcome and quality of life are traded off against
(n = 424) (Bach et al., 2009) (Table 4.2) identified potentially poorer oncological outcome. It can be a com-
depth of invasion, maximum tumour diameter and the plex model for decision-making in ERC management,
presence of LVI as independent predictors for LR. The balancing optimal oncological treatment with patient
lowest LR rate of <5% was seen in well or moderately wishes to minimize the adverse effects of treatment.
differentiated pT1 sm1 lesions, without intramural LVI,
measuring <3 cm. However, the majority of pT1-2N0 Local excision with curative intent should be
rectal cancers had one or more of the identified risk offered through endoscopic means (TEM, TEO,
Table 4.2 Rates of LR 36 months following full thickness TEM of well or moderately differentiated tumours stratified according
to depth of invasion, tumour diameter and the presence of LVI (Bach et al., 2009).
Maximum Tumour Diameter (cm)
Depth of invasion LyV ≤1 1.1–2 2.1–3 3.1–4 4.1–5 5.1+
pT1 sm1 3.0 3.6 4.4 5.4 6.6 8.1

+ 5.2 6.4 7.7 9.4 11.4 13.7
pT1 sm2/3 10.5 12.7 15.3 18.5 22.1 26.4
+ 17.8 21.4 25.5 30.3 35.7 41.8
pT2 9.8 11.9 14.3 17.3 20.7 24.7
+ 16.7 20.0 23.9 28.5 33.7 39.5
TAMIS) in preference to traditional per-anal exci- number of patients treated in this way, by placing
sion. emphasis on pre-treatment assessment by expert
Recommendation grade C MDTs.
Recommendation grade C
Local full thickness excision with negative mar-
gins of pT1 sm1 tumours (well or moderately differ- After local excision alone, patients should be fol-
entiated) leads to very low local recurrence rates and lowed up under a defined surveillance protocol to
may be considered standard of care. detect recurrent disease at the earliest stage possible.
Recommendation grade C Current recommendations are 3–6 monthly MRI,
CEA and flexible sigmoidoscopy.
4.1.3.5 Subsequent management after local excision Recommendation grade C
Following local excision pathology review, patients
deemed be at an unacceptably high risk of LR should 4.1.3.6 Preoperative radiotherapy for early rectal
be considered for completion radical surgery. This cancer
approach is believed to offer good oncological out- Maas et al. (2010) reviewed 2323 patients treated with
comes (Bach et al., 2009; Hahnloser et al., 2005) and CRT demonstrating a clear correlation between the clini-
is quite different to salvage surgery for recurrent disease, cal T-stage and the pCR rate (cT1: 58%, cT2: 28%, cT3:
where more extensive multimodality treatment may be 16% and cT4: 12%). The success rate of an organ preserv-
necessary. Surgical outcomes are similar to radical sur- ing approach that incorporates radiotherapy will be
gery performed as the first procedure in terms of mor- dependent on the tumour stages treated. Combining
bidity, mortality and length of hospital stay (Hompes radiotherapy with TEM surgery may: (a) remove minimal
et al., 2013). Anecdotally it is often technically more residual primary tumour, (b) effectively treat microscopic
difficult that primary TME and permanent stoma rates mesorectal lymph node metastases, (c) facilitate local
may be higher compared to use of TME as primary excision with clear margins and (d) reduce the likelihood
treatment (van Gijn et al., 2013). There is no consensus of tumour implantation at surgery. However, limited
on timing of completion surgery after local excision, prospective evidence exists to guide the use of radiother-
which can vary from a few weeks to several months. apy and local excision as curative treatment for ERC.
Complications of local excision, such as wound dehis- The ACOSOG Z6041 (Garcia-Aguilar et al., 2012)
cence cause inflammation of the mesorectum and adher- and CARTS (Verseveld et al., 2015) trials investigated
ence of the mesorectal fascia to the pelvic side-wall. the safety and effectiveness of CRT and transanal exci-
Postoperative radiotherapy may be considered for sion for treatment of ERC. In addition, Appelt et al.,
‘high-risk’ patients who are unable or unwilling to (Appelt et al., 2015) studied the effectiveness of CRT
undergo TME surgery. However, the benefit of adju- combined with brachytherapy. Each of these studies
vant radiotherapy in reducing recurrence risk following reported high rates of organ preservation combined with
local excision remains unproven (Greenberg et al., low rates of LR, but all observed marked treatment-
2008; Rackley et al., 2016) and requires further high related toxicities that negated any benefit. A retrospec-
quality prospective research. tive analysis of a cohort of UK patients (n = 62) with
In view of the increased risk of LR following local ERC, who were predominantly unfit for TME, treated
excision alone, patients must be offered regular surveil- with short course radiotherapy (SCRT) 25 Gy in 5 frac-
lance to facilitate detection of recurrent disease at the tions and TEM reported high pCR rates (32%), low
earliest opportunity, in order to maximize the success of recurrence rates and low toxicity (Smart et al., 2016).
radical salvage surgery. Early detection can mitigate the The TREC trial evaluated the feasibility of randomizing
impact of LR (De Graaf et al., 2009). Although the fit patients with ERC between standard TME and rectal
optimal surveillance strategy remains undefined, endo- preservation using SCRT followed by TEM, is due to
scopic assessment at 3–6 monthly intervals coupled with report results shortly. The international STAR-TREC
MRI pelvis at 3–6 monthly intervals and CT to detect trial will randomize patients with ERC into one of three
distant metastases at 12 monthly intervals for 3–5 years arms; (a) standard surgery, (b) rectal preservation with
is generally used. mesorectal CRT and selective transanal excision or (c)
rectal preservation with mesorectal SCRT and selective
After local excision, patients with unfavourable transanal excision. This study aims to recruit over 400
pathology should be offered completion surgery patients in the UK, Netherlands and Denmark to deter-
with anterior resection or abdominoperineal resec- mine if TME surgery results in demonstrably lower pel-
tion. Every effort should be made to minimize the vic relapse rates than the rectal sparing techniques.
In summary, multimodal treatment of ERC using (76% v 44%; P = 0.004), with no difference in morbidity,
CRT combined with either TEMS or brachytherapy has LR, and 2-year OS (Gerard et al., 2004). A randomized
resulted in unacceptable toxicities, defeating the concept trial (OPERA) evaluating whether a CXB boost improves
of rectal sparing surgery. These treatments may be taken organ preservation when compared to an EBRT boost,
forward in clinical studies such as STAR-TREC, which has started to recruit in France and plans are in progress
will introduce new mesorectal irradiation techniques for to open this trial in the UK (Gerard et al., 2011).
ERC, designed to reduce treatment related toxicities. The role of preoperative high dose-rate (HDR)
The application of radiotherapy in ERC remains the brachytherapy was evaluated by NICE (IPG 531), stat-
subject of clinical trials. ing that current evidence on the safety of this treatment
for rectal cancer and its efficacy in reducing tumour size
Local excision after SCRT or CRT may be consid- appears adequate (National Institute for Health and
ered in patients with early rectal cancer who are unfit Clinical Excellence, 2015c) but there is no evidence
or refuse standard resectional surgery and appear to that it provides additional benefit when used as a boost
have residual disease. The role of preoperative radio- to EBRT. However, rectal HDR brachytherapy can be
therapy and local excision in patients with early rectal offered for bulky residual rectal tumours following
cancer, who are fit for TME remains the subject of EBRT, in patients not suitable for surgery or CXB. Rec-
clinical trials. tal HDR brachytherapy can also be offered for recurrent
Recommendation grade C tumours following surgery or EBRT for symptom con-
trol (Hoskin et al., 2004).
4.1.3.7 Contact x-ray brachytherapy (Papillon) and
high dose-rate brachytherapy Contact x-ray brachytherapy (CXB) is considered
An alternative strategy for treating ERC is with 50 KV a treatment option for patients with early rectal can-
contact x-ray brachytherapy (CXB), also known as the cer as an alternative to TEM, for patients considered
Papillon technique, on small lesions (<3 cm), either alone not suitable for surgery or for patients considered
(cT1 tumours) or combined with a course of pelvic suitable for surgery, but who decline operation. This
external beam radiotherapy (EBRT) for cT2 tumours or should only be offered with the appropriate arrange-
cT1-2 tumours >3 cm (Hershman et al., 2003). Several ments in place for clinical governance, consent, audit
studies have reported promisingly low LR rates (Sun and research, as recommended by NICE IPG 532.
Myint et al., 2007). Since introduction of CXB to the Recommendation grade B
UK in 1993 (Sun Myint, 2007), although its use remains
limited, several UK centres are being equipped with a 4.1.4 Resectable rectal cancer not involving the
new generation of CXB machines (Gerard et al., 2011). mesorectal fascia
NICE (IPG 532) has recommended that in patients for (cT2-4[peritoneum] N0-2 M0, MRF ve)
whom surgery is not considered suitable, current evidence
on the efficacy and safety of CXB for early-stage rectal 4.1.4.1 Introduction
cancer is adequate to support its use. However in patients Two meta-analyses (Camma et al., 2000; Colorectal
who are considered suitable for surgery, but choose not Cancer Collaborative Group, 2001), a systematic review
to have an operation, although the evidence on the safety (Munro & Bentley, 2002) and a Cochrane review
of CXB is adequate, the evidence on efficacy is inadequate (Wong et al., 2007) of randomized trials comparing the
(National Institute for Health and Clinical Excellence, addition of radiotherapy (RT) to standard surgery con-
2015b). Patient selection to undergo CXB should be sistently demonstrate a reduction of LR risk, with both
through a colorectal MDT, which includes a clinical pre- and postoperative RT, reduction of rectal cancer
oncologist and a colorectal surgeon with expertise in local deaths but not improvement of OS. Radiotherapy deliv-
excision techniques. Patients should be informed of all ery techniques in the early trials were sub-optimal by
available different treatment options to enable shared today’s standards, including use of large parallel-
decision making before proceeding with treatment. Data opposed fields, which were associated with increased
on patients undergoing CXB should be submitted to a non-cancer deaths (Colorectal Cancer Collaborative
NICE-supported audit database, based at Guildford. Group, 2001).
There are few randomized trial data on the use of Preoperative RT to the pelvis can either be delivered
CXB alone in patients with ERC (Lindegaard et al., by conventional fractionation (long course RT) of 45–
2007). One randomized trial evaluating the role of CXB 50.4 Gy in 25–28 fractions over 5 weeks or by a short
boost following EBRT reported a significant increase in course of preoperative RT (SCPRT) of 25 Gy in 5 frac-
sphincter preservation compared to the no boost group tions over 1 week.
Long course RT is often used to shrink or ‘down- 22921 were randomized to receive adjuvant 5FU in a
stage’ the tumour prior to surgical resection and can be 2 9 2 trial design, whereas all patients in FFCD 9203
made more effective by adding synchronous fluropyrim- received adjuvant 5FU. TME was not a protocol
idine-based chemotherapy, also known as chemoradio- requirement in either trial. Both trials demonstrated
therapy (CRT). Surgery is usually performed 6– that synchronous 5FU with long course RT significantly
10 weeks after completion of CRT, to allow time for reduced LR compared to RT alone (8–9% vs 17%).
maximal response to occur. In contrast, SCPRT delivers Compliance with adjuvant 5FU was poor (only 43%
a lower dose of radiation using larger doses per fraction, received the protocol dose in EORTC 22921). Despite
over a short duration followed by immediate surgery, an improvement in pCR rate and reduced LR the addi-
which is scheduled for the following week. The short tion of chemotherapy in EORTC 22921 and FFCD
interval between commencing radiotherapy and surgery 9203 did not translate into an improvement in either 5-
(usually ≤10 days) does not allow for any significant year distant metastases or OS.
tumour shrinkage or downstaging. More recently, oral fluorpyrimidines (capecitabine
and UFT) has replaced intravenous 5FU in various indi-
4.1.4.2 Efficacy of SCPRT and long course CRT cations and tumour sites. Capecitabine has been
The Swedish Rectal Cancer trial (n = 1168) defined clini- demonstrated to be non-inferior to infusional 5FU in
cal practice in the 1990s (Folkesson et al., 2005; Swedish preoperative CRT regimens for rectal cancer (Hofheinz
Rectal Cancer Trial, 1997). It compared the addition of et al., 2012; O’Connell et al., 2014).
SCPRT prior to surgery with surgery alone and reported
fewer LRs and improved 5-year OS with SCPRT. Since 4.1.4.3 Efficacy of SCPRT vs long course CRT
then significant advances in the multidisciplinary manage- Two randomized trials compared SCPRT with long
ment of rectal cancer have resulted in a marked reduction course CRT in resectable rectal cancer. The Polish trial
of LR after TME alone, with centres reporting LR rates (n = 316) compared SCPRT followed by immediate
as low as 3–6% (Heald & Ryall, 1986; Martling et al., TME with CRT followed by TME at 4–6 weeks in
2000). This raised the question of whether there patients with low (palpable) rectal cancers (Bujko et al.,
remained any benefits for SCPRT in addition to TME. 2004). Approximately one third of patients in each arm
Two trials were designed to address this question: underwent APE with no difference in sphincter preser-
the Dutch Colorectal Cancer Group trial (n = 1861) vation rate, which was the primary end point. Although
(Kapiteijn et al., 2001; Peeters et al., 2007) and the pathological complete response (pCR) was more com-
UK MRC CR07/NCIC-CTG C016 trial (n = 1350) mon with long course CRT (15% vs 1% for SCPRT),
(Sebag-Montefiore et al., 2009). Patients were random- this did not translate into improved LR (14% vs 9%),
ized between SCPRT followed by immediate surgery or DFS or OS (Bujko et al., 2006).
initial surgery followed by selective postoperative RT The Trans-Tasman Radiation Oncology Group
(Dutch trial) or CRT (CR 07) in patients found to have (TROG) 01.04 trial (n = 326) compared SCPRT, imme-
a CRM ≤1 mm. Unlike the Dutch trial, TME was not a diate TME and 6 cycles adjuvant 5FU with CRT, TME
protocol requirement in CR 07 but was performed in at 4–6 weeks and 4 cycles adjuvant 5FU in patients with
93%. The use of SCPRT halved the risk of LR from ultrasound or MRI-staged T3N0-2M0 rectal cancer
10.9% to 5.6% (P < 0.001) and from 11.5% to 4.7% at (Ngan et al., 2012a). There was no difference in 3-year
5-years (HR 0.39, P < 0.0001) respectively. There was LR (7.5% vs 4.4%, P = 0.24), 5-year distant metastases
no difference in OS in both trials, although neither was (27% vs 30%, P = 0.92) or OS (74% vs 70%, P = 0.62).
statistically powered to detect a difference. The com-
monest cause of death was distant metastatic disease. 4.1.4.4 Preoperative vs postoperative CRT
Although patients found to have an involved CRM Meta-analysis of radiotherapy trials in rectal cancer sug-
following SCPRT and TME remain at significant risk of gested that the benefit of postoperative RT is smaller
LR (Marijnen et al., 2003), further radiotherapy given than with preoperative RT in terms of local disease con-
postoperatively is contraindicated. The risk of long-term trol, but with no significant effect on either cancer
radiation toxicity associated with this approach is con- specific survival or OS (Colorectal Cancer Collaborative
siderable (over 84% at 5-years) (Svoboda et al., 1999). Group, 2001).
The EORTC 22921 trial (n = 1011) (Bosset et al., The German GAO/ARO/AIO-94 trial (n = 823)
2005; Bosset et al., 2006) and the FFCD 9203 trial compared preoperative long course CRT, TME at
(n = 733) (Gerard et al., 2006) compared preoperative 6 weeks and adjuvant 5FU with TME, postoperative
long course CRT with long course RT in resectable CRT and adjuvant 5FU in patients with resectable uT3-4
(cT3-4) mid and low rectal cancers. Patients in EORTC rectal cancers. Preoperative CRT was more effective with
fewer LRs (6% vs 13%; P = 0.006) and was associated differences were seen in QOL between irradiated and
with lower acute and late toxicity (12% vs 24%; P = 0.01) non-radiated patients (Marijnen et al., 2005). The pres-
(Sauer et al., 2004). However, there was no difference in ence of a stoma did not significantly affect health-related
distant metastases, DFS or OS (Sauer et al., 2012). QOL. The CR 07 trial showed that the main adverse
effect in male patients was sexual dysfunction. The main
4.1.4.5 Early toxicity of SCPRT and long course CRT cause for this was the surgery, but was made worse with
Early trials of SCPRT using large parallel-opposed radia- the addition of SCPRT (Stephens et al., 2010). A recent
tion fields reported increased postoperative mortality, report did not find any increase in second malignancy in
especially in elderly patients (Cedermark et al., 1995). clinical trials of pelvic radiotherapy (Wiltink et al., 2015).
More recent trials of SCPRT using 3- or 4-fields fol- The German GAO/ARO/AIO-94 trial reported fewer
lowed by immediate surgery have not demonstrated any late grade 3–4 toxicities with CRT given preoperatively
overall increased risk (Marijnen et al., 2002; Sebag- compared to postoperatively (14% vs 24%, P = 0.01),
Montefiore et al., 2009; Swedish Rectal Cancer Trial, including chronic diarrhoea, small bowel obstruction and
1997). However, if surgery is performed beyond anastomotic strictures (Sauer et al., 2004).
11 days of commencing SCPRT, there is evidence that When comparing SCPRT with long course CRT, the
postoperative morbidity and mortality is increased par- Polish trial did not identify any difference in patient
ticularly in older patients (Glimelius, 2014; van den reported anorectal or sexual function (Pietrzak et al.,
Broek et al., 2013). With long course CRT, there does 2007) and the TROG 01.04 trial did not identify any
not appear to be increased postoperative mortality or difference in RTOG/EORTC late radiation toxicity
complications (Sauer et al., 2004). (5.8% vs 8.2%, P = 0.53) (Ngan et al., 2012a) or long-
Use of SCPRT can impair perineal wound healing term QOL (Ngan et al., 2012b).
after APE (35% vs 22% in CR 07) but in patients under-
going anterior resection, anastomotic leak rate is not 4.1.4.7 Selection of patients for preoperative
significantly increased (9% vs 7% in CR 07) (Sebag- radiotherapy
Montefiore et al., 2009). Acute grade 3–4 toxicity of The routine use of MRI for locoregional staging has
long course CRT is significantly higher than SCPRT significantly improved the ability of the Colorectal
(18.2% vs 3.2% in Polish trial) (Bujko et al., 2004). MDT to predict the T and N stage and more impor-
SCPRT can occasionally cause acute lumbosacral tantly, identify patients at risk of an involved CRM
plexopathy, which is associated with early onset pain or (Beets-Tan et al., 2001; Brown et al., 2003). The
discomfort in the gluteal region and radiating down the MERCURY trial demonstrated that MRI accurately pre-
legs (Frykholm et al., 1993; Marijnen et al., 2002). dicts a clear CRM (MERCURY Study Group, 2006).
Reporting lymph nodes with heterogeneous signal
4.1.4.6 Late toxicity and quality of life following intensity and irregular border as involved, rather than
SCPRT or long course CRT and surgery based on size alone increases accuracy (Smith & Brown,
There are currently more data published on late mor- 2008). However, more than 50% of involved lymph
bidity following SCPRT and surgery than following nodes measure <5 mm in diameter and will not be visi-
long course CRT (Glimelius, 2006). Recognized late ble on MRI (Wang et al., 2005). Newer diffusion
adverse events include bowel obstruction, bowel dys- weighted MRI sequences may detect more lymph nodes
function presenting as faecal incontinence to gas, loose but does not reliably characterize their nature (Heijnen
or solid stool, evacuation problems or urgency, urinary et al., 2013). MRI identifies EMVI (Smith et al., 2008)
and sexual dysfunction, pelvis and femoral neck frac- and predicts the depth of extramural invasion (MER-
tures and increased second malignancies (Birgisson CURY Study Group, 2007), both proven to correlate
et al., 2007; Dahlberg et al., 1998; Gilbert et al., with prognosis. Significant data now exists to suggest
2015). Fewer late adverse events were reported in more that EMVI as identified on baseline MRI, on MRI after
recent studies, which may be due to improved radio- neoadjuvant therapy or pathologically acts as a poor
therapy techniques and smaller volumes irradiated. prognostic factor for recurrence risk (Al-Sukhni et al.,
The Dutch trial reported that irradiated patients were 2012; Battersby et al., 2015; Chand et al., 2015).
more likely to experience faecal incontinence (62% vs If disease does not involve or threaten the MRF,
38%) and have less satisfaction with bowel function, both SCPRT and long course CRT reduce the relative
which impacted on daily activities. However there were risk of LR by approximately 50% and appear equally
no differences in stoma function or urinary symptoms effective. However, the absolute benefit remains small
(Peeters et al., 2005). SCPRT had a negative effect on (5–6%) with the number needed to treat (NNT) rang-
sexual function in males and females although no ing from 17 to 20, and the majority of patients receive
futile treatment. In addition, there is no effect on risk If a patient requires radiotherapy in addition to
of distant metastases or improvement of OS. surgery, this should be given preoperatively. Patients
Presence of involved mesorectal lymph nodes and who have undergone initial surgery and deemed to
EMVI are associated with a higher risk of LR, despite be at high risk of LR, such as involved CRM,
achieving a clear CRM. Both Dutch TME and CR 07 although not ideal, should be considered for postop-
trials reported significant LR reduction in stage III rec- erative CRT. A dose of at least 45 Gy in 25 frac-
tal cancers from 19% to 9% (P < 0.001) and 15.4% to tions with synchronous 5FU is recommended.
7.4% (HR 0.46; P < 0.001) with SCPRT respectively Recommendation grade A
(NNT 10–12). The Dutch TME trial also reported
improved 10-year OS with SCPRT in stage III patients 4.1.5 Rectal cancer threatening, involving or beyond
(50% vs 40%; P = 0.032). the mesorectal fascia
Therefore, accurate initial staging of rectal cancers is (cT3-4 N0-2 M0, MRF +ve)
key to selecting patients for the most appropriate preop- Prior to the widespread availability of MRI, the Second
erative treatment strategy and to avoid unnecessary use MRC Rectal Cancer trial (n = 279) randomized patients
of radiation in as many as possible, as this increases late with clinically fixed or tethered cancers to long course RT
morbidity with no clinically meaningful benefit. The followed by surgery 4 weeks later or surgery alone and
majority of patients with resectable rectal cancer not demonstrated a reduction of LR with RT (Medical
involving the mesorectal fascia (cT2-4[peritoneum] N0- Research Council Rectal Cancer Working Party, 1996).
2 MRF ve), particularly if mrT2-3a-b N0, will be at a The ability of MRI to accurately assess the proximity
very low risk (<3%) of LR following surgery alone pro- of the primary rectal cancer, tumour deposits and EMVI
viding the surgeon achieves a good quality TME with a to the MRF enables patients who are at risk of an
clear CRM (Marijnen et al., 2002; Quirke et al., 2009; involved CRM and consequent high-risk of local disease
Taylor et al., 2011). failure to be identified prior to surgery. Such patients
can then be offered neoadjuvant treatment in an
With optimal MRI staging, most patients with attempt to improve their outcomes. In this situation,
resectable rectal cancer not involving the mesorectal the use of preoperative long course CRT with a concur-
fascia (cT2-4[peritoneum] N0-2 M0, MRF ve) rent single-agent fluoropyrimidine of either intravenous
should be amenable to surgery alone. 5FU or oral capecitabine, followed by surgery 6–
Recommendation grade B 12 weeks later is recommended.
This strategy is based on data demonstrating signifi-
Patients with resectable rectal cancer not involving cant tumour shrinkage and downstaging on imaging
the mesorectal fascia (cT2-4[peritoneum] N0-2 M0, and histological assessment, when compared to that
MRF ve) with MRI features suggesting a higher risk predicted on clinical staging. There are presently no
of LR (T3c disease, mesorectal lymph node involve- randomized trial results on this specific group of
ment or EMVI) may be considered for preoperative patients, although the UK ARISTOTLE trial
RT to reduce local recurrence. In this situation both (ISRCTN09351447) is ongoing.
SCPRT followed by immediate surgery or long course The significance of MRI-detected mesorectal lymph
CRT followed by delayed surgery are acceptable. nodes lying close to the MRF and its impact on choice
Recommendation grade A of neoadjuvant therapy and LR remains contentious.
The presence of these findings in the absence of other
In patients receiving SCPRT, surgery should be high-risk features, is unlikely to result in an involved
performed within 11 days from the first fraction of CRM (Shihab et al., 2010) providing a good quality
radiotherapy to minimize risk of complications. If TME is achieved.
surgery cannot be performed within this interval An audited series of 88 such patients whose disease
and the patient has already commenced radiother- was ≤1 mm from the MRF on pre-treatment MRI
apy, surgery should be delayed beyond 4 weeks. demonstrated that overall only 76% were able to
Recommendation grade B undergo surgery with achievement of a clear CRM and
the overall pCR rate was 15% (Kulkarni et al., 2008). A
In patients receiving long course CRT, surgery retrospective pooled analysis of data from 7 UK centres
should be scheduled 6–10 weeks after completion of of 680 patients with clinically fixed or MRI MRF
CRT. A dose of at least 45 Gy in 25 fractions with syn- involved rectal cancers reported 63% achieving a clear
chronous 5FU or oral capecitabine is recommended. CRM following long course CRT (Sebag-Montefiore
Recommendation grade B et al., 2005).
The use of SCPRT followed by a 4–12 week delay to Radiotherapy should be planned and delivered
surgery can result in downstaging in rectal cancers of any according to standardized protocols, such as the UK
initial stage, with pCR rates ranging from 9% in locally ARISTOTLE trial protocol.
advanced disease (Radu et al., 2008) to 35% in early can- Recommendation grade D
cers (Bujko et al., 2009). In patients who require down-
staging treatment but are not able to tolerate CRT, 4.1.6 Low rectal cancer
SCPRT with delayed surgery is an accepted option Approximately 40% of all rectal cancers originate in the
(Bujko & Kolodziejczyk, 2008; Pettersson et al., 2012). lower rectum, commonly defined as a tumour with its
Several phase II trials in this group of patients incor- lower edge at, or below, the origin of the levators at the
porated irinotecan or oxaliplatin with 5FU-based CRT pelvic sidewall, usually corresponding to within 6 cm of
have reported clear CRM resections in 70–80% and the anal verge (www.lorec.nhs.uk). There is general
pCR in 15–20%. The current UK ARISTOTLE trial is acknowledgement that low rectal cancers are amongst
comparing the combination of irinotecan with capecita- the most challenging for patients, and for colorectal
bine CRT vs capecitabine CRT. In the UK the National MDTs, and for surgeons. They have worse oncological
Cancer Research Institute (NCRI) Radiotherapy Trials outcomes with a higher risk of CRM involvement and
Quality Assurance Team (RTTQA) designs and imple- tumour perforation at surgery and consequently, a
ments quality assurance (QA) programmes for all NIHR higher risk of LR and poorer survival compared with
CRN Clinical Research Portfolio trials that include a mid and upper rectal cancers (Nagtegaal et al., 2005).
radiotherapy component which is aimed at improving This is partly due to tapering of the mesorectum leading
quality and minimizing variations between participating to ‘waisting’ of the specimen and compromise of resec-
centres (http://www.rttrialsqa.org.uk). The radiother- tion margins. The anorectum is anatomically and func-
apy planning protocol within the UK has been devel- tionally complex. The technical challenge is that there is
oped by consensus for the phase III ARISTOTLE trial a conflict between achieving oncological clearance and
and adopted as the standard of care by most centres. In sphincter preservation to maintain function.
the future, intensity modulated radiotherapy (IMRT) Curative management for a low rectal cancer often
using volumetric modulated arc therapy (VMAT) is entails the need for a permanent stoma. Even if the
likely to be able to deliver treatment more efficiently, sphincters do not require surgical excision, the combi-
adopting similar volumes but with potentially more nation of commonly-used neoadjuvant therapy, and a
small bowel sparing. subsequent very low anastomosis often results in sub-
optimal anal function, and on occasion complete incon-
Patients with rectal cancer threatening, involving tinence, with a major impact on quality of life (How
or beyond the mesorectal fascia (cT3-4 N0-2 M0, et al., 2012). The external sphincter and puborectalis
MRF +ve) should be considered for preoperative RT are contiguous with the levator complex with very little
to improve the likelihood of achieving a clear CRM. surrounding mesorectum at this level (none at the distal
In this situation the most effective strategy is long extremity) to act as a barrier to cancer spread. Thus an
course CRT, followed by surgery 8–12 weeks later. advanced rectal tumour may invade the external sphinc-
A dose of at least 45 Gy in 25 fractions with syn- ter/levator complex and require complete excision of
chronous 5FU or oral capecitabine is recommended. the sphincter complex and levator by an abdominoper-
Recommendation grade B ineal excision (APE).
MRI can effectively visualize the lower rectum, and
Patients with rectal cancer threatening, involving surrounding structures, enabling effective decision-mak-
or beyond the mesorectal fascia (cT3-4 N0-2 M0, ing and personalized, precision surgery (Salerno et al.,
MRF +ve) and are not sufficiently fit to tolerate long 2009; Shihab et al., 2009; Shihab et al., 2011) and facil-
course CRT, should be offered SCPRT followed by itating appropriate selection for neoadjuvant therapy to
delayed surgery 8–12 weeks later, to allow time for improve curative resection rates (Burton et al., 2006).
maximal tumour shrinkage. Published reports suggest suboptimal surgery in
Recommendation grade C patients undergoing APE (Marr et al., 2005; Nagtegaal
et al., 2005) and a suggestion of overtreatment by neoad-
Patients should be restaged with MRI pelvis and juvant radiotherapy for some lower-risk patients (Moran
CT chest, abdomen and pelvis towards the end of et al., 2014). Simultaneously evidence has suggested that
the 8–12 week interval between completion of RT APE surgical technique can be improved by a focused
and planned surgery. approach, with wider resection margins, in what is now
Recommendation grade C termed an extralevator APE (ELAPE) (West et al., 2010).
The Low Rectal Cancer Development Programme For a low rectal cancer lying above the level of
(LOREC; www.lorec.nhs.uk) was attended by 147 out the anal sphincter, which is not threatening
of 164 (89.6%) MDT’s from 151 English NHS Trusts (>1 mm) the levator muscle or MRF, the mesorec-
(some Trusts have two Colorectal MDT’s) and key mes- tal plane can be used. A TME and coloanal anasto-
sages published (Moran et al., 2014). mosis may be feasible. If this is not feasible, an
There are no specific low rectal cancer trials, but sub- APE (conventional or intersphincteric) should be
set analysis of phase III studies suggests an approximate performed.
halving of LR. There is no strong evidence to support Recommendation grade B
the use of radiotherapy to increase sphincter salvage and
additionally, adverse effects on sphincter function need For a low rectal cancer lying above the level of
to be considered. Based on the above considerations, the anal sphincter, which is ≤1 mm from the levator
the randomized phase II UK SAILOR trial (ISRCTN muscle or MRF or invading the levator, an ELAPE
02406823) is currently exploring the feasibility of tak- should be performed. ELAPE is an anatomical term
ing patients with a low rectal cancer requiring an APE, implying surgical excision on the inferior aspect of
with a predicted negative surgical resection margin, the levator and the extent of levator excision is tai-
straight to surgery without preoperative CRT. lored to the patient and the tumour. This is gener-
The key aim of surgical intervention is R0 resection, ally preceded by long course CRT and an 8–
that is, a clear distal and circumferential margin in the 12 week gap.
resected specimen. Surgical resection of an advanced low Recommendation grade B
rectal cancer generally requires an ELAPE but an under-
standing of the anatomy, and the terminology, translates For a low rectal cancer lying at the level of the
into the fact that ELAPE may be performed with the sphincter, which is involving the submucosa only or
patient in the supine or prone jack-knife position (Moore the inner layer of the muscularis propria, the
& Moran, 2012). In addition an inter-sphincteric APE is mesorectal plane can be used, continuing inferiorly
an excellent oncological procedure if the external sphinc- into the intersphincteric plane as an APE (conven-
ter is not involved and where reconstruction is deemed tional or intersphincteric).
not feasible or safe. The entire hindgut is removed and the Recommendation grade B
circular external sphincter is apposed with interrupted
sutures, with resulting superior healing rates in most For a low rectal cancer lying at the level of the
patients, even in those who have had preoperative therapy. sphincter, which involves the full thickness of
Perineal wound healing is a problem after APE and there the muscularis propria or extends into or beyond
is evidence to support an adjunct to aid perineal wound heal- the intersphincteric plane to involve the external
ing, including options such as a greater omental graft (Butt sphincter, an ELAPE should be performed. This is
et al., 2013), a biological mesh (Marshall et al., 2012) or a generally preceded by long course CRT and an 8–
plastic surgical flap (Barker et al., 2013; Holm et al., 2007). 12 week gap.
There is on-going debate as to the need for these interven- Recommendation grade B
tions to address the perineal wound due to a lack of informa-
tion on the outcomes in large numbers of patients. 4.1.7 Future directions in the management of rectal
The following recommendations are in addition to cancer
relevant recommendations in the previous 2 sections Although the use of preoperative radiotherapy, with or
(4.1.4 and 4.1.5): without synchronous chemotherapy reduces local pelvic
recurrence, this has not been shown to reduce distant
The overall treatment strategy of low rectal cancers, metastatic relapse or improve OS. With increasing surgi-
in particular the optimal surgical approach should be cal quality through the use of TME and ELAPE, where
informed by detailed pelvic MRI assessment. appropriate, plus selective preoperative radiotherapy,
Recommendation grade B local pelvic recurrence is now markedly reduced com-
pared to historical reports, leaving distant metastatic
The use of SCPRT and immediate surgery or relapse as the main cause of death. Strategies to improve
long course CRT followed by surgery at 8–12 weeks outcomes include increasing the efficacy of CRT and
or no preoperative radiotherapy in low rectal cancers introducing neoadjuvant chemotherapy before any other
should be based on the existing NICE 2011 clinical treatment, to address the issue of micrometastases as
guidelines risk groups. early as possible in the treatment pathway (Gollins &
Recommendation grade B Sebag-Montefiore, 2016).
4.1.7.1 Improving the efficacy of CRT compared to conventional adjuvant chemotherapy, with
A review of phase II and III studies identified an overall a minimal risk of progression during treatment. The
pCR rate of 13.5 per cent using a single agent fluoropy- EXPERT and EXPERT-C trials used 12 weeks of oxali-
rimidine as a radiation sensitizer (Hartley et al., 2005). platin/capecitabine (OxCap), then CRT, then surgery.
It was suggested that the pCR rate could be increased A radiological response rate was seen in 70%, with only
with increased doses of RT and the addition of a second two patients (1%) progressing (Chau et al., 2006; Chua
cytotoxic drug. With regard to the latter strategy several et al., 2010; Dewdney et al., 2012). The GCR3 phase
promising phase II trials incorporating irinotecan have II trial (n = 108) of pre- vs postoperative OxCap
been reported (Gollins et al., 2011) but as yet no demonstrated lower toxicity and better compliance
phase III trials although the ongoing UK phase III when given preoperatively (Fernandez-Martos et al.,
ARISTOTLE trial (ISRCTN09351447) is examining 2010). The CRUK-funded phase II COPERNICUS
the addition of irinotecan to capecitabine in MRI- pilot trial (n = 60) showed that 8 weeks oxaliplatin/flu-
defined unresectable/borderline resectable rectal cancer. orouracil (OxFU) prior to SCPRT and surgery is feasi-
However, five randomized phase III trials have been ble with a high response rate (Gollins et al., 2015).
reported adding oxaliplatin to either 5FU or capecita- A Polish phase III trial compared standard long
bine during CRT: STAR-01 (Aschele et al., 2011), course CRT followed by surgery, with SCPRT, then
ACCORD 12/0405 PRODIGE 2 (Gerard et al., 6 weeks of FOLFOX neoadjuvant chemotherapy then
2012), CAO/ARO/AIO-04 (Rodel et al., 2015), surgery in 541 patients with fixed T3 or T4 tumours
NSABP R04 (Allegra et al., 2014) and PETACC-6 (MRI staging was not mandated) (Bujko et al., 2016).
(Schmoll et al., 2013). Only two have published long- Although there was no difference in R0 resection rate
term outcomes as full-length reports, the French (the primary end point), local and distant failure or
ACCORD12 (Gerard et al., 2012) and German AIO-04 DFS, a marginally statistically significant improvement in
(Rodel et al., 2015). The ACCORD 12 trial (n = 598) overall survival was reported in the neoadjuvant
compared 45 Gy with capecitabine against 50 Gy with chemotherapy arm (73% vs 65%; P = 0.046).
oxaliplatin and capecitabine and reported no difference Two further phase III trials employed a similar
in pCR rate (the primary endpoint), 3-year DFS or OS design to the Polish study although with differing dura-
(Gerard et al., 2012). The German CAO/ARO/AIO- tions of chemotherapy following SCPRT in the experi-
04 trial (n = 1265) compared long course 5FU-contain- mental arm, 18 weeks in the Dutch/Scandinavian
ing CRT followed by 16 weeks of 5FU-based postoper- RAPIDO trial (NCT01558921, recruitment completed
ative chemotherapy, with or without oxaliplatin. The in mid 2016) and 12 weeks in the Chinese STELLAR
addition of oxaliplatin increased DFS from 71.2% to trial (NCT02533271, recruitment ongoing). The US
75.9% (HR 0.79, P = 0.03) (Rodel et al., 2015). How- PROSPECT (NCT01515787) is comparing 12 weeks
ever the benefit of intensified CRT is not known due to of FOLFOX alone followed by surgery (although poorly
the addition of oxaliplatin to both the concurrent and responding patients also receive preoperative long
adjuvant chemotherapy components and the use of dif- course CRT) and a further 12 weeks of postoperative
ferent 5FU dose intensities between treatment arms. FOLFOX, against standard long course CRT, surgery
The NSABP R-04 (Allegra et al., 2014) and and 16 weeks of adjuvant FOLFOX.
PETACC 6 trials (Schmoll et al., 2013), reported in
abstract form, do not describe any improvement in can- 4.1.7.3 Watch and wait
cer outcomes for their primary end point (LR and DFS It is well established that 10–20% of patients achieve
respectively) and data are awaited from the STAR 01 pCR following preoperative CRT. If such patients can
trial (Aschele et al., 2011). be accurately identified following CRT, it may be possi-
At present, no reliable predictive biomarkers of ble to avoid surgery (Maas et al., 2015). However, no
response to long course CRT have been identified, randomized controlled trial data currently exist. Pub-
which have subsequently been verified as usable in rou- lished retrospective series demonstrate considerable
tine clinical practice (Glynne-Jones et al., 2013; heterogeneity in patient selection, imaging modalities,
Glynne-Jones & Harrison, 2011). However, this is cur- CRT regimens, methods of defining clinical complete
rently an active area for research. response (cCR) and follow-up protocols (Glynne-Jones
& Hughes, 2012).
4.1.7.2 Neoadjuvant chemotherapy Habr-Gama’s group in Brazil have carefully followed
A number of phase II trials have evaluated the addition patients presenting with digitally palpable low rectal
of neoadjuvant chemotherapy to long course CRT, sug- cancers who have a cCR following 5FU-containing long
gesting higher compliance and lower acute toxicity course CRT. In a recent report of 70 patients with
tumours within 7 cm of the anal verge, 47 (68%) had a 4.2.1 Adjuvant chemotherapy
cCR and 50% of long-term responders avoided surgery
4.2.1.1 General recommendations
(Habr-Gama et al., 2013). However, it is unclear how
The choice of adjuvant therapy should be made jointly
these single-institution results in predominantly smaller,
by the patient and the supervising oncologist, taking
low rectal cancers might be applicable to more advanced
into account the patient’s risk factors for recurrence,
cancers of the mid or upper rectum with presumed
their co-morbidities and performance status, any specific
greater incidence of nodal metastases in the larger
contraindications, side-effect profile of the agent(s) and
tumours.
the patient’s preference for method of administration.
A recently reported propensity score-matched cohort
analysis of 129 patients with rectal cancer achieving a
4.2.1.2 Lymph node positive (stage III) disease
cCR in North West UK (OnCoRe) who were watched
It has been convincingly demonstrated that adjuvant
within a more intensive follow up protocol, showed 44
fluoropyrimidine chemotherapy improves disease-free
(34%) had local re-growth, with 36 of 41 (88%) with
survival (DFS) and overall survival (OS) in stage III
non-metastatic re-growth being surgically salvaged.
(Dukes’ C) colon cancers (National Institute for Health
There was no difference in 3-year OS between the
and Care Excellence, 2011). By extrapolation, current
matched cohorts. By contrast, patients managed by watch
national guidelines (NICE, ESMO etc) also recommend
and wait had a better 3-year colostomy-free survival (74%
the use of adjuvant chemotherapy in rectal cancer.
vs 47%, HR 0.445, P < 0.0001) (Renehan et al., 2015).
Oral forms of 5FU, namely uracil-tegafur (UFT) and
A Royal Marsden study (NCT01047969) examined
capecitabine have been shown to be as effective as intra-
the safety of deferred surgery in patients achieving a
venous (i.v.) modulated 5FU and are licensed for adju-
cCR and a Danish Colorectal Cancer Group prospective
vant therapy (Lembersky et al., 2006; Twelves et al.,
observational study in patient with low rectal cancer
2012). Many patients prefer oral chemotherapy for its
(NCT00952926) is assessing the frequency of LR after
convenience. Although the toxicity profile is altered, the
CRT in patients with low rectal cancer. In addition the
overall level of toxicity is similar to i.v. modulated 5FU.
European Network for Watchful Waiting has been
NICE (TA 100) has approved oral capecitabine for
started in Denmark ([email protected]).
adjuvant use (National Institute for Health and Care
A watch and wait policy in a patient achieving radio-
Excellence, 2006).
logically and endoscopically confirmed cCR is presently
The addition of oxaliplatin to fluoropyrimidine
considered a trade off between oncological and func-
chemotherapy in stage III patients reduces recurrence risk
tional outcomes. Patients need to be aware this
further. Three randomized phase III trials (MOSAIC,
approach remains a new management under evaluation
NSABP C-07, XELOXA) comparing oxaliplatin/5FU
and that this should not be offered as an intention to
(Andre et al., 2004; Yothers et al., 2011) and oxali-
treat. There remains some confusion within the litera-
platin/capecitabine (Haller et al., 2011) with modulated
ture as some treatment series include ‘near’ cCR (which
5FU monotherapy have demonstrated consistent results
is not clearly defined), and managed by local surgery,
(total 6624 patients). NICE (TA 100) has approved oxali-
rather than watch and wait only.
platin for this indication (National Institute for Health
and Care Excellence, 2006). Long-term follow up data
In selected patients with complete clinical
from the MOSAIC trial has shown a 4.2% OS improve-
response (cCR) after preoperative long course CRT,
ment in stage III but no difference in stage II patients
a watch and wait approach can be considered. A
(Andre et al., 2009). However, the benefits of adding
defined surveillance protocol, such as used in
oxaliplatin should be weighed against the side-effects and
OnCoRe, is necessary to identify local disease re-
acceptability of the regimen. In general, a higher risk,
growth at the earliest stage possible.
otherwise fit patient should be offered an oxaliplatin-
Recommendation grade C
based combination as their risk of death from cancer sig-
nificantly outweighs their risk of death from other causes.
4.2 Systemic Chemotherapy for Colorectal Cancer The elderly population are identified to be under-
represented in randomized controlled trials, as the med-
Chemotherapy plays an increasing role in the manage-
ian age of trial patients is often around 10 years younger
ment of colorectal cancer and has contributed to the
than the median age of patients diagnosed with colorectal
continued improvement in outcomes over the last two
cancer. Meta-analyses have hinted at a lack of benefit
decades. The use of chemotherapy should be agreed by
from the addition of oxaliplatin to 5FU (McCleary et al.,
the colorectal MDT and should be administered, within
2013), however data from the most recent XELOXA trial
facilities conforming to national standards.
suggest that the elderly population gain similar benefits Pathologists recommend the assessment of MSI either
to their younger counterparts (Haller et al., 2011). by genetic assessment or by immunocytochemistry for
However, this will be at the expense of increased toxicity. the four mismatch repair (MMR) proteins in stage II
There are competing risks with age, particularly risk of patients who are being considered for adjuvant therapy.
dying from other causes and therefore careful assessment Commercially available novel array-based platforms have
of the individual is warranted. been developed to fine tune stage II patients into high
A number of trials have explored additional agents as and low risk groups, in order to refine discussions with
adjuvant strategies in colon cancer, including irinotecan individual patients about the pros and cons of adjuvant
(Van Cutsem et al., 2009), cetuximab (Alberts et al., therapy. To date these tests add significant cost and
2005) and bevacizumab (de Gramont et al., 2012). So may add little over and above MSI assessment for the
far these trials have not demonstrated any improve- individual patient (Gray et al., 2011).
ments in DFS or OS. There are a number of trials The recurrence risk of stage I (Dukes’ A) colon can-
(completed or ongoing, including the UK SCOT trial) cers is generally low, with a 5-year OS of over 90%
investigating the use of a shorter duration of oxali- (Cancer Research UK, 2016). Although no trials have
platin-based chemotherapy, comparing 3 months with formally evaluated the role of adjuvant chemotherapy in
the standard 6 months of treatment. this group of patients, it is unlikely to be of any clini-
An alternative strategy is to use neoadjuvant cally useful benefit.
chemotherapy, which is a standard of care in oesophageal
and gastric cancers. The UK FOXTROT trial is currently 4.2.1.4 Adjuvant chemotherapy in rectal cancer
investigating the role of neoadjuvant oxaliplatin-based Current UK practice, supported by NICE guidance (GC
chemotherapy in radiologically defined higher-risk colon 131) (National Institute for Health and Care Excellence,
cancer (Foxtrot Collaborative Group, 2012). 2011), is to complete local treatment of the primary
tumour with surgery, with or without pelvic radiother-
4.2.1.3 Lymph node negative (stage I and II) disease apy, before considering adjuvant systemic chemotherapy.
There is less evidence supporting the use of adjuvant Although a systematic review of 9785 patients with rec-
chemotherapy in stage II (Dukes’ B) than in stage III. tal cancer in 21 randomized trials demonstrated modest
The UK QUASAR 1 trial was designed to determine the DFS (HR 0.75) and OS (HR 0.83) improvements with
benefit of adjuvant chemotherapy in patients considered postoperative chemotherapy (Maas et al., 2015), these
to be at lower risk of recurrence. The trial randomized trials pre-dated the widespread use of optimal TME sur-
3239 patients (91% with stage II) to i.v. modulated 5FU gery and preoperative radiotherapy. The one study
or observation. Use of chemotherapy reduced relative which tested adjuvant chemotherapy following preopera-
risk of recurrence by 22% (HR 0.78) and improved OS tive radiotherapy (EORTC 22921) failed to demonstrate
by 3.6% (Gray et al., 2007). Sub-group analysis of stage a benefit (HR 0.91). Recent meta-analysis of four trials
II patients treated within the MOSAIC trial showed a that incorporated preoperative radiotherapy suggested
smaller but statistically borderline significant incremental limited or no benefit from adjuvant chemotherapy (DFS
benefit by adding oxaliplatin (Tournigand et al., 2012). HR 0.91, P = 0.230) (Breugom et al., 2015).
Oxaliplatin is not routinely recommended or licensed Several factors combine to reduce the effectiveness of
in patients with stage II cancers (National Institute for adjuvant chemotherapy in rectal cancer, including treat-
Health and Care Excellence, 2011), although there may ment delay and poor compliance. Ongoing morbidity
be rationale to consider its use in stage II patients with from surgery and radiotherapy reduces patients’ tolerance
multiple high-risk factors, given their overlapping poor of adjuvant chemotherapy. Temporary ileostomies, which
prognosis with stage III disease. Known high-risk fea- are expected to be performed in approximately 75% of
tures in stage II cancers include pT4 stage, obstructed patients having a low anterior resections, can cause dehy-
tumours, poor or mucinous differentiation, EMVI and dration and electrolyte imbalance from a high output and
fewer than 12 lymph nodes assessed histologically. reduce compliance to chemotherapy, leading to reduced
Microsatellite instability (MSI) appears to confer a DFS and OS. In EORTC 22921 and CHRONICLE less
better DFS in stage II colon cancers (especially right than half of patients (43% and 48% respectively) com-
sided) compared to microsatellite stable tumours (Popat pleted all cycles of chemotherapy. In EORTC 22921 and
et al., 2005), with no apparent benefit from adjuvant the I-CNR-RT trial 27% and 28% of patients respectively
chemotherapy. Initial reports that MSI is also a predic- were unable to start adjuvant chemotherapy.
tive marker for the lack of efficacy from adjuvant 5FU
(Des Guetz et al., 2009) have been largely refuted Fluoropyrimidines with or without oxaliplatin
(Hutchins et al., 2011). The UK Royal College of should be considered as options for the adjuvant
treatment of patients with stage III colorectal cancer improvement in 3-year PFS approaching statistical sig-
following potentially curative surgery. nificance (HR 0.79; P = 0.058). The New EPOC trial
Recommendation grade A focused on a similar group of patients with potentially
resectable liver only metastases, with KRAS exon 2
In general a higher risk, otherwise fit, patient wild-type tumours, comparing the addition of cetux-
should be offered an oxaliplatin-based regimen. imab to oxaliplatin/5FU/folinic acid (FOLFOX). This
Recommendation grade A trial closed early after it became evident that the addi-
tion of cetuximab resulted in a worse DFS despite an
Patients with high-risk stage II colorectal cancer improved response rate (Primrose et al., 2014).
should be considered for adjuvant chemotherapy. These results have been variably interpreted as either
Recommendation grade A suggesting a benefit, or alternatively no benefit from
peri-operative oxaliplatin/5FU chemotherapy in this
MSI or MMR protein assessment should be avail- setting. Many now offer adjuvant chemotherapy to
able to clinicians, allowing fully informed discus- patients as standard and those with high-risk syn-
sions with the patient diagnosed with stage II chronous disease are offered neoadjuvant chemotherapy
colorectal cancer and being considered for adjuvant but optimum practice remains undefined.
chemotherapy. Where metastases are unresectable, currently patients
Recommendation grade B fall into 2 groups:
• metastatic disease is inoperable at presentation, how-
4.2.2 Systemic chemotherapy for advanced disease ever, might become resectable with curative intent if
a good response to therapy occurs.
4.2.2.1 Locoregional recurrence
• metastatic disease will not become suitable for poten-
Local recurrence of colorectal cancers should be consid- tially curative surgery, even if a good response to
ered for salvage resection, in selected cases seeking the therapy occurs.
opinion of a centre specializing in extended resectional Sub-group analyses from randomized trials and non-
surgery. If resection is not deemed possible, palliative randomized evidence exists to support the use of preoper-
treatment with chemotherapy (or chemoradiotherapy) ative combination chemotherapy +/ biological therapy,
may achieve significant tumour shrinkage and in discus- prior to resection in patients with ‘potentially’ operable
sion with the patient and MDT may offer the opportu- liver metastases (National Institute for Health and Clini-
nity to reconsider salvage surgery. cal Excellence, 2009). Such patients should be discussed
by the MDT, in the presence of a hepatic surgeon. If
4.2.2.2 Unresectable primary disease appropriate, following radiological and surgical review,
Unresectable primary disease is most commonly seen in preoperative combination chemotherapy should be deliv-
rectal cancers, but also occurs in colon cancers. The use ered for at least 8 weeks prior to re-imaging.
of chemotherapy and/or radiotherapy may improve
symptoms and survival. In some patients, a good 4.2.2.4 Inoperable metastatic disease
response to treatment may enable reconsideration of Selection of patients for chemotherapy requires the opin-
surgical intervention. ion of an oncologist experienced in delivering colorectal
cancer chemotherapy. A large number of factors includ-
4.2.2.3 Operable metastatic disease ing performance status, serum biochemistry and overall
Patients with technically operable liver or lung metastases tumour burden influence the choice of chemotherapy
may benefit from resection. Five-year survival following and the patient’s ability to tolerate treatment. These can
resection of colorectal metastases is around 40%, though also independently predict for progression and survival.
no randomized controlled trial data exists (Garden et al., Performance status is a particularly potent indicator. In a
2006; Kanas et al., 2012). Whether patients with lung meta-analysis of patients treated in trials of 5-FU based
only metastases, benefit from surgical resection remains chemotherapy, median survival times were 4, 10 and
debated. PulMICC is a randomized phase III trial for 14 months for patients with ECOG performance status
patients with resectable lung metastases, exploring the scores of 2, 1 and 0 respectively (Thirion et al., 1999).
role of surgical resection vs palliative chemotherapy. A number of meta-analyses of palliative single-agent
The EPOC (EORTC 40983) trial compared oxali- chemotherapy have shown improved survival in the
platin/5FU given before and after surgery, to surgery region of 3–6 months with chemotherapy compared
alone in patients with liver limited metastatic disease with best supportive care alone, in advanced colorectal
(Nordlinger et al., 2008) reported a marginal cancer. When reported, chemotherapy either improved
or maintained quality of life (Simmonds, 2000). The VEGF and PlGF, has been shown to improve survival in
oral 5FU prodrugs, UFT and capecitabine have shown combination with irinotecan and 5FU (FOLFIRI) in the
equivalent survival and increased ease of administration second-line (Tabernero et al., 2014) but is not approved
compared to bolus 5FU and low dose folinic acid, and by NICE (TA 307) (National Institute for Health and
are approved by NICE (TA 61) as single agents for Care Excellence, 2014).
first-line treatment (National Institute for Health and Cetuximab and panitumumab, epidermal growth fac-
Care Excellence, 2003). tor receptor (EGFR) inhibitors, are potentially active in
Combination regimens with intravenous 5FU plus patients with RAS wild-type tumours. Data on the addi-
either, irinotecan or oxaliplatin have been shown to tion of cetuximab to irinotecan and oxaliplatin combi-
offer survival benefits in both first and second-line situa- nations in the first-line setting are inconsistent;
tions. Current NICE guidance supports the use of all improvement of PFS and OS was demonstrated in some
three of the active drugs (a fluoropyrimidine, oxaliplatin trials (Bokemeyer et al., 2009; Van Cutsem et al.,
and irinotecan) and as such has deemed them to be cost 2009) but not in other trials (Maughan et al., 2011).
effective (National Institute for Health and Care Excel- Addition of cetuximab to irinotecan as second-line ther-
lence, 2005). Improved results have been reported in apy (Sobrero et al., 2008) and as a single agent in the
studies in which all three of these agents are used in the last line setting (Jonker et al., 2007; Karapetis et al.,
majority of patients (Grothey & Sargent, 2005). 2008) has also demonstrated improved PFS and OS.
In patients with stable or responding disease after Panitumumab, which is fully humanized and adminis-
3 months therapy, a rest from treatment with close obser- tered 2–3 weekly, has been used in addition to an oxali-
vation until disease progression was not shown to be platin combination as first-line therapy (Douillard et al.,
detrimental to survival and contributed to improved qual- 2010) in addition to an irinotecan combination as second-
ity of life in the UK COIN trial (Adams et al., 2011). line therapy (Peeters et al., 2010) and as a single agent in
Within this trial it was suggested that a sub-group of the last line setting (Amado et al., 2008; Van Cutsem
patients with thrombocytosis benefited from a continua- et al., 2007) and demonstrated improved PFS and OS.
tion of therapy beyond 12 weeks, although this awaits val- The UK PICCOLO trial combined panitumab and single
idation in other trial sets. The Dutch CAIRO 3 trial has agent iriotecan in the second-line and failed to demon-
demonstrated a survival advantage in patients receiving strate any benefit in patients (Seymour et al., 2013).
4 months of oxaliplatin, capecitabine and bevacizumab The European licensing of cetuximab and panitu-
and then being maintained on bevacizumab and capecita- mumab has now been changed to include both NRAS and
bine compared to bevacizumab alone (adjusted HR 0.8, KRAS wild-type (RAS wt) tumours. In 2009, NICE (TA
P = 0.035) (Simkens et al., 2015). 176) gave approval for cetuximab to be used in combina-
Raltitrexed, a folate anti-metabolite is licensed for tion with FOLFOX or FOLFIRI chemotherapy for
use as a substitute for 5FU/FA or capecitabine, when patients with RAS wild-type tumours who have potentially
these are contraindicated. The common reasons are car- resectable liver metastases (National Institute for Health
diotoxicity and DPD deficiency. NICE (GC 131) has and Care Excellence, 2007; National Institute for Health
recommended the use of raltitrexed under these circum- and Clinical Excellence, 2009), based on the high expected
stances (National Institute for Health and Care Excel- response rates in this cohort of patients. Panitumumab has
lence, 2011). not been formally appraised by NICE and is thus not
approved. More recently, NICE (TA 439) approved
4.2.2.5 Addition of biological therapies cetuximab and panitumumab to be used in combination
Targeted monoclonal antibodies have been used in con- with FOLFOX or FOLFIRI in RAS wild-type metastatic
junction with chemotherapy. Bevacizumab, an antibody colorectal cancer as a first-line regimen (National Institute
to vascular endothelial growth factor (VEGF), has been for Health and Care Excellence, 2017).
shown to improve overall and progression-free survival The recent FIRE 3 trial is the first phase III study to
when used in addition to first-line irinotecan (Hurwitz directly compare the biological agents, bevacizumab and
et al., 2004) and first and second-line oxaliplatin-based cetuximab in combination with FOLFIRI in the first-line
combinations (Giantonio et al., 2007; Saltz et al., 2008). setting. It showed a 3.7 month OS improvement (28.7
In patients who received bevacizumab during first-line vs 25.0 months, HR 0.77; P = 0.017) in the RAS wild-
therapy, there is evidence of benefit in continuing this into type cohort of patients receiving cetuximab/FOLFIRI vs
second-line therapy (Bennouna et al., 2013). However bevacizumab/FOLFIRI (Stintzing et al., 2013) despite
bevacizumab is currently not approved by NICE (TA there being no difference in response rate or PFS.
212) (National Institute for Health and Care Excellence, Regorafenib is a novel oral tyrosine kinase inhibitor,
2010). Aflibercept (Zaltrap), a fusion protein binding which has demonstrated a 1.4 month OS benefit vs best
supportive care alone in the last line setting (6.4 vs Management of pain and other symptoms and provision
5.0 months, HR 0.77; P = 0.0052) (Grothey et al., of psychological, social and spiritual support is para-
2013). Regorafenib has not been formally appraised by mount. The goal of palliative care is achievement of the
NICE (TA 334) and has not been approved. best quality of life for patients and their families. Many
The RECOURSE phase III trial compared trifluridine- aspects of palliative care are also applicable earlier in the
tipiracil, an oral combination of a thymidine analogue (tri- course of the illness in conjunction with other treat-
fluridine) and a thymidine phosphorylase inhibitor (tipira- ments’ (National Institute for Health and Clinical
cil hydrochloride) with a placebo in patients with Excellence, 2004). Although palliative care is mainly
chemorefractory metastatic colorectal cancer. It demon- focused on ‘advanced, progressive’ stages of colorectal
strated a 1.8 months improvement in OS (7.1 vs cancer, particularly in the very last months of life, more
5.3 months, HR 0.68; P < 0.001) (Mayer et al., 2015). can be achieved by introducing some aspects of this
NICE (TA 405) has approved the use of trifluridine-tipir- ‘earlier in the course of the illness in conjunction with
acil as a treatment option, within the licensed indication other treatments’, as in the NICE guidance, in terms of
on an agreed patient access scheme (National Institute for health-related and psychological benefits to patients and
Health and Care Excellence, 2016). their carers (Smith et al., 2012; Temel et al., 2010).
Over the past two decades, ‘supportive care’ as a sep-
Fit patients with resectable or potentially resect- arate but overlapping concept has developed. Support-
able liver or lung metastases should be reviewed in ive care is defined as: ‘[helping] the patient and their
the MDT with a hepatobiliary (or thoracic) surgeon family to cope with cancer and treatment of it – from
and colorectal oncologist, to evaluate operability and pre-diagnosis, through the process of diagnosis and treat-
to decide on a combined plan of management to ment, to cure, continuing illness or death and into
optimize the chance of achieving complete resection bereavement. It helps the patient to maximize the benefits
of all metastatic disease. of treatment and to live as well as possible with the effects
Recommendation grade B of the disease’ (National Institute for Health and Clinical
Excellence, 2004). It is distinct from palliative care in
Patients with unresectable metastatic disease three main respects: First, it should start at beginning
should be discussed by the MDT and if appropriate, of the cancer illness, based on the individual needs of
should be referred to an oncologist for consideration the patient and family rather than being determined by
of chemotherapy. the notion of prognosis. Second, it is concerned with
Recommendation grade C managing acute treatment-related toxicities such as nau-
sea, vomiting and diarrhoea, as well as long-term effects
Surgeons and oncologists who deal with colorec- such as neuropathy and fatigue. Third, supportive care
tal cancer should make it a priority to build close continues into ‘survivorship’ and rehabilitation for
links with palliative care specialists and units. return to normal life after cancer. For these reasons, it
Recommendation grade D is claimed that ‘Supportive care makes excellent cancer
care possible’ (http://www.mascc.org).
All clinicians who deal with colorectal cancer
should be trained in communication skills, in the Supportive and palliative care services should be
control of pain and other cancer symptoms. available to all colorectal cancer patients at any stage
Recommendation grade D of disease.
It is important that patients with colorectal cancer
are offered the opportunity to ask questions and to 4.3.2 Supportive care in the oncology setting
have important information repeated at each consul- The ‘Multinational Association for Supportive Care in
tation. Information giving should be seen as an Cancer’ (MASCC) has produced several guidelines
essential part of every consultation. (http://www.mascc.org/guidelines) for delivery of sup-
Recommendation grade D portive care, enabling oncologists to deliver optimal doses
of anti-cancer treatment. The MASCC also produces vali-
dated assessment tools, eg for chemotherapy induced
4.3 Supportive and Palliative Care
emesis, EGFR inhibitor skin toxicity. Adherence to the
4.3.1 Definitions latest 2016 MASCC anti-emetic guidelines could improve
Palliative care is defined as the ‘the active holistic care the experience of the large majority of patients receiving
of patients with advanced, progressive illness. chemotherapy (Herrstedt et al., 2017).
In UK cancer centres, trained specialist nurses and in 2007, has led to a multiplicity of models of support
allied health professionals, as well as the oncologists rou- and care for survivors. Each cancer centre should be
tinely deliver aspects of supportive care. As anti-cancer able to provide patients with information about how to
treatments become increasingly more complex and with access such support.
newly emerging toxicities from biological, immunomodu- Patients who have persisting late side-effects from
lating and other antibody-based treatments it becomes anti-cancer treatments are often in a difficult position,
more important for services to adapt to changing MASCC because primary care services are not trained to monitor
and other supportive care guidelines. and manage these, whilst oncology centres are poorly
There is evidence that initiating lifestyle changes and equipped to offer long-term support. In the larger
encouraging exercise regimes early on, even before initi- cities, some acute hospital-based palliative care teams
ation of adjuvant treatment and during it, may help may be able to manage specific issues such as late drug
patients make an earlier recovery and return to produc- side-effects and for the monitoring and weaning of
tive life (Li et al., 2013). At present ‘pre-habilitation’ doses of analgesics and other symptom medications.
and rehabilitation during treatment are not widely avail-
able. Patients may benefit from being referred to ser- Colorectal cancer patients who have completed
vices outside the cancer centre, including some anti-cancer treatment should have access to support-
hospices, which are developing rehabilitation units. ive care including rehabilitation.
Symptoms arising during anti-cancer treatment are Recommendation grade D
managed by experienced members of the oncology team,
especially by specialist nurses and nurse prescribers. For Long-term survivors of colorectal cancer should
patients who fail to respond to locally initiated symptom be monitored for late side-effects of treatment and
management, or who develop intolerable side-effects, be offered specialist support as needed.
hospital or community-based specialist palliative care ser- Recommendation grade C
vices can offer an extra layer of advice and supervision.
Acute oncology services should also have access to spe- 4.3.4 Palliative care in advanced disease and end of
cialist palliative care backup (Shankland et al., 2012). life care
There is no clear demarcation of when the ‘end of life’
Oncology teams should be familiar with guidance begins, but the accepted timeframe is from when it is
for supportive care, including MASCC guidelines thought by the clinical team that the patient has one
and assessment tools. year or less of expected survival. Prognostication
Recommendation grade B towards the end of life remains difficult and inaccurate,
even in palliative care settings and clinicians must be
4.3.3 Supportive care after cancer treatment clear and honest with patients who want to know their
Once patients have completed their primary cancer prognosis, explaining the reasons for uncertainty.
treatment, there is a drive to discharge patients earlier Patients should be encouraged to make ‘advance care
back to the care of their primary care services. Whilst plans’ (ACPs) to cover a range of topics including: pre-
this may work well for many patients, some remain bur- ferred place of care, preferred place of death, advance
dened by late side-effects or may have problems in decisions of refusal of treatments, do not attempt resusci-
adjusting to daily life. Post-treatment rehabilitation may tation (DNAR) choices. Having an ACP in place can help
help. Patients may be referred or self-refer to organiza- patients and their families feel more comfortable that
tions such as Maggie’s Centres (https://www.maggie future events have been reflected on and can reduce hos-
scentres.org/), which offer programmes for exercise, pital admissions for elderly patients at the end of life
managing stress, nutritional advice and social security (Martin et al., 2016). Discussion about concepts of
benefits. Many larger cities have information and sup- ACPs should be performed with sensitivity and in stages,
port centres attached to, or separate from, the cancer reflecting the clinical course of cancer in each individual.
centres and these may offer similar programmes. Exer- There is no place for ‘enforced’ discussion of these topics,
cise-based rehabilitation programmes can improve fati- especially preferred place of death or DNAR decisions,
gue and quality of life in cancer survivors but there is particularly at the beginning of advance care planning.
large variability in protocols and adherence to them Oncology teams should at the same time, be considering
(Mishra et al., 2012). the ceiling of care for each patient and communicate this
For patients who are living longer after the comple- with other acute and community services. This needs to
tion of treatment and are currently disease-free, the be kept under frequent review, and wherever possible,
National Cancer Survivorship programme, which started based on discussion with the patient and their families.
The 2015 Royal College of Physicians national hos- provided in all hospices. Efforts should be made to pro-
pital end of life care audit found that on the final hospi- vide local solutions to circumvent these issues.
tal admission of over 9000 patients, only 4% of patients Availability of specialist palliative care support within
had an ACP known to the caring team (Royal College UK acute hospital trusts, in terms of 24 h, 7 days a week
of Physicians, 2016). The audit also showed that by the advice and 7 days a week access to a palliative medicine
time it was recognized that a patient may die during doctor remains inconsistent and generally poor (Royal
the admission, the median survival was <36 h. Recog- College of Physicians, 2016). Therefore some oncology
nizing dying so late and not having an ACP can com- services need to make arrangements with local hospices in
promise patients’ and families’ wellbeing, particularly if order to gain out of hours advice and support.
inappropriate interventions are started or other treat-
ments are unnecessarily withdrawn. Hospitals caring for patients with advanced col-
During the last months of life, patients are often orectal cancer should work towards round the clock
referred to specialist palliative care services but being access to specialist palliative care support.
referred too early or in an abrupt way can lead to rejec- Recommendation grade D
tion by some services, or be distressing to patients. Ide-
ally patients should have access to information about 4.3.6 Last days of life
the availability and potential benefits of specialist pallia- The NICE guideline for ‘Care of the dying adult in the
tive care ‘should they need it’ in a non-threatening way last days of life’ places emphasis on the need to be alert
before referrals are made. As well as specialist medical to signs and symptoms of impending death, but also
and nursing support, patients in the last year of life may being aware of changes that could indicate stabilization
need access to other members of the multidisciplinary or even temporary recovery (National Institute for
palliative care team, e.g. physiotherapy, occupational Health and Clinical Excellence, 2015a). It makes rec-
therapy, dietetics, psychological and spiritual support ommendations about communication and shared deci-
and benefits advice. sion-making; the maintenance of hydration including
clinically assisted hydration if indicated and desired by
Patients with advanced colorectal cancer entering the patient; pharmacological management of key symp-
the last months of life should be encouraged and toms (pain, nausea and vomiting, breathlessness, anxi-
supported to make advance care plans. ety, delirium, agitation) and noisy respiratory secretions
Recommendation grade C in the final days and hours; and the role of anticipatory
prescribing. The NICE guideline stresses that all care,
Colorectal cancer patients at the end of life including prescribing for current and anticipated symp-
should be offered information and access to special- toms and for hydration, should be individualized and
ist palliative care services in a sensitive way as early not done in a ‘one-size-fits-all’ fashion, as was previ-
as possible. ously considered.
Recommendation grade D Although there has been much emphasis on enabling
patients to die in their own homes according to their
Patients with advanced colorectal cancer should wishes, many circumstances make this ideal not possible
have access to members of the wider palliative care or desirable. These include new or increasing symptoms,
team in all settings. or the need for hospital-based interventions for com-
Recommendation grade D fort. The initiation of appropriate clinically assisted
hydration should be done in any setting and not be
4.3.5 Provision of specialist palliative care services and seen as the reason for hospital admission. Patients with
hospices subacute and long-term bowel obstruction from col-
The UK has a particularly developed network of special- orectal cancer may also be managed at home for pro-
ist palliative care services, many of these operated and longed periods using central or peripheral lines for
funded by national or local charitable institutions and hydration, together with specialist palliative care input
are based at hospices, which are remote from cancer for managing vomiting and pain.
centres or hospitals (The Economist Intelligence Unit,
2015). They provide both inpatient and day-patient All care including prescribing of medications and
facilities. The disconnection from the acute hospital can clinically assisted hydration should be given on an
be a problem in some circumstances, e.g. patients need- individualized basis according to clinical need and
ing acute oncology support or interventions such as regardless of the setting. Anticipatory prescribing
paracentesis or blood transfusion, which are not for future symptoms is encouraged, especially if the
patient expected to die out of hours or in the com- Bridgewater J, Tabah-Fisch I, de Gramont A. Oxaliplatin,
munity setting. fluorouracil, and leucovorin as adjuvant treatment for colon
Recommendation grade C cancer. N Engl J Med 2004; 350: 2343–51.
Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Top-
ham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de
Conflicts of interest Gramont A. Improved overall survival with oxaliplatin, fluo-
rouracil, and leucovorin as adjuvant treatment in stage II or
Simon Bach has been a consultant for Ethicon Inc., III colon cancer in the MOSAIC trial. J Clin Oncol 2009;
Cincinnati, USA. Arthur Sun Myint has been a specialty 27: 3109–16.
adviser for NICE IPG 532 guideline on low energy con- Appelt AL, Ploen J, Harling H, Jensen FS, Jensen LH, Jor-
tact X-ray brachytherapy (Papillon) for early stage rectal gensen JC, Lindebjerg J, Rafaelsen SR, Jakobsen A. High-
cancer. Andrew Renehan has received Lecture honoraria dose chemoradiotherapy and watchful waiting for distal rec-
from Merck Serona and Sanofi and been a member of tal cancer: a prospective observational study. Lancet Oncol
the advisory board of Beating Bowel Cancer. Sam 2015; 16: 919–27.
Ahmedzai has been employed by the National Institute Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G,
of Health Research as National Specialty Lead for sup- Artale S, Tagliagambe A, Ambrosini G, Rosetti P, Bonetti
A, Negru ME, Tronconi MC, Luppi G, Silvano G, Corsi
portive and community-based cancer research and has
DC, Bochicchio AM, Chiaulon G, Gallo M, Boni L. Primary
been Chair of the National Cancer Research Institute
tumor response to preoperative chemoradiation with or
clinical studies group for supportive and palliative care without oxaliplatin in locally advanced rectal cancer: patho-
research. The other authors have no conflicts to declare. logic results of the STAR-01 randomized phase III trial. J
Clin Oncol 2011; 29: 2773–80.
Ashraf S, Hompes R., Slater A, Lindsey I, Bach S, Mortensen
References
N. J, Cunningham C., and on behalf of the Association of
Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Coloproctology of Great Britain and Ireland Transanal
Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, Endoscopic Microsurgery (TEM) Collaboration. A critical
Rogers P, Wasan H, Falk S, Gollins S, Hickish T, Bessell appraisal of endorectal ultrasound and transanal endoscopic
EM, Propper D, Kennedy MJ, Kaplan R, Maughan TS. microsurgery and decision-making in early rectal cancer. Col-
Intermittent versus continuous oxaliplatin and fluoropyrim- orectal Disease 2012; 14: 821–826.
idine combination chemotherapy for first-line treatment of Bach SP, Hill J, Monson JR, Simson JN, Lane L, Merrie A,
advanced colorectal cancer: results of the randomised Warren B, Mortensen NJ. A predictive model for local
phase 3 MRC COIN trial. Lancet Oncol 2011; 12: recurrence after transanal endoscopic microsurgery for rectal
642–53. cancer. Br J Surg 2009; 96: 280–90.
Al-Sukhni E, Milot L, Fruitman M, Beyene J, Victor JC, Sch- Barendse RM, van den Broek FJ, van Schooten J, Bemelman WA,
mocker S, Brown G, McLeod R, Kennedy E. Diagnostic Fockens P, de Graaf EJ, Dekker E. Endoscopic mucosal resec-
accuracy of MRI for assessment of T category, lymph node tion vs transanal endoscopic microsurgery for the treatment of
metastases, and circumferential resection margin involvement large rectal adenomas. Colorectal Dis 2012; 14: e191–6.
in patients with rectal cancer: a systematic review and meta- Barker T, Branagan G, Wright E, Crick A, McGuiness C,
analysis. Ann Surg Oncol 2012; 19: 2212–23. Chave H. Vertical rectus abdominis myocutaneous flap
Alberts SR, Sinicrope FA, Grothey A. N0147: a randomized reconstruction of the perineal defect after abdominoperineal
phase III trial of oxaliplatin plus 5-fluorouracil/leucovorin excision is associated with low morbidity. Colorectal Dis
with or without cetuximab after curative resection of stage 2013; 15: 1177–83.
III colon cancer. Clin Colorectal Cancer 2005; 5: 211–3. Battersby NJ, How P, Moran B, Stelzner S, West NP, Brana-
Allegra C, Michael G, O’Connell J, Roh M, Lopa S, Petrelli gan G, Strassburg J, Quirke P, Tekkis P, Pedersen BG,
N, Beart R, Sharif S, Wolmark N, Graham H. Final results Gudgeon M, Heald B, Brown G. Prospective validation of
from NSABP protocol R-04: Neoadjuvant chemoradiation a low rectal cancer magnetic resonance imaging staging
(RT) comparing continuous infusion (CIV) 5-FU with cape- system and development of a local recurrence risk stratifi-
citabine (Cape) with or without oxaliplatin (Ox) in patients cation model: the MERCURY II study. Ann Surg 2015;
with stage II and III rectal cancer. J Clin Oncol 2014; 32: 263: 751–60.
suppl; abstr 3603. Beets-Tan RG, Beets GL, Vliegen RF, Kessels AG, Van Boven
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Free- H, De Bruine A, von Meyenfeldt MF, Baeten CG, van
man DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson Engelshoven JM. Accuracy of magnetic resonance imaging
SD, Chang DD. Wild-type KRAS is required for panitu- in prediction of tumour-free resection margin in rectal can-
mumab efficacy in patients with metastatic colorectal cancer. cer surgery. Lancet 2001; 357: 497–504.
J Clin Oncol 2008; 26: 1626–34. Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van
Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero Cutsem E, von Moos R, Vieitez JM, Bouche O, Borg C,
J, Hickish T, Topham C, Zaninelli M, Clingan P, Steffens CC, Alonso-Orduna V, Schlichting C, Reyes-Rivera
I, Bendahmane B, Andre T, Kubicka S. Continuation of rectal cancer with immediate radical re-operation for poor
bevacizumab after first progression in metastatic colorectal responders. Radiother Oncol 2009; 92: 195–201.
cancer (ML18147): a randomised phase 3 trial. Lancet Oncol Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak
2013; 14: 29–37. L, Krynski J, Michalski W, Oledzki J, Kusnierz J, Zajac L,
Birgisson H, Pahlman L, Gunnarsson U, Glimelius B. Late Bednarczyk M, Szczepkowski M, Tarnowski W, Kosa-
adverse effects of radiation therapy for rectal cancer - a sys- kowska E, Zwolinski J, Winiarek M, Wisniowska K, Party-
tematic overview. Acta Oncol 2007; 46: 504–16. cki M, Beczkowska K, Polkowski W, Stylinski R,
Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Wierzbicki R, Bury P, Jankiewicz M, Paprota K, Lewicka
Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, M, Cisel B, Skorzewska M, Mielko J, Bebenek M,
Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, Maciejczyk A, Kapturkiewicz B, Dybko A, Hajac L, Woj-
leucovorin, and oxaliplatin with and without cetuximab in nar A, Lesniak T, Zygulska J, Jantner D, Chudyba E,
the first-line treatment of metastatic colorectal cancer. J Clin Zegarski W, Las-Jankowska M, Jankowski M, Kolodziejski
Oncol 2009; 27: 663–71. L, Radkowski A, Zelazowska-Omiotek U, Czeremszynska
Bosset JF, Calais G, Mineur L, Maingon P, Radosevic-Jelic B, Kepka L, Kolb-Sielecki J, Toczko Z, Fedorowicz Z,
L, Daban A, Bardet E, Beny A, Briffaux A, Collette L. Dziki A, Danek A, Nawrocki G, Sopylo R, Markiewicz W,
Enhanced tumorocidal effect of chemotherapy with preop- Kedzierawski P, Wydmanski J. Long-course oxaliplatin-
erative radiotherapy for rectal cancer: preliminary results– based preoperative chemoradiation versus 5 x 5 Gy and
EORTC 22921. J Clin Oncol 2005; 23: 5620–7. consolidation chemotherapy for cT4 or fixed cT3 rectal
Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radose- cancer: results of a randomized phase III study. Ann
vic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC. Che- Oncol 2016; 27: 834–42.
motherapy with preoperative radiotherapy in rectal cancer. Burton S, Brown G, Daniels IR, Norman AR, Mason B, Cun-
N Engl J Med 2006; 355: 1114–23. ningham D. MRI directed multidisciplinary team preopera-
Breugom AJ, Swets M, Bosset JF, Collette L, Sainato A, tive treatment strategy: the way to eliminate positive
Cionini L, Glynne-Jones R, Counsell N, Bastiaannet E, van circumferential margins? Br J Cancer 2006; 94: 351–7.
den Broek CB, Liefers GJ, Putter H, van de Velde CJ. Adju- Butt HZ, Salem MK, Vijaynagar B, Chaudhri S, Singh B. Per-
vant chemotherapy after preoperative (chemo)radiotherapy ineal reconstruction after extra-levator abdominoperineal
and surgery for patients with rectal cancer: a systematic excision (eLAPE): a systematic review. Int J Colorectal Dis
review and meta-analysis of individual patient data. Lancet 2013; 28: 1459–68.
Oncol 2015; 16: 200–7. Camma C, Giunta M, Fiorica F, Pagliaro L, Craxi A, Cottone
Brown G, Radcliffe AG, Newcombe RG, Dallimore NS, M. Preoperative radiotherapy for resectable rectal cancer: a
Bourne MW, Williams GT. Preoperative assessment of prog- meta-analysis. JAMA 2000; 284: 1008–15.
nostic factors in rectal cancer using high-resolution magnetic Cancer Research UK (2016) Bowel cancer survival statistics:
resonance imaging. Br J Surg 2003; 90: 355–64. http://www.cancerresearchuk.org/health-professional/cancer-
Brown IS, Bettington ML, Bettington A, Miller G, Rosty C. statistics/statistics-by-cancer-type/bowel-cancer/survival#head
Adverse histological features in malignant colorectal polyps: ing-Three (accessed 19 May 2017).
a contemporary series of 239 cases. J Clin Pathol 2016; 69: Cataldo PA, O’Brien S, Osler T. Transanal endoscopic micro-
292–9. surgery: a prospective evaluation of functional results. Dis
Bujko K, Kolodziejczyk M. The 5 x 5 Gy with delayed surgery Colon Rectum 2005; 48: 1366–71.
in non-resectable rectal cancer: a new treatment option. Cedermark B, Johansson H, Rutqvist LE, Wilking N. The
Radiother Oncol 2008; 87: 311–3. Stockholm I trial of preoperative short term radiotherapy in
Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski operable rectal carcinoma. A prospective randomized trial.
W, Bebenek M, Kryj M. Long-term results of a randomized Stockholm Colorectal Cancer Study Group. Cancer 1995;
trial comparing preoperative short-course radiotherapy with 75: 2269–75.
preoperative conventionally fractionated chemoradiation for Chand M, Evans J, Swift RI, Tekkis PP, West NP, Stamp G,
rectal cancer. Br J Surg 2006; 93: 1215–23. Heald RJ, Brown G. The prognostic significance of
Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski postchemoradiotherapy high-resolution MRI and
W, Bebenek M, Pudelko M, Kryj M, Oledzki J, Szmeja J, histopathology detected extramural venous invasion in rectal
Sluszniak J, Serkies K, Kladny J, Pamucka M, Kukolowicz cancer. Ann Surg 2015; 261: 473–9.
P. Sphincter preservation following preoperative radiother- Chau I, Brown G, Cunningham D, Tait D, Wotherspoon A,
apy for rectal cancer: report of a randomised trial compar- Norman AR, Tebbutt N, Hill M, Ross PJ, Massey A, Oates
ing short-term radiotherapy vs. conventionally fractionated J. Neoadjuvant capecitabine and oxaliplatin followed by syn-
radiochemotherapy. Radiother Oncol 2004; 72: chronous chemoradiation and total mesorectal excision in
15–24. magnetic resonance imaging-defined poor-risk rectal cancer.
Bujko K, Richter P, Kolodziejczyk M, Nowacki MP, Kulig J, J Clin Oncol 2006; 24: 668–74.
Popiela T, Gach T, Oledzki J, Sopylo R, Meissner W, Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G,
Wierzbicki R, Polkowski W, Kowalska T, Stryczynska G, Wotherspoon A, Tait D, Massey A, Tebbutt NC, Chau I.
Paprota K. Preoperative radiotherapy and local excision of Neoadjuvant capecitabine and oxaliplatin before
chemoradiotherapy and total mesorectal excision in MRI- randomized study of concomitant chemoradiotherapy fol-
defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol lowed by surgery and adjuvant capecitabine plus oxaliplatin
2010; 11: 241–8. (CAPOX) compared with induction CAPOX followed by
Colorectal Cancer Collaborative Group. Adjuvant radiotherapy concomitant chemoradiotherapy and surgery in magnetic
for rectal cancer: a systematic overview of 8,507 patients resonance imaging-defined, locally advanced rectal cancer:
from 22 randomised trials. Lancet 2001; 358: 1291–304. Grupo cancer de recto 3 study. J Clin Oncol 2010; 28:
Dahlberg M, Glimelius B, Graf W, Pahlman L. Preoperative 859–65.
irradiation affects functional results after surgery for rectal Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius
cancer: results from a randomized study. Dis Colon Rectum B, Gunnarsson U. Swedish Rectal Cancer Trial: long lasting
1998; 41: 543–9; discussion 549–51. benefits from radiotherapy on survival and local recurrence
De Graaf EJ, Doornebosch PG, Tollenaar RA, Meershoek- rate. J Clin Oncol 2005; 23: 5644–50.
Klein Kranenbarg E, de Boer AC, Bekkering FC, van de Foxtrot Collaborative Group. Feasibility of preoperative
Velde CJ. Transanal endoscopic microsurgery versus total chemotherapy for locally advanced, operable colon cancer:
mesorectal excision of T1 rectal adenocarcinomas with cura- the pilot phase of a randomised controlled trial. Lancet
tive intention. Eur J Surg Oncol 2009; 35: 1280–5. Oncol 2012; 13: 1152–60.
de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Frykholm GJ, Glimelius B, Pahlman L. Preoperative or postop-
Clarke S, Moore MJ, Cunningham D, Cartwright TH, erative irradiation in adenocarcinoma of the rectum: final
Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Main- treatment results of a randomized trial and an evaluation of
drault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki late secondary effects. Dis Colon Rectum 1993; 36: 564–72.
M, Shang A, Andre T, Hoff PM. Bevacizumab plus oxali- Garcia-Aguilar J, Mellgren A, Sirivongs P, Buie D, Madoff RD,
platin-based chemotherapy as adjuvant treatment for colon Rothenberger DA. Local excision of rectal cancer without
cancer (AVANT): a phase 3 randomised controlled trial. adjuvant therapy: a word of caution. Ann Surg 2000; 231:
Lancet Oncol 2012; 13: 1225–33. 345–51.
Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere Garcia-Aguilar J, Shi Q, Thomas CR Jr, Chan E, Cataldo P,
JF, Uzzan B. Does microsatellite instability predict the effi- Marcet J, Medich D, Pigazzi A, Oommen S, Posner MC. A
cacy of adjuvant chemotherapy in colorectal cancer? A sys- phase II trial of neoadjuvant chemoradiation and local exci-
tematic review with meta-analysis. Eur J Cancer 2009; 45: sion for T2N0 rectal cancer: preliminary results of the ACO-
1890–6. SOG Z6041 trial. Ann Surg Oncol 2012; 19: 384–91.
Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glime- Garden OJ, Rees M, Poston GJ, Mirza D, Saunders M, Leder-
lius B, Cervantes A, Tait D, Brown G, Wotherspoon A, mann J, Primrose JN, Parks RW. Guidelines for resection of
Gonzalez de Castro D, Chua YJ, Wong R, Barbachano Y, colorectal cancer liver metastases. Gut 2006; 55(Suppl 3):
Oates J, Chau I. Multicenter randomized phase II clinical iii1–8.
trial comparing neoadjuvant oxaliplatin, capecitabine, and Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Lafay I,
preoperative radiotherapy with or without cetuximab fol- Hennequin C, Etienne PL, Vendrely V, Francois E, de La
lowed by total mesorectal excision in patients with high-risk Roche G, Bouche O, Mirabel X, Denis B, Mineur L, Berdah
rectal cancer (EXPERT-C). J Clin Oncol 2012; 30: 1620–7. JF, Mahe MA, Becouarn Y, Dupuis O, Lledo G, Seitz JF,
Doornebosch PG, Tollenaar RA, Gosselink MP, Stassen LP, Bedenne L, Juzyna B, Conroy T. Clinical outcome of the
Dijkhuis CM, Schouten WR, van de Velde CJ, de Graaf EJ. ACCORD 12/0405 PRODIGE 2 randomized trial in rectal
Quality of life after transanal endoscopic microsurgery and cancer. J Clin Oncol 2012; 30: 4558–65.
total mesorectal excision in early rectal cancer. Colorectal Dis Gerard JP, Chapet O, Nemoz C, Hartweig J, Romestaing P,
2007; 9: 553–8. Coquard R, Barbet N, Maingon P, Mahe M, Baulieux J,
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Baru- Partensky C, Papillon M, Glehen O, Crozet B, Grandjean
gel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, JP, Adeleine P. Improved sphincter preservation in low rec-
Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Sma- tal cancer with high-dose preoperative radiotherapy: the lyon
kal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. R96-02 randomized trial. J Clin Oncol 2004; 22: 2404–9.
Randomized, phase III trial of panitumumab with infusional Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O,
fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus Closon-Dejardin MT, Untereiner M, Leduc B, Francois E,
FOLFOX4 alone as first-line treatment in patients with pre- Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M,
viously untreated metastatic colorectal cancer: the PRIME Bedenne L. Preoperative radiotherapy with or without con-
study. J Clin Oncol 2010; 28: 4697–705. current fluorouracil and leucovorin in T3-4 rectal cancers:
Endreseth BH, Myrvold HE, Romundstad P, Hestvik UE, results of FFCD 9203. J Clin Oncol 2006; 24: 4620–5.
Bjerkeset T, Wibe A. Transanal excision vs. major surgery Gerard JP, Myint AS, Croce O, Lindegaard J, Jensen A, Myer-
for T1 rectal cancer. Dis Colon Rectum 2005; 48: 1380–8. son R, Hannoun-Levi JM, Marcie S. Renaissance of contact
Fernandez-Martos C, Pericay C, Aparicio J, Salud A, Safont M, x-ray therapy for treating rectal cancer. Expert Rev Med
Massuti B, Vera R, Escudero P, Maurel J, Marcuello E, Devices 2011; 8: 483–92.
Mengual JL, Saigi E, Estevan R, Mira M, Polo S, Hernan- Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell
dez A, Gallen M, Arias F, Serra J, Alonso V. Phase II, EP, Alberts SR, Schwartz MA, Benson AB 3rd. Bevacizumab
in combination with oxaliplatin, fluorouracil, and leucovorin Grothey A, Sargent D. Overall survival of patients with
(FOLFOX4) for previously treated metastatic colorectal can- advanced colorectal cancer correlates with availability of fluo-
cer: results from the Eastern Cooperative Oncology Group rouracil, irinotecan, and oxaliplatin regardless of whether
Study E3200. J Clin Oncol 2007; 25: 1539–44. doublet or single-agent therapy is used first line. J Clin
Gilbert A, Ziegler L, Martland M, Davidson S, Efficace F, Oncol 2005; 23: 9441–2.
Sebag-Montefiore D, Velikova G. Systematic review of radia- Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A,
tion therapy toxicity reporting in randomized controlled tri- Ychou M, Humblet Y, Bouche O, Mineur L, Barone C,
als of rectal cancer: a comparison of patient-reported Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM,
outcomes and clinician toxicity reporting. Int J Radiat Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D. Rego-
Oncol Biol Phys 2015; 92: 555–67. rafenib monotherapy for previously treated metastatic col-
Glimelius B. Rectal cancer irradiation. Long course, short orectal cancer (CORRECT): an international, multicentre,
course or something else? Acta Oncol 2006; 45: 1013–7. randomised, placebo-controlled, phase 3 trial. Lancet 2013;
Glimelius B. Optimal time intervals between pre-operative 381: 303–12.
radiotherapy or chemoradiotherapy and surgery in rectal Habr-Gama A, Sabbaga J, Gama-Rodrigues J, Sao Juliao GP,
cancer? Front Oncol 2014; 4: 50. Proscurshim I, Bailao Aguilar P, Nadalin W, Perez RO. Watch
Glynne-Jones R, Hadaki M, Harrison M. The status of tar- and wait approach following extended neoadjuvant chemora-
geted agents in the setting of neoadjuvant radiation therapy diation for distal rectal cancer: are we getting closer to anal
in locally advanced rectal cancers. J Gastrointest Oncol 2013; cancer management? Dis Colon Rectum 2013; 56: 1109–17.
4: 264–84. Hahnloser D, Wolff BG, Larson DW, Ping J, Nivatvongs S.
Glynne-Jones R, Harrison M. Or why translational research is Immediate radical resection after local excision of rectal can-
vital for the future treatment of rectal cancer. Clin Transl cer: an oncologic compromise? Dis Colon Rectum 2005; 48:
Oncol 2011; 13: 701–2. 429–37.
Glynne-Jones R, Hughes R. Critical appraisal of the ‘wait and Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van
see’ approach in rectal cancer for clinical complete respon- Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ.
ders after chemoradiation. Br J Surg 2012; 99: 897–909. Capecitabine plus oxaliplatin compared with fluorouracil and
Gollins S, Sebag-Montefiore D. Neoadjuvant treatment strate- folinic acid as adjuvant therapy for stage III colon cancer. J
gies for locally advanced rectal cancer. Clin Oncol (R Coll Clin Oncol 2011; 29: 1465–71.
Radiol) 2016; 28: 146–51. Hartley A, Ho KF, McConkey C, Geh JI. Pathological com-
Gollins S, Sebag-Montefiore D, Richard AR, Saunders M, plete response following pre-operative chemoradiotherapy in
Grieve R, Scott N, Brown G, Quirke P, Butlin L, Ray R, rectal cancer: analysis of phase II/III trials. Br J Radiol
Griffiths G, Hurt C. A phase II single arm feasibility trial of 2005; 78: 934–8.
neoadjuvant chemotherapy (NAC) with oxaliplatin/fluo- Heald RJ, Husband EM, Ryall RD. The mesorectum in rectal
rouracil (OxMdG) then short-course preoperative radiother- cancer surgery–the clue to pelvic recurrence? Br J Surg
apy (SCPRT) then immediate surgery in operable rectal 1982; 69: 613–6.
cancer (ORC): COPERNICUS (NCT01263171). J Clin Heald RJ, Ryall RD. Recurrence and survival after total mesorec-
Oncol 2015; 33: suppl; abstr 3609. tal excision for rectal cancer. Lancet 1986; 1: 1479–82.
Gollins S, Sun Myint A, Haylock B, Wise M, Saunders M, Healthcare Quality Improvement Partnership (2015) Bowel
Neupane R, Essapen S, Samuel L, Dougal M, Lloyd A, Cancer Audit Report 2015.
Morris J, Topham C, Susnerwala S. Preoperative chemora- Heijnen LA, Lambregts DM, Mondal D, Martens MH, Riedl
diotherapy using concurrent capecitabine and irinotecan in RG, Beets GL, Beets-Tan RG. Diffusion-weighted MR
magnetic resonance imaging-defined locally advanced rectal imaging in primary rectal cancer staging demonstrates but
cancer: impact on long-term clinical outcomes. J Clin Oncol does not characterise lymph nodes. Eur Radiol 2013; 23:
2011; 29: 1042–9. 3354–60.
Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr Herrstedt J, Roila F, Warr D, Celio L, Navari RM, Hesketh
DJ. Adjuvant chemotherapy versus observation in patients PJ, Chan A, Aapro MS. 2006 updated MASCC/ESMO
with colorectal cancer: a randomised study. Lancet 2007; consensus recommendations: prevention of nausea and vom-
370: 2020–9. iting following high emetic risk chemotherapy. Support Care
Gray RG, Quirke P, Handley K, Lopatin M, Magill L, Baehner Cancer 2017; 25: 277–288.
FL, Beaumont C, Clark-Langone KM, Yoshizawa CN, Lee Hershman MJ, Myint AS, Makin CA. Multi-modality approach
M, Watson D, Shak S, Kerr DJ. Validation study of a quan- in curative local treatment of early rectal carcinomas.
titative multigene reverse transcriptase-polymerase chain Colorectal Dis 2003; 5: 445–50.
reaction assay for assessment of recurrence risk in patients Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S,
with stage II colon cancer. J Clin Oncol 2011; 29: 4611–9. Hartmann JT, Muller L, Link H, Moehler M, Kettner E,
Greenberg JA, Shibata D, Herndon JE 2nd, Steele GD Jr, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kre-
Mayer R, Bleday R. Local excision of distal rectal cancer: an mers S, Constantin C, Hipp M, Hartung G, Gencer D,
update of cancer and leukemia group B 8984. Dis Colon Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy
Rectum 2008; 51: 1185–91 ; discussion 1191–4. with capecitabine versus fluorouracil for locally advanced
rectal cancer: a randomised, multicentre, non-inferiority, Kulkarni T, Gollins S, Maw A, Hobson P, Byrne R, Widdow-
phase 3 trial. Lancet Oncol 2012; 13: 579–88. son D. Magnetic resonance imaging in rectal cancer down-
Holm T, Ljung A, Haggmark T, Jurell G, Lagergren J. staged using neoadjuvant chemoradiation: accuracy of
Extended abdominoperineal resection with gluteus maximus prediction of tumour stage and circumferential resection
flap reconstruction of the pelvic floor for rectal cancer. Br J margin status. Colorectal Dis 2008; 10: 479–89.
Surg 2007; 94: 232–8. Lembersky BC, Wieand HS, Petrelli NJ, O’Connell MJ, Colan-
Hompes R, McDonald R, Buskens C, Lindsey I, Armitage N, gelo LH, Smith RE, Seay TE, Giguere JK, Marshall ME,
Hill J, Scott A, Mortensen NJ, Cunningham C. Completion Jacobs AD, Colman LK, Soran A, Yothers G, Wolmark N.
surgery following transanal endoscopic microsurgery: assess- Oral uracil and tegafur plus leucovorin compared with intra-
ment of quality and short- and long-term outcome. Colorec- venous fluorouracil and leucovorin in stage II and III carci-
tal Dis 2013; 15: e576–81. noma of the colon: results from National Surgical Adjuvant
Hoskin PJ, de Canha SM, Bownes P, Bryant L, Glynne Jones Breast and Bowel Project Protocol C-06. J Clin Oncol
R. High dose rate afterloading intraluminal brachytherapy 2006; 24: 2059–64.
for advanced inoperable rectal carcinoma. Radiother Oncol Li C, Carli F, Lee L, Charlebois P, Stein B, Liberman AS, Kaneva
2004; 73: 195–8. P, Augustin B, Wongyingsinn M, Gamsa A, Kim DJ, Vassiliou
How P, Stelzner S, Branagan G, Bundy K, Chandrakumaran MC, Feldman LS. Impact of a trimodal prehabilitation pro-
K, Heald RJ, Moran B. Comparative quality of life in gram on functional recovery after colorectal cancer surgery: a
patients following abdominoperineal excision and low ante- pilot study. Surg Endosc 2013; 27: 1072–82.
rior resection for low rectal cancer. Dis Colon Rectum 2012; Lindegaard J, Gerard JP, Sun Myint A, Myerson R, Thomsen
55: 400–6. H, Laurberg S. Whither papillon? Future directions for con-
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, tact radiotherapy in rectal cancer. Clin Oncol (R Coll
Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Radiol) 2007; 19: 738–41.
Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kab- Maas M, Lambregts DM, Nelemans PJ, Heijnen LA, Martens
binavar F. Bevacizumab plus irinotecan, fluorouracil, and MH, Leijtens JW, Sosef M, Hulsewe KW, Hoff C, Breukink
leucovorin for metastatic colorectal cancer. N Engl J Med SO, Stassen L, Beets-Tan RG, Beets GL. Assessment of clin-
2004; 350: 2335–42. ical complete response after chemoradiation for rectal cancer
Hutchins G, Southward K, Handley K, Magill L, Beaumont C, with digital rectal examination, endoscopy, and MRI: selec-
Stahlschmidt J, Richman S, Chambers P, Seymour M, Kerr tion for organ-saving treatment. Ann Surg Oncol 2015; 22:
D, Gray R, Quirke P. Value of mismatch repair, KRAS, and 3873–80.
BRAF mutations in predicting recurrence and benefits from Maas M, Nelemans PJ, Valentini V, Das P, Rodel C, Kuo LJ,
chemotherapy in colorectal cancer. J Clin Oncol 2011; 29: Calvo FA, Garcia-Aguilar J, Glynne-Jones R, Haustermans
1261–70. K, Mohiuddin M, Pucciarelli S, Small W Jr, Suarez J,
Johnston CF, Tomlinson G, Temple LK, Baxter NN. The Theodoropoulos G, Biondo S, Beets-Tan RG, Beets GL.
management of patients with T1 adenocarcinoma of the low Long-term outcome in patients with a pathological complete
rectum: a decision analysis. Dis Colon Rectum 2013; 56: response after chemoradiation for rectal cancer: a pooled
400–7. analysis of individual patient data. Lancet Oncol 2010; 11:
Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, 835–44.
Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt Maas M, Nelemans PJ, Valentini V, Crane CH, Capirci C,
NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. R€odel C, Nash GM, Kuo LJ, Glynne-Jones R, Garcıa-
Cetuximab for the treatment of colorectal cancer. N Engl J Aguilar J, Suarez J, Calvo FA, Pucciarelli S, Biondo S, Theo-
Med 2007; 357: 2040–8. doropoulos G, Lambregts DM, Beets-Tan RG, Beets GL.
Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Adjuvant chemotherapy in rectal cancer: defining subgroups
Mowat FS, Alexander DD, Choti MA, Poston G. Survival who may benefit after neoadjuvant chemoradiation and
after liver resection in metastatic colorectal cancer: review resection: a pooled analysis of 3,313 patients. Int J Cancer
and meta-analysis of prognostic factors. Clin Epidemiol 2015; 137: 212–20.
2012; 4: 283–301. Marijnen CA, Kapiteijn E, van de Velde CJ, Martijn H, Steup
Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, Kranenbarg EK, Leer JW. Acute side
WH, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van effects and complications after short-term preoperative
Krieken JH, Leer JW, van de Velde CJ. Preoperative radio- radiotherapy combined with total mesorectal excision in pri-
therapy combined with total mesorectal excision for resect- mary rectal cancer: report of a multicenter randomized trial.
able rectal cancer. N Engl J Med 2001; 345: 638–46. J Clin Oncol 2002; 20: 817–25.
Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Marijnen CA, Nagtegaal ID, Kapiteijn E, Kranenbarg EK,
Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Noordijk EM, van Krieken JH, van de Velde CJ, Leer JW.
Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore Radiotherapy does not compensate for positive resection
MJ, Zalcberg JR. K-ras mutations and benefit from cetux- margins in rectal cancer patients: report of a multicenter ran-
imab in advanced colorectal cancer. N Engl J Med 2008; domized trial. Int J Radiat Oncol Biol Phys 2003; 55:
359: 1757–65. 1311–20.
Marijnen CA, van de Velde CJ, Putter H, van den Brink M, Maas MERCURY Study Group. Diagnostic accuracy of preoperative
CP, Martijn H, Rutten HJ, Wiggers T, Kranenbarg EK, Leer magnetic resonance imaging in predicting curative resection
JW, Stiggelbout AM. Impact of short-term preoperative of rectal cancer: prospective observational study. BMJ 2006;
radiotherapy on health-related quality of life and sexual func- 333: 779.
tioning in primary rectal cancer: report of a multicenter ran- MERCURY Study Group. Extramural depth of tumor invasion
domized trial. J Clin Oncol 2005; 23: 1847–58. at thin-section MR in patients with rectal cancer: results of
Marr R, Birbeck K, Garvican J, Macklin CP, Tiffin NJ, Parsons the MERCURY study. Radiology 2007; 243: 132–9.
WJ, Dixon MF, Mapstone NP, Sebag-Montefiore D, Scott Mishra SI, Scherer RW, Geigle PM, Berlanstein DR, Topaloglu
N, Johnston D, Sagar P, Finan P, Quirke P. The modern O, Gotay CC, Snyder C. Exercise interventions on health-
abdominoperineal excision: the next challenge after total related quality of life for cancer survivors. Cochrane Database
mesorectal excision. Ann Surg 2005; 242: 74–82. Syst Rev 2012: CD007566.
Marshall MJ, Smart NJ, Daniels IR. Biologic meshes in per- Moore JS, Cataldo PA, Osler T, Hyman NH. Transanal endo-
ineal reconstruction following extra-levator abdominoper- scopic microsurgery is more effective than traditional transa-
ineal excision (elAPE). Colorectal Dis 2012; 14(Suppl 3): nal excision for resection of rectal masses. Dis Colon Rectum
12–8. 2008; 51: 1026–30 ; discussion 1030–1.
Martin RS, Hayes B, Gregorevic K, Lim WK. The effects of Moore TJ, Moran BJ. Precision surgery, precision terminology:
advance care planning interventions on nursing home resi- the origins and meaning of ELAPE. Colorectal Dis 2012;
dents: a systematic review. J Am Med Dir Assoc 2016; 17: 14: 1173–4.
284–93. Moran B, Dattani M. “SPECC and SPECULATION”: is a sig-
Martling AL, Holm T, Rutqvist LE, Moran BJ, Heald RJ, nificant polyp benign or an early colorectal cancer? How do
Cedemark B. Effect of a surgical training programme on we know and what do we do? Colorectal Dis 2016; 18:
outcome of rectal cancer in the County of Stockholm. 745–8.
Stockholm Colorectal Cancer Study Group, Basingstoke Moran BJ, Holm T, Brannagan G, Chave H, Quirke P, West
Bowel Cancer Research Project. Lancet 2000; 356: 93–6. N, Brown G, Glynne-Jones R, Sebag-Montefiore D, Cun-
Maughan TS, Adams RA, Smith CG, Meade AM, Seymour ningham C, Janjua AZ, Battersby NJ, Crane S, McMeeking
MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny A. The English national low rectal cancer development pro-
SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, gramme: key messages and future perspectives. Colorectal
Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan Dis 2014; 16: 173–8.
R, Cheadle JP. Addition of cetuximab to oxaliplatin-based Morino M, Risio M, Bach S, Beets-Tan R, Bujko K, Panis Y,
first-line combination chemotherapy for treatment of Quirke P, Rembacken B, Rullier E, Saito Y, Young-Fadok
advanced colorectal cancer: results of the randomised phase T, Allaix ME. Early rectal cancer: the European Association
3 MRC COIN trial. Lancet 2011; 377: 2103–14. for Endoscopic Surgery (EAES) clinical consensus confer-
Mawdsley S, Glynne-Jones R, Grainger J, Richman P, Makris ence. Surg Endosc 2015; 29: 755–73.
A, Harrison M, Ashford R, Harrison RA, Osborne M, Liv- Munro AJ, Bentley AHM. Adjuvant radiotherapy in operable
ingstone JI, MacDonald P, Mitchell IC, Meyrick-Thomas J, rectal cancer: a systematic review. Semin Colon Rectal Surg
Northover JM, Windsor A, Novell R, Wallace M. Can 2002; 13: 31–42.
histopathologic assessment of circumferential margin after Nagtegaal ID, Gosens MJ, Marijnen CA, Rutten HJ, van de
preoperative pelvic chemoradiotherapy for T3-T4 rectal can- Velde CJ, van Krieken JH. Combinations of tumor and
cer predict for 3-year disease-free survival? Int J Radiat treatment parameters are more discriminative for prognosis
Oncol Biol Phys 2005; 63: 745–52. than the present TNM system in rectal cancer. J Clin Oncol
Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Car- 2007; 25: 1647–50.
bonero R, Mizunuma N, Yamazaki K, Shimada Y, Taber- Nagtegaal ID, Marijnen CA, Kranenbarg EK, van de Velde CJ,
nero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran van Krieken JH. Circumferential margin involvement is still
B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen an important predictor of local recurrence in rectal carci-
H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A. noma: not one millimeter but two millimeters is the limit.
Randomized trial of TAS-102 for refractory metastatic col- Am J Surg Pathol 2002; 26: 350–7.
orectal cancer. N Engl J Med 2015; 372: 1909–19. Nagtegaal ID, Quirke P. What is the role for the circumferen-
McCleary NJ, Meyerhardt JA, Green E, Yothers G, de Gra- tial margin in the modern treatment of rectal cancer? J Clin
mont A, Van Cutsem E, O’Connell M, Twelves CJ, Saltz Oncol 2008; 26: 303–12.
LB, Haller DG, Sargent DJ. Impact of age on the efficacy of Nagtegaal ID, van de Velde CJ, Marijnen CA, van Krieken JH,
newer adjuvant therapies in patients with stage II/III colon Quirke P. Low rectal cancer: a call for a change of approach in
cancer: findings from the ACCENT database. J Clin Oncol abdominoperineal resection. J Clin Oncol 2005; 23: 9257–64.
2013; 31: 2600–6. National Institute for Health and Care Excellence (2003)
Medical Research Council Rectal Cancer Working Party. Ran- Guidance on the use of capecitabine and tegafur with uracil
domised trial of surgery alone versus radiotherapy followed for metastatic colorectal cancer. Technology appraisal guid-
by surgery for potentially operable locally advanced rectal ance (TA61): https://www.nice.org.uk/guidance/ta61 (ac-
cancer. Lancet 1996; 348: 1605–10. cessed 19 May 2017).
National Institute for Health and Care Excellence (2005) Interventional procedures guidance (IPG531): https://www.
Colorectal cancer (advanced) - irinotecan, oxaliplatin and nice.org.uk/guidance/ipg531 (accessed 19 May 2017).
raltitrexed. Technology appraisal guidance (TA93): https:// Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D,
www.nice.org.uk/guidance/ta93 (accessed 19 May 2017). Joseph D, Ackland SP, Schache D, McClure B, McLachlan
National Institute for Health and Care Excellence (2006) SA, McKendrick J, Leong T, Hartopeanu C, Zalcberg J,
Capecitabine and oxaliplatin in the adjuvant treatment of Mackay J. Randomized trial of short-course radiotherapy
stage III (Dukes’ C) colon cancer. Technology appraisal versus long-course chemoradiation comparing rates of local
guidance (TA100): https://www.nice.org.uk/guidance/ recurrence in patients with T3 rectal cancer: Trans-Tasman
TA100 (accessed 19 May 2017). Radiation Oncology Group trial 01.04. J Clin Oncol 2012a;
National Institute for Health and Care Excellence (2007) 30: 3827–33.
Bevacizumab and cetuximab for the treatment of metastatic Ngan SY, Fisher R, Burmeister B, Mackay J, McLachlan S,
colorectal cancer. Technology appraisal guidance (TA118): Beresford J, McClure B, Goldstein D, Joseph D, Solomon
https://www.nice.org.uk/guidance/TA118 (accessed 19 M. Long-term quality of life in patients treated in TROG
May 2017). 01.04: a randomized trial comparing short course and long
National Institute for Health and Care Excellence (2010) course preoperative radiation therapy for rectal cancer. Int J
Bevacizumab in combination with oxaliplatin and either flu- Radiat Oncol Biol Phys 2012b; 84: S143–4.
orouracil plus folinic acid or capecitabine for the treatment Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM,
of metastatic colorectal cancer. Technology appraisal guid- Rougier P, Bechstein WO, Primrose JN, Walpole ET,
ance (TA212): https://www.nice.org.uk/guidance/TA212 Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L,
(accessed 19 May 2017). Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruen-
National Institute for Health and Care Excellence (2011) berger T. Perioperative chemotherapy with FOLFOX4 and
Colorectal cancer: diagnosis and management. Clinical surgery versus surgery alone for resectable liver metastases
guideline (CG131): https://www.nice.org.uk/guidance/ from colorectal cancer (EORTC Intergroup trial 40983): a
CG131 (accessed 19 May 2017). randomised controlled trial. Lancet 2008; 371: 1007–16.
National Institute for Health and Care Excellence (2014) O’Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra
Aflibercept in combination with irinotecan and fluorouracil- CJ, Sharif S, Pitot HC, Shields AF, Landry JC, Ryan DP,
based therapy for treating metastatic colorectal cancer that Parda DS, Mohiuddin M, Arora A, Evans LS, Bahary N,
has progressed following prior oxaliplatin-based chemother- Soori GS, Eakle J, Robertson JM, Moore DF Jr, Mullane
apy. Technology appraisal guidance (TA307): https://www. MR, Marchello BT, Ward PJ, Wozniak TF, Roh MS,
nice.org.uk/Guidance/ta307 (accessed 19 May 2017). Yothers G, Wolmark N. Capecitabine and oxaliplatin in the
National Institute for Health and Care Excellence (2016) Tri- preoperative multimodality treatment of rectal cancer: sur-
fluridine–tipiracil for previously treated metastatic colorectal gical end points from National Surgical Adjuvant Breast
cancer. Technology appraisal guidance (TA405): https:// and Bowel Project trial R-04. J Clin Oncol 2014; 32:
www.nice.org.uk/guidance/ta405 (accessed 19 May 2017). 1927–34.
National Institute for Health and Clinical Excellence (2004) Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Put-
Improving supportive and palliative care for adults with can- ter H, Wiggers T, Rutten H, Pahlman L, Glimelius B, Leer
cer. Cancer service guideline [CSG4]: https://www.nice. JW, van de Velde CJ. The TME trial after a median follow-
org.uk/guidance/csg4 (accessed 19 May 2017). up of 6 years: increased local control but no survival benefit
National Institute for Health and Clinical Excellence (2009) in irradiated patients with resectable rectal carcinoma. Ann
Cetuximab for the first line treatment of metastatic colorectal Surg 2007; 246: 693–701.
cancer. Technology appraisal guidance (TA176): https:// Peeters KC, van de Velde CJ, Leer JW, Martijn H, Junggeburt
www.nice.org.uk/Guidance/TA176 (accessed 19 May 2017). JM, Kranenbarg EK, Steup WH, Wiggers T, Rutten HJ,
National Institute for Health and Clinical Excellence (2011) Marijnen CA. Late side effects of short-course preoperative
Colorectal cancer: diagnosis and management. NICE guide- radiotherapy combined with total mesorectal excision for
lines (CG131): https://www.nice.org.uk/guidance/cg131 rectal cancer: increased bowel dysfunction in irradiated
(accessed 19 May 2017). patients–a Dutch colorectal cancer group study. J Clin Oncol
National Institute for Health and Clinical Excellence (2015a) 2005; 23: 6199–206.
Care of dying adults in the last days of life. NICE guideline Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M,
(NG31): https://www.nice.org.uk/guidance/ng31 (ac- Hotko Y, Andre T, Chan E, Lordick F, Punt CJ, Strickland
cessed 19 May 2017). AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E,
National Institute for Health and Clinical Excellence (2015b) Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Ran-
Low energy contact X-ray brachytherapy (the Papillon tech- domized phase III study of panitumumab with fluorouracil,
nique) for early stage rectal cancer. Interventional proce- leucovorin, and irinotecan (FOLFIRI) compared with FOL-
dures guidance [IPG532]: https://www.nice.org.uk/guida FIRI alone as second-line treatment in patients with meta-
nce/ipg532 (accessed 19 May 2017). static colorectal cancer. J Clin Oncol 2010; 28: 4706–13.
National Institute for Health and Clinical Excellence (2015c) PELICAN Cancer Foundation About LOREC: http://www.
Preoperative high dose rate brachytherapy for rectal cancer. lorec.nhs.uk/ (accessed 19 May 2017).
Pettersson D, Holm T, Iversen H, Blomqvist L, Glimelius B, results of the multicentre, open-label, randomised, phase 3
Martling A. Preoperative short-course radiotherapy with trial. Lancet Oncol 2015; 16: 979–89.
delayed surgery in primary rectal cancer. Br J Surg 2012; Royal College of Physicians (2016) End of Life Care Audit –
99: 577–83. Dying in Hospital: National report for England 2016:
Pietrzak L, Bujko K, Nowacki MP, Kepka L, Oledzki J, Rut- https://www.rcplondon.ac.uk/projects/outputs/end-life-ca
kowski A, Szmeja J, Kladny J, Dymecki D, Wieczorek A, re-audit-dying-hospital-national-report-england-2016 (ac-
Pawlak M, Lesniak T, Kowalska T, Richter P. Quality of life, cessed 19 May 2017).
anorectal and sexual functions after preoperative radiother- Rutten HJ, den Dulk M, Lemmens VE, van de Velde CJ, Marij-
apy for rectal cancer: report of a randomised trial. Radiother nen CA. Controversies of total mesorectal excision for rectal
Oncol 2007; 84: 217–25. cancer in elderly patients. Lancet Oncol 2008; 9: 494–501.
Popat S, Hubner R, Houlston RS. Systematic review of Salerno G, Daniels IR, Brown G. Magnetic resonance imaging
microsatellite instability and colorectal cancer prognosis. J of the low rectum: defining the radiological anatomy.
Clin Oncol 2005; 23: 609–18. Colorectal Dis 2006a; 8(Suppl 3): 10–3.
Primrose J, Falk S, Finch-Jones M, Valle J, O’Reilly D, Siriwar- Salerno G, Sinnatamby C, Branagan G, Daniels IR, Heald RJ,
dena A, Hornbuckle J, Peterson M, Rees M, Iveson T, Moran BJ. Defining the rectum: surgically, radiologically
Hickish T, Butler R, Stanton L, Dixon E, Little L, Bowers and anatomically. Colorectal Dis 2006b; 8(Suppl 3): 5–9.
M, Pugh S, Garden OJ, Cunningham D, Maughan T, Salerno GV, Daniels IR, Moran BJ, Heald RJ, Thomas K,
Bridgewater J. Systemic chemotherapy with or without Brown G. Magnetic resonance imaging prediction of an
cetuximab in patients with resectable colorectal liver metas- involved surgical resection margin in low rectal cancer. Dis
tasis: the New EPOC randomised controlled trial. Lancet Colon Rectum 2009; 52: 632–9.
Oncol 2014; 15: 601–11. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A,
Quirke P, Durdey P, Dixon MF, Williams NS. Local recur- Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Cou-
rence of rectal adenocarcinoma due to inadequate surgical ture F, Sirzen F, Cassidy J. Bevacizumab in combination
resection. Histopathological study of lateral tumour spread with oxaliplatin-based chemotherapy as first-line therapy in
and surgical excision. Lancet 1986; 2: 996–9. metastatic colorectal cancer: a randomized phase III study. J
Quirke P, Steele R, Monson J, Grieve R, Khanna S, Couture J, Clin Oncol 2008; 26: 2013–9.
O’Callaghan C, Myint AS, Bessell E, Thompson LC, Parmar Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C,
M, Stephens RJ, Sebag-Montefiore D. Effect of the plane of Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF,
surgery achieved on local recurrence in patients with opera- Karstens JH, Liersch T, Schmidberger H, Raab R. Preopera-
ble rectal cancer: a prospective study using data from the tive versus postoperative chemoradiotherapy for rectal can-
MRC CR07 and NCIC-CTG CO16 randomised clinical cer. N Engl J Med 2004; 351: 1731–40.
trial. Lancet 2009; 373: 821–8. Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W,
Rackley TP, Ma RM, Brown CJ, Hay JH. Transanal local exci- Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann
sion for patients with rectal cancer: can radiation compensate H, Wittekind C, Beissbarth T, Rodel C. Preoperative versus
for what is perceived as a nondefinitive surgical approach? postoperative chemoradiotherapy for locally advanced rectal
Dis Colon Rectum 2016; 59: 173–8. cancer: results of the German CAO/ARO/AIO-94 random-
Radu C, Berglund A, Pahlman L, Glimelius B. Short-course pre- ized phase III trial after a median follow-up of 11 years. J
operative radiotherapy with delayed surgery in rectal cancer - Clin Oncol 2012; 30: 1926–33.
a retrospective study. Radiother Oncol 2008; 87: 343–9. Schmoll HJ, Haustermans K, Price T, Nordlinger B, Hofheinz
Renehan AG, Malcomson L, Emsley R, Gollins S, Maw A, R, Daisne JF, Janssens J, Brenner B, Schmidt P, Reinel H,
Myint AS, Rooney PS, Susnerwala S, Blower A, Saunders Hollerbach S, Caca K, Fauth F, Hannig CVZJ, Tebbutt N,
MP, Wilson MS, Scott N, O’Dwyer ST. Watch-and-wait Mauer M, Messina C, Lutz M, Van CE. Preoperative
approach versus surgical resection after chemoradiotherapy chemoradiotherapy and postoperative chemotherapy with
for patients with rectal cancer (the OnCoRe project): a capecitabine and oxaliplatin vs. capecitabine alone in locally
propensity-score matched cohort analysis. Lancet Oncol advanced rectal cancer: Response to the local treatment after
2015; 17: 174–83. chemoradiation and surgery as secondary endpoin. Ann
Ricciardi R, Madoff RD, Rothenberger DA, Baxter NN. Popu- Oncol 2013; 24: iv120.
lation-based analyses of lymph node metastases in colorectal Sebag-Montefiore D, Glynne-Jones R, Mortensen N, Bedi C,
cancer. Clin Gastroenterol Hepatol 2006; 4: 1522–7. Wilson C, Geh J, McDonald AC. Pooled analysis of out-
Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, come measures including the histopathological R0 resection
Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Wel- rate after pre-operative chemoradiation for locally advanced
zenbach M, Raab HR, Wittekind C, Strobel P, Staib L, Wil- rectal cancer. Colorectal Dis 2005; 7: 1–143.
helm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve
Schlenska-Lange A, Folprecht G, Sauer R, Liersch T. Oxali- R, Khanna S, Quirke P, Couture J, de Metz C, Myint AS,
platin added to fluorouracil-based preoperative chemoradio- Bessell E, Griffiths G, Thompson LC, Parmar M. Preopera-
therapy and postoperative chemotherapy of locally advanced tive radiotherapy versus selective postoperative chemoradio-
rectal cancer (the German CAO/ARO/AIO-04 study): final therapy in patients with rectal cancer (MRC CR07 and
NCIC-CTG C016): a multicentre, randomised trial. Lancet EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kroning
2009; 373: 811–20. H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris
Seymour MT, Brown SR, Middleton G, Maughan T, Richman HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan
S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, after fluoropyrimidine and oxaliplatin failure in patients
Chau I, Hill M, Dawson L, Falk S, O’Callaghan A, Benstead with metastatic colorectal cancer. J Clin Oncol 2008; 26:
K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P. 2311–9.
Panitumumab and irinotecan versus irinotecan alone for Stephens RJ, Thompson LC, Quirke P, Steele R, Grieve R,
patients with KRAS wild-type, fluorouracil-resistant Couture J, Griffiths GO, Sebag-Montefiore D. Impact of
advanced colorectal cancer (PICCOLO): a prospectively short-course preoperative radiotherapy for rectal cancer on
stratified randomised trial. Lancet Oncol 2013; 14: 749–59. patients’ quality of life: data from the Medical Research
Shankland K, Kirkbride P, Bourke A-M, Price J, Walkington L, Council CR07/National Cancer Institute of Canada Clinical
Danson S. The acute oncologist’s role in managing patients Trials Group C016 randomized clinical trial. J Clin Oncol
with cancer and other comorbidities. J Comorb 2012; 2: 2010; 28: 4233–9.
10–7. Stintzing S, Jung A, Rossius L, Modest DP, Weikersthal L,
Shihab OC, Heald RJ, Rullier E, Brown G, Holm T, Quirke Decker T, M€ ohler M, Scheithauer W, Kirchner T, Heine-
P, Moran BJ. Defining the surgical planes on MRI improves mann V. Analysis of KRAS/NRAS and BRAF mutations in
surgery for cancer of the low rectum. Lancet Oncol 2009; FIRE-3: A randomized phase III study of FOLFIRI plus
10: 1207–11. cetuximab or bevacizumab as first-line treatment for wild-
Shihab OC, How P, West N, George C, Patel U, Quirke P, type KRAS (exon 2) metastatic colorectal cancer patients. In
Heald RJ, Moran BJ, Brown G. Can a novel MRI staging ECCO Abstract E17-7073. 2013, Amsterdam
system for low rectal cancer aid surgical planning? Dis Colon Sun Myint A. Radiotherapy for early rectal cancer. Clin Oncol
Rectum 2011; 54: 1260–4. (R Coll Radiol) 2007; 19: 637–8.
Shihab OC, Quirke P, Heald RJ, Moran BJ, Brown G. Mag- Sun Myint A, Grieve RJ, McDonald AC, Levine EL, Ramani S,
netic resonance imaging-detected lymph nodes close to the Perkins K, Wong H, Makin CA, Hershman MJ. Combined
mesorectal fascia are rarely a cause of margin involvement modality treatment of early rectal cancer: the UK experience.
after total mesorectal excision. Br J Surg 2010; 97: 1431–6. Clin Oncol (R Coll Radiol) 2007; 19: 674–81.
Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers Svoboda V, Beck-Bornholdt HP, Herrmann T, Alberti W,
GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van Jung H. Late complications after a combined pre and post-
der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoe- operative (sandwich) radiotherapy for rectal cancer. Radio-
ven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, ther Oncol 1999; 53: 177–87.
Honkoop AH, Mol L, Punt CJ, Koopman M. Maintenance Swedish Rectal Cancer Trial. Improved survival with preopera-
treatment with capecitabine and bevacizumab in metastatic tive radiotherapy in resectable rectal cancer. Swedish Rectal
colorectal cancer (CAIRO3): a phase 3 randomised con- Cancer Trial. N Engl J Med 1997; 336: 980–7.
trolled trial of the Dutch Colorectal Cancer Group. Lancet Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P,
2015; 385: 1843–52. van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ,
Simmonds PC. Palliative chemotherapy for advanced colorectal Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept ver-
cancer: systematic review and meta-analysis. Colorectal Can- sus placebo in combination with fluorouracil, leucovorin and
cer Collaborative Group. BMJ 2000; 321: 531–5. irinotecan in the treatment of previously treated metastatic
Smart CJ, Korsgen S, Hill J, Speake D, Levy B, Steward M, colorectal cancer: prespecified subgroup analyses from the
Geh JI, Robinson J, Sebag-Montefiore D, Bach SP. Multi- VELOUR trial. Eur J Cancer 2014; 50: 320–31.
centre study of short-course radiotherapy and transanal Tait D. Background/CASPAR study. Proceedings of the Inter-
endoscopic microsurgery for early rectal cancer. Br J Surg national Cancer Imaging Society (ICIS) 15th Annual Teach-
2016; 103: 1069–75. ing Course. Cancer Imaging 2015; 15(Suppl 1): O1.
Smith N, Brown G. Preoperative staging of rectal cancer. Acta Taylor F, Mangat N, Swift IR, Brown G. Proforma-based
Oncol 2008; 47: 20–31. reporting in rectal cancer. Cancer Imaging 2010; 10(Spec
Smith NJ, Barbachano Y, Norman AR, Swift RI, Abulafi AM, no A): S142–50.
Brown G. Prognostic significance of magnetic resonance Taylor FG, Quirke P, Heald RJ, Moran B, Blomqvist L, Swift
imaging-detected extramural vascular invasion in rectal can- I, Sebag-Montefiore DJ, Tekkis P, Brown G. Preoperative
cer. Br J Surg 2008; 95: 229–36. high-resolution magnetic resonance imaging can identify
Smith TJ, Temin S, Alesi ER, Abernethy AP, Balboni TA, good prognosis stage I, II, and III rectal cancer best man-
Basch EM, Ferrell BR, Loscalzo M, Meier DE, Paice JA, aged by surgery alone: a prospective, multicenter, European
Peppercorn JM, Somerfield M, Stovall E, Von Roenn JH. study. Ann Surg 2011; 253: 711–9.
American Society of Clinical Oncology provisional clinical Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S,
opinion: the integration of palliative care into standard Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl
oncology care. J Clin Oncol 2012; 30: 880–7. WF, Billings JA, Lynch TJ. Early palliative care for patients
Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abu- with metastatic non-small-cell lung cancer. N Engl J Med
bakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer 2010; 363: 733–42.
The Economist Intelligence Unit (2015) The 2015 Quality of van den Broek CB, Vermeer TA, Bastiaannet E, Rutten HJ,
Death Index: Ranking palliative care across the world: van de Velde CJ, Marijnen CA. Impact of the interval
http://www.apcp.com.pt/uploads/2015-EIU-Quality-of-Dea between short-course radiotherapy and surgery on outcomes
th-Index-Oct-6-FINAL.pdf (accessed 19 May 2017). of rectal cancer patients. Eur J Cancer 2013; 49: 3131–9.
The Royal College of Radiologists (2014) Recommendations van Gijn W, Brehm V, de Graaf E, Neijenhuis PA, Stassen LP,
for cross-sectional imaging in cancer management, Second Leijtens JW, Van De Velde CJ, Doornebosch PG. Unex-
edition Vol. 2016. https://www.rcr.ac.uk/publication/ pected rectal cancer after TEM: outcome of completion sur-
recommendations-cross-sectional-imaging-cancer-manageme gery compared with primary TME. Eur J Surg Oncol 2013;
nt-second-edition (accessed 19 May 2017). 39: 1225–9.
Thirion P, Wolmark N, Haddad E, Buyse M, Piedbois P. Sur- Verseveld M, de Graaf EJ, Verhoef C, van Meerten E, Punt
vival impact of chemotherapy in patients with colorectal CJ, de Hingh IH, Nagtegaal ID, Nuyttens JJ, Marijnen CA,
metastases confined to the liver: a re-analysis of 1458 non- de Wilt JH. Chemoradiation therapy for rectal cancer in the
operable patients randomised in 22 trials and 4 meta-ana- distal rectum followed by organ-sparing transanal endo-
lyses. Meta-Analysis Group in Cancer. Ann Oncol 1999; 10: scopic microsurgery (CARTS study). Br J Surg 2015; 102:
1317–20. 853–60.
Tournigand C, Andre T, Bonnetain F, Chibaudel B, Lledo G, Wang C, Zhou Z, Wang Z, Zheng Y, Zhao G, Yu Y, Cheng
Hickish T, Tabernero J, Boni C, Bachet JB, Teixeira L, de Z, Chen D, Liu W. Patterns of neoplastic foci and lymph
Gramont A. Adjuvant therapy with fluorouracil and oxali- node micrometastasis within the mesorectum. Langenbecks
platin in stage II and elderly patients (between ages 70 and Arch Surg 2005; 390: 312–8.
75 years) with colon cancer: subgroup analyses of the Multi- West NP, Anderin C, Smith KJ, Holm T, Quirke P. Multicen-
center International Study of Oxaliplatin, Fluorouracil, and tre experience with extralevator abdominoperineal excision
Leucovorin in the Adjuvant Treatment of Colon Cancer for low rectal cancer. Br J Surg 2010; 97: 588–99.
trial. J Clin Oncol 2012; 30: 3353–60. Wibe A, Moller B, Norstein J, Carlsen E, Wiig JN, Heald
Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel RJ, Langmark F, Myrvold HE, Soreide O. A national
G, Wong A, Diaz-Rubio E, Gilberg F, Cassidy J. Capecita- strategic change in treatment policy for rectal cancer–im-
bine versus 5-fluorouracil/folinic acid as adjuvant therapy plementation of total mesorectal excision as routine treat-
for stage III colon cancer: final results from the X-ACT ment in Norway. A national audit. Dis Colon Rectum
trial with analysis by age and preliminary evidence of a 2002; 45: 857–66.
pharmacodynamic marker of efficacy. Ann Oncol 2012; 23: Williams JG, Pullan RD, Hill J, Horgan PG, Salmo E, Bucha-
1190–7. nan GN, Rasheed S, McGee SG, Haboubi N. Management
Tytherleigh MG, Warren BF, Mortensen NJ. Management of of the malignant colorectal polyp: ACPGBI position state-
early rectal cancer. Br J Surg 2008; 95: 409–23. ment. Colorectal Dis 2013; 15(Suppl 2): 1–38.
Ueno H, Mochizuki H, Hashiguchi Y, Ishiguro M, Miyoshi Williams P, Warwick R. (1980). Splanchnology, 36th edn.
M, Kajiwara Y, Sato T, Shimazaki H, Hase K. Potential Churchill Livingstone, London.
prognostic benefit of lateral pelvic node dissection for rectal Wiltink LM, Nout RA, Fiocco M, Meershoek-Klein Kranen-
cancer located below the peritoneal reflection. Ann Surg barg E, Jurgenliemk-Schulz IM, Jobsen JJ, Nagtegaal ID,
2007; 245: 80–7. Rutten HJ, van de Velde CJ, Creutzberg CL, Marijnen CA.
UKCCCR (1989) Handbook for the clinicopathological assess- No increased risk of second cancer after radiotherapy in
ment and staging of colorectal cancer. patients treated for rectal or endometrial cancer in the ran-
Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, domized TME, PORTEC-1, and PORTEC-2 trials. J Clin
Nordlinger B, Topham C, Tabernero J, Andre T, Sobrero Oncol 2015; 33: 1640–6.
AF, Mini E, Greil R, Di Costanzo F, Collette L, Cisar L, Wong RK, Tandan V, De SS, Figueredo A. Pre-operative
Zhang X, Khayat D, Bokemeyer C, Roth AD, Cunningham radiotherapy and curative surgery for the management of
D. Randomized phase III trial comparing biweekly infu- localized rectal carcinoma. Cochrane Database Syst Rev
sional fluorouracil/leucovorin alone or with irinotecan in 2007: CD002102.
the adjuvant treatment of stage III colon cancer: PETACC- Yothers G, O’Connell MJ, Allegra CJ, Kuebler JP, Colangelo
3. J Clin Oncol 2009; 27: 3117–25. LH, Petrelli NJ, Wolmark N. Oxaliplatin as adjuvant therapy
Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, for colon cancer: updated results of NSABP C-07 trial,
Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson including survival and subset analyses. J Clin Oncol 2011;
G, Wolf M, Amado RG. Open-label phase III trial of pani- 29: 3768–74.
tumumab plus best supportive care compared with best You YN, Baxter NN, Stewart A, Nelson H. Is the increasing
supportive care alone in patients with chemotherapy-refrac- rate of local excision for stage I rectal cancer in the United
tory metastatic colorectal cancer. J Clin Oncol 2007; 25: States justified? a nationwide cohort study from the National
1658–64. Cancer Database. Ann Surg 2007; 245: 726–33.

ACPGBI CRC Part 4

Uploaded by

Copyright:

Available Formats

ACPGBI CRC Part 4

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

ACPGBI CRC Part 4

Uploaded by

Copyright:

Available Formats

Guidelines doi:10.1111/codi.

Association of Coloproctology of Great Britain & Ireland

adenocarcinoma with a distal margin at or below 15 cm

Risk of pelvic local recurrence Characteristics of rectal tumours predicted by MRI

Low (resectable) cT1 or cT2 or cT3a and

Maximum Tumour Diameter (cm)

Depth of invasion LyV ≤1 1.1–2 2.1–3 3.1–4 4.1–5 5.1+

pT1 sm1 3.0 3.6 4.4 5.4 6.6 8.1

You might also like