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Perioperative chemotherapy and radiotherapy for colorectal cancer
surgery with SCPRT and delay with long-course
radiotherapy prior to surgery. An interim analysis
of 120 patients treated with SCPRT and delay
reported a pCR rate of 12.5%.50 This strategy
warrants wider evaluation, offers an alternative
treatment when preoperative CRT is not feasible
(comorbidity, relative contraindications to 5FU)
and has been incorporated into three randomised
trials described in the section ‘Neoadjuvant
Chemotherapy’ below.
Late toxicity and second
malignancy
Although preoperative radiotherapy and CRT reduce
the risk of local recurrence, there is no evidence
of an improvement in survival. The benefit in the
reduction in local recurrence must be compared with
the risks of late toxicity. Long-term side-effects of
pelvic radiotherapy for rectal cancer include bowel,
sexual and urinary dysfunction and sterility.
initial Swedish report using wide field radiotherapy
suggested an increased risk of second malignancy.52
However, more recent analysis of Dutch54 and
Swedish55 trials failed to confirm this.
Quality-of-life data from the CR07 trial
demonstrate a significant impairment in sexual
function attributable to surgery and a further
detriment due to radiotherapy.53 Both the Dutch
and CR07 trials show a similar pattern for faecal
incontinence.
51,53
The Polish and TROG trials
have not shown a difference in clinician-assessed
late toxicity when short-course radiotherapy was
compared with preoperative CRT. A systematic
review of randomised controlled trials in rectal
51–53
An
46,47
cancer showed that patient-reported outcomes
demonstrated consistently higher toxicity than
clinician-reported outcomes and that there was
variable quality between studies.
56
Patient selection
The routine use of preoperative radiotherapy is
difficult to justify if good quality TME alone reduces
the risk of local recurrence to low levels and a more
selective approach is needed.
The MERCURY international phase II
observational study established the role of pelvic
magnetic resonance imaging (MRI) in the staging of
rectal cancer.57 This study demonstrated equivalence
between the measured extramural spread of
tumour seen on high-resolution MRI and the same
measurement on histopathology whole mounts after
surgery alone. Further reports have described a good
prognosis group of patients in whom the risk of
local recurrence is very low without radiotherapy.58
MRI can also identify when the primary tumour
extends to or within 1 mm of the mesorectal fascia59
(Fig. 7.3), a situation where downstaging with
preoperative CRT is indicated (Fig.7.4). The recent
MERCURY II prospective observational study has
suggested that MRI scanning for low rectal cancers
can identify tumours in which there is a ‘safe’
resection plane and preoperative radiotherapy is
not indicated.
Many centres have adopted a risk-stratified
approach. The 2011 UK NICE guidelines12
defined three risk groups for local recurrence. In
the low-risk group, radiotherapy is not given and
preoperative CRT is recommended in the highrisk, margin-threatened group (Table 7.3). In the
60
a
Figure7.3 • MRI is now a standard preoperative technique to identify rectal cancer that threatens, involves or breaches
mesorectal fascia. Such patients can then be selected for more aggressive preoperative treatment to try to downsize the
tumour and facilitate complete resection. In (a) a low rectal tumour threatens the mesorectal fascia anteriorly (white arrow)
and also sits very close to the right levator ani at 8 o’clock. In (b) a mid-rectal cancer breaches the mesorectal fascia
(white dashed line) to involve the bladder wall anteriorly (black arrow).
b
81
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Chapter 7
a
Figure7.4 • Response to neoadjuvant chemoradiotherapy. (a) A bulky mid-rectal tumour threatens the expected CRM
anteriorly (white arrow). (b) Following an excellent response to neoadjuvant CRT, the CRM is no longer threatened.
Table7.3 • NICE stratification of rectal cancer according
to risk of local pelvic recurrence
b
tumours. Surgical quality based on TME gradually
improved during the Dutch and CR07 trials but has
also continued to improve since. These advances have
Risk of local pelvic
recurrence
Low (resectable) cT1 or cT2 or cT3a and
Moderate (resectable) any cT3b or greater, in which
High (borderline resectable
or unresectable, i.e.
threatened or involved
CRM)
NICE Guideline CG131; 2011.
Characteristics of rectal
tumours predicted by MRI
no lymph node involvement
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
a threatened (<1 mm) or
breached resection margin or
low tumours encroaching onto
the intersphincteric plane or with
levator involvement
12
markedly improved outcomes using surgery alone,
resulting in low rates of local recurrence. A Norwegian
population-based series of 15 193 rectal cancer patients
from 1993 to 2010 showed that local recurrence rates
following surgery alone were initially high, at 14.1%
(1993–1997), but a decade later had fallen dramatically
to 5.3% (2007–2010).61 Patients who received
preoperative radiotherapy between 2007 and 2010 had
only a marginally lower recurrence rate of 4.3%.
For lower rectal cancers extra-levator abdominoperineal excision has been reported to reduce risks
of resection margin involvement and specimen
perforation and an increasing use of this technique may
in time reduce the use of preoperative radiotherapy.
62,63
However wide variation in radiotherapy usage
exists. In a recent report, among 9201 patients who
had a rectal cancer resection (all disease stages),
across 148 English NHS Trusts, the proportion of
rectal cancer patients managed with surgery alone
varied from as little as 22% to 95%.
64
medium-risk group either SCPRT or preoperative
Sphincter preservation
CRT may be used as there is evidence to support
both approaches and no clear evidence that one is
superior to the other. ESMO guidelines advocate a
similar approach.28 The choice between SCPRT and
CRT remains controversial, particularly because
neither has been shown to increase overall survival.
There is increasing evidence that modern preoperative
staging, combined with adoption of best-quality
TME surgery, produces low recurrence rates using
surgery alone in patients with non-margin-threatened
There is very little evidence to support the view
that preoperative CRT increases the chance of a
sphincter-preserving resection. In the majority of
patients with a mid or upper rectal cancer, an anterior
resection is feasible without tumour shrinkage. Very
low tumours less than 4 cm from the anal verge
require an abdominoperineal excision. Therefore, it
is only in a very small group of patients whose distal
tumour extent is 4–6 cm from the anal verge where
82
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Perioperative chemotherapy and radiotherapy for colorectal cancer
preoperative CRT may play a role in achieving a
sphincter-preserving procedure.
65
Organ preservation
There is increasing interest in the role of non-surgical
therapy to avoid major resectional surgery. This
approach has been pioneered by Habr; patients with
complete clinical response after chemoradiotherapy
undergo intensive follow-up, with surgery reserved
for locoregional failure. Approximately 20–30%
of patients have sustained local control without
radical surgery.
A Dutch publication describes similar results.69
However, only 10% of the patients treated with
CRT achieved a complete clinical response (CCR)
and entered the study. The definition of CCR was
rigorous, consisting of negative biopsy, complete
clinical resolution, no suspicious findings on flexible
sigmoidoscopy and no evidence of residual tumour
on pelvic MRI.
In a recent UK report, 129 rectal cancer patients
achieving a complete clinical response to CRT were
managed by a watch-and-wait approach. A substantial
proportion avoided major surgery, with 44 (34%)
experiencing local regrowths and 36 (88%) of 41
patients with non-metastatic local regrowths being
salvaged.70 There was no difference in overall survival
compared to a matched cohort undergoing surgery,
although the watch-and-wait group had superior 3-year
colostomy-free survival (74% vs 47%, P = 0.0001).
An alternative strategy is to use transanal endoscopic
microsurgery (TEMS)71 to accurately assess the
impact of a good clinical response to preoperative
treatment to determine which patients can undergo
intensive follow-up and those who require a formal
resection based on histopathological findings. Such a
strategy has recently been described for a cohort of 62
patients from four regional UK centres with cT1–2 N0
rectal cancers, staged using high-quality MRI and
endorectal ultrasonography. Following SCRT and
TEMS, 60 patients achieved an R0 resection, 20
resected specimens were ypT0 and only in four
patients were there intraluminal local recurrences.
Prospective multicentre studies are required to
determine the benefits of both of the above strategies.
It is likely that the patients most likely to benefit
from a non-surgical approach are those with early
stage disease. In the UK, this group of patients is not
normally treated with preoperative radiotherapy at all.
Therefore, prospective studies are essential to determine
the value of this approach. The UK phase II TREC
trial (ISRCTN14422743) examined the feasibility of
randomising patients between standard TME versus
SCRT followed by TEMS (results awaited).
Modern radiotherapy techniques, including intensity-
modulated radiotherapy (IMRT) and volumetric arc
therapy (VMAT) (Fig. 7.2), allow increased conformality
66–68
72
of treated volumes. This potentially allows delivery
of increased dose to the tumour without excessive
morbidity to surrounding normal tissues, thereby
reducing short- and long-term toxicity compared to
conventional 3DCT planning. This may have relevance
to an organ-sparing approach although prospective
studies are needed to prove clinical benefit.
73
Low-energy contact X-ray brachytherapy (CXB,
the Papillon technique) involves insertion of an
X-ray tube through the anus and placing it in
close contact with the tumour.74 Recent NICE
Interventional Procedures Guidance (IPG532)75
indicates that CXB is an option for patients with
early rectal cancer in whom surgery is not considered
suitable. Further evidence is required regarding the
benefit of CXB in addition to CRT.
Future directions:
intensification of
neoadjuvant treatment
Reduction of rectal cancer local recurrence has not had
any significant impact on distant metastatic relapse and
this is now the major cause of death.
histological examination of resected specimens predict
increased risk of postoperative systemic recurrence,
including more than 5 mm invasion of disease through
the muscularis propria into the mesorectum (≥T3c),
extramural vascular invasion (EMVI) and lymph node
involvement. For patients with such features, with
optimum surgery and selective use of preoperative
radiotherapy, distant metastatic relapse is about sixfold
greater than local recurrence (about 30% vs 5%).
MRI scanning is the pre-treatment investigation that
can most reliably identify such features.
Potential strategies to improve neoadjuvant therapy
include adding a second drug to preoperative CRT
and the introduction of neoadjuvant chemotherapy
(NAC) prior to LCCRT or SCRT.
Addition of a second concurrent
chemotherapy agent during LCCRT
Five randomised phase III trials have added oxaliplatin
to either 5FU or capecitabine during CRT, with
variable results. Two have thus far published longterm outcomes in full-length reports, The ACCORD
12 trial compared 45 Gy capecitabine CRT with
50 Gy oxaliplatin and capecitabine in 598 patients
and reported no difference in the rate of pCR (the
primary end-point) or 3-year disease-free survival
(DFS) or overall survival.80 The German CAO/ARO/
AIO-04 trial randomised 1265 patients to LCCRT
using concurrent 5FU then 16weeks of postoperative
5FU-based chemotherapy, with or without oxaliplatin.
DFS was increased from 71.2 to 75.9% (HR 0.79,
24,40,76
79
Features on
40,76,77
78
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83
Chapter 7
P = 0.03).77 However, because oxaliplatin was added
to both the concurrent and adjuvant chemotherapy
components and different 5FU dose intensities
were used between treatment arms, the benefit of
oxaliplatin-intensified CRT is not known. The NSABP
R-04,81 PETTAC 682 and STAR 183 trials, reported in
abstract form, do not describe any improvement in
cancer outcomes for their primary end-point (local
recurrence, DFS and overall survival respectively).
Concurrent single agent fluoropyrimidine (5FU or
capecitabine) CRT remains the standard of care. The
currently recruiting UK phase III ARISTOTLE trial
(ISRCTN09351447) compares capecitabine-based
CRT with or without additional irinotecan.
Neoadjuvant chemotherapy
Administering systemic neoadjuvant chemotherapy
(NAC) before local pelvic treatment is attractive
because treatment delivery is potentially improved
and micrometastases receive full-dose chemotherapy
months earlier than with postoperative adjuvant
chemotherapy. NAC can improve pelvic tumourrelated symptoms84 and also allows earlier
defunctioning stoma reversal, with potential quality
of life and health economic benefits. However,
theoretical disadvantages to the use of NAC include
delayed time to surgery and disease progression and
decreased effectiveness of subsequent radiotherapy
due to emergence of radio-resistant clones.
Several phase II trials of NAC have suggested
acceptable toxicity, low rates of progression whilst
on NAC and promising response rates.
phase III randomised trial from Poland87 compared
standard LCCRT followed by surgery, with SCPRT
then 6weeks of FOLFOX chemotherapy then surgery.
A total of 541 patients with fixed T3 or T4 tumours
were included, although staging MRI was not
mandated. Oxaliplatin was included initially in both
standard and experimental arms but later allowed
to be omitted. There was no difference between the
arms in R0 resection rate (the primary end-point),
local failure, distant failure or DFS. A marginally
statistically significant difference in overall survival
was reported (73% vs 65%, P = 0.046), although this
significance disappeared once patients with recurrent
tumours were removed from the analysis.
Two other trials have a similar design, the DutchScandinavian RAPIDO trial (NCT01558921),
which completed accrual of 920 patients in June
2016, and the Chinese 552-patient STELLAR trial
(NCT02533271), currently recruiting. Recruitment
continues in the 460-patient French PRODIGE 23 trial
(NCT01804790), comparing standard preoperative
LCCRT including capecitabine, with 12 weeks of
FOLFIRINOX prior to LCCRT. The US PROSPECT
trial (NCT01515787) in 1060 patients compares NAC
with preoperative LCCRT in early tumours (T2–3 N1
or T3N0) not intended for abdominoperineal excision.
In the experimental arm LCCRT is used only if there is
a poor response with NAC.
84–86
One
Key points
• Between 1971 and 2011, age-standardised 5-year bowel cancer survival increased from 24% to
59%. It is likely that improved staging, perioperative care, surgical technique and adjuvant therapy
have all had a role in this improvement.
• Oxaliplatin-fluoropyrimidine adjuvant chemotherapy improves survival and is standard for stage III
colon cancer and is commonly used for high-risk stage II colon cancer.
• Adjuvant chemotherapy is used in rectal cancer by extrapolation from colon cancer but the evidence
to support its use following high-quality TME surgery and preoperative (chemo)radiotherapy is weak.
• There is no evidence to support the use of targeted agents as adjuvant therapy.
• There is a strong evidence base demonstrating that preoperative radiotherapy reduces the risk of
local recurrence after resection of rectal cancer, although it does not improve overall survival.
• The addition of concurrent 5FU to long-course radiotherapy reduces the risk of local recurrence.
• A risk-adapted policy for the use of preoperative radiotherapy based on optimum preoperative
staging including pelvic MRI scanning, balances the benefit and risks.
• Earlier stage tumours have a greater chance of achieving a complete response to pelvic
chemoradiation, thereby potentially avoiding radical surgery. However, different potential strategies to
achieve organ preservation require further prospective multicentre study.
• Strategies incorporating neoadjuvant preoperative chemotherapy in rectal cancer are attractive
because micrometastatic disease (the main cause of rectal cancer death), is treated earlier than with
current standard postoperative chemotherapy. However, further prospective evidence is required to
confirm the benefit of this approach.
84
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Perioperative chemotherapy and radiotherapy for colorectal cancer
Full references available at http://expertconsult.
inkling.com
Key references
4. TwelvesC, WongA, NowackiMP, etal. Capecitabine
as adjuvant treatment for stage III colon cancer. N Engl
J Med 2005;352(26):2696–704. PMID: 15987918.
The X-ACT study showed equivalence between
bolus 5FU and folinic acid and oral fluoropyrimidine
capecitabine after 6.9 years of follow-up.
5. Andre T, Boni C, Mounedji-Boudiaf L, et al.
Oxaliplatin, fluorouracil, and leucovorin as
adjuvant treatment for colon cancer. N Engl J Med
2004;350:2343–51. PMID: 15175436.
6. YothersG, O'ConnellMJ, AllegraCJ, etal. Oxaliplatin
as adjuvant therapy for colon cancer: updated results
of NSABP C-07 trial, including survival and subset
analyses. J Clin Oncol 2011;29:3768–74. PMID:
21859995.
The NSABP C07 study demonstrated that the addition
of oxaliplatin to infusional 5FU/LV resulted in a better
5-year disease-free survival and overall survival. This
benefit was at the expense of increased acute toxicity,
including neurotoxicity.
7. HallerDG, TaberneroJ, MarounJ, etal. Capecitabine
plus oxaliplatin compared with fluorouracil and folinic
acid as adjuvant therapy for stage III colon cancer. J
Clin Oncol 2011;29:1465–71. PMID: 21383294.
23. BossetJF, ColletteL, CalaisG, etal. Chemotherapy
with preoperative radiotherapy in rectal cancer. N
Engl J Med 2006;355:1114–23. PMID: 16971718.
The EORTC 22921 trial showed that the addition of 5FU/
LV to long-course radiotherapy halved the risk of local
recurrence but without any difference in overall survival.
38. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al.
Preoperative radiotherapy combined with total
mesorectal excision for resectable rectal cancer. N
Engl J Med 2001;345:638–46. PMID: 11547717.
39. van Gijn W, Marijnen CA, Nagtegaal ID, et al.
Preoperative radiotherapy combined with total
mesorectal excision for resectable rectal cancer:
12-year follow-up of the multicentre, randomised
controlled TME trial. Lancet Oncol 2011;12:575–82.
PMID: 21596621.
The Dutch TME trial demonstrated that the addition of
short-course preoperative radiotherapy halved the risk
of local recurrence but with no evidence of en effect on
overall survival.
40. Sebag-Montefiore D, Stephens RJ, Steele R, et al.
Preoperative radiotherapy versus selective postoperative
chemoradiotherapy in patients with rectal cancer (MRC
CR07 and NCIC-CTG C016): a multicentre, randomised
trial. Lancet 2009;373:811–20. PMID: 19269519.
The MRC CR07 trial demonstrated that the addition of
short-course preoperative radiotherapy halved the risk
of local recurrence but with no evidence of an effect on
overall survival.
42. GérardJP, ConroyT, BonnetainF, etal. Preoperative
radiotherapy with or without concurrent fluorouracil
and leucovorin in T3–4 rectal cancers: results of
FFCD 9203. J Clin Oncol 2006;24:4620–5. PMID:
17008704.
The FFCD 9203 trial showed that the addition of 5-FU/
LV to long-course radiotherapy halved the risk of local
recurrence but without any difference in overall survival.
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85
8
8
Advanced and recurrent colorectal cancer
Omer Aziz
Introduction
The treatment of advanced and recurrent colorectal
cancer represents a significant challenge to
oncologists and surgeons, requiring a multimodality
treatment approach. As a result, these patients are
best managed in specialist centres by an advanced
colorectal cancer multidisciplinary team (MDT).
For the purposes of this chapter, advanced primary
colon and rectal cancer is defined as any or all of the
following:
• Tumours that locally invade into adjacent organs
or structures (T4a and T4b lesions according to
AJCC TNM classification 7th edition). In the
case of rectal cancer, these are tumours that have
grown beyond the facial plane removed in a
total mesorectal excision (beyond-TME).
• Tumours that have spread to lymph nodes
outside their regional lymphatic drainage area
(AJCC TNM classification 7th edition, stage 4
disease).
• Tumours that present with systemic (e.g. liver
or lung) or peritoneal (e.g. ovaries or omentum)
metastases (AJCC TNM classification 7th
edition, stage 4 disease).
Recurrent colorectal cancer is defined as any or all
of the following:
• Local recurrence at site of previous surgery.
• Peritoneal recurrence (colon or rectal peritoneal
metastases – CRPM).
• Systemic recurrence (non-locoregional nodal or
solid organ metastases).
Incidence
Despite improved access to screening, colorectal
cancer still presents as advanced primary or
recurrent disease. Population-based studies suggest
surgery with curative intent for all-stage disease
has a 5-year local recurrence cumulative incidence
of 13% (23% for rectal cancer), and systemic
metastasis cumulative incidence of 26%.
timing and sites of distant metastases are important
to consider:
• Liver metastases: Synchronous liver metastases
are found in 15% of presenting colorectal
cancers. Metachronous liver metastases within
5years of diagnosis occur in 13% of cases.
• Lung metastases: Synchronous lung metastases
are found in 11% of presenting colorectal
cancers. Metachronous lung metastases within
5years of diagnosis occur in 6% of cases.
• Colorectal peritoneal metastases (CRPM) are
found in 10.3% of primary right-sided cancers
and 6.2% of left-sided cancers.5 They are found
in up to 27% of primary rectal cancers.
• Bone metastases: The 5-year incidence is 10%.
• Brain metastases: The 5-year incidence is 2%.
Survival from surgery for advanced and recurrent
colorectal cancer can be presented as relative survival
(RS). This is the ratio of observed survival rate to the
expected survival rate in a comparable population
of patients without colorectal cancer. Longitudinal
studies looking at Western populations over the last
40years have suggested that the volume of surgery
taking place for locally recurrent colorectal cancer
6
1,2
The
3
4
7
8
86
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with curative intent has risen from 16% of cases
to 58%, with a 5-year RS of 36%. In the same
population over the same time period, the volume of
surgery with curative intent for metastatic colorectal
cancer has risen from 7% to 24% of cases, with a
5-year RS of 24%.9 The median overall survival
for patients being treated for metastatic colorectal
cancer reported in phase III oncology trials and large
observational series is 30months.
10
Diagnosis and staging of
advanced and recurrent CRC
Histological confirmation and
biomarkers
Histological conrmation through biopsy is
important before treatment. DNA- and RNA-based
biomarker testing such as RAS and BRAF mutation
analysis not only guides epidermal derived growth
factor (EGFR)-based antibody therapy (cetuximab
and panitumumab), but also has prognostic
signicance:
Extended RAS analysis to include KRAS exons 2, 3
and 4, and NRAS exons 2, 3 and 4 is recommended.
Tumours harbouring any of these RAS mutations
respond poorly to EGFR antibody therapy.
BRAF should accompany RAS analysis, as this is
a signicant negative prognostic indicator with regard
to overall survival (OS) and may also predict EGFR
antibody therapy response.
DNA mismatch repair (MMR) status (by microsatellite
instability or MMR- immunohistochemistry) can assist
genetic counselling and have prognostic importance.
In patients with advanced disease and those with
local recurrence, colonoscopy may be used to obtain
these samples. Other options include radiological
biopsy or in selected cases of CRPM, laparoscopic
assessment.
The serial enlargement of a lesion accompanied
by either positive PET–CT or rising CEA level may be
accepted for tumour diagnosis.
In cases where biopsy is not possible, biomarker
analysis of the original archived specimen has
reasonable concordance rates.
10
11
Advanced and recurrent colorectal cancer
Figure8.1 • CT scan with oral and intravenous contrast
demonstrating CRPM in the omentum (arrow) of a patient
who previously had a right hemicolectomy for a T4N1M0
adenocarcinoma of the hepatic flexure. The distinction
between this and the adjacent loop of small bowel (B), which
has been opacified with oral contrast, can easily be made.
contrast is the gold standard for disease staging.
Oral contrast opacifies small bowel and identifies
sites of extraluminal disease (Fig. 8.1). CT also plays
an important role in image-guided biopsy.
11
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is a
discriminatory test to stage tumours in the pelvis. In
locally advanced/recurrent rectal cancer and CRPM
involving the pelvis, MRI helps identify the planes
of dissection and structures that require removal
to achieve complete tumour clearance. Pelvic
examination under anaesthesia is used alongside
MRI to determine R0 resectability. MRI liver is
more sensitive for lesions <10 mm in diameter
than CT. Its diagnostic accuracy for liver lesions
may be improved through contrast enhancers
(gadoxetate).
11
Positron emission tomography
Positron emission tomography (PET) CT is an
investigation for the detection of extrahepatic
metastases and local recurrence, and has been shown
to change management in 8–30% of cases. Its role
is limited to selected cases, with no consensus on its
routine use.
11
Radiology
Computed tomography
Computed tomography (CT) scanning of the thorax,
abdomen and pelvis with oral and intravenous
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Ultrasonography
Ultrasonography (US) may include endorectal
ultrasonography (ERUS) for targeted biopsy and
assessement of sphincter involvement, and contrastenhanced US for characterisation of liver lesions,
surgical planning and biopsy.
87
Chapter 8
The advanced colorectal
cancer MDT
Advanced colorectal cancer MDTs should include
appropriately experienced colorectal surgeons,
clinical and medical oncologists, radiologists,
pathologists and clinical nurse specialists. In
centres undertaking pelvic clearance (exenteration)
surgery for locally advanced and recurrent
rectal cancer, the MDT should be supported by
urologists, gynaecological oncologists and plastic
(reconstructive) surgeons. Units undertaking
sacrectomy and pelvic bony excisions will need
spinal and orthopaedic surgeons. For CRPM, liver
and lung metastases there should also be a defined
pathway to discuss patients with peritoneal tumour,
hepatobiliary and thoracic specialist MDTs.
The advanced colorectal cancer MDT plans
appropriate diagnostic work-up and establishes goals
of treatment. A personalised approach accounting
for previous treatment is required. If the disease is not
potentially resectable with 'R0' margins (complete
resection with clear margins of at least 1 mm and
no microscopic residual disease) then neoadjuvant
treatment such as chemo- and/or radiotherapy should
be considered for downstaging. If an R0 resection
cannot be obtained, then the goal of treatment is to
strike a balance between quality of life and duration
of disease control. For chemotherapy this involves
taking into account toxicity, and for surgery, the
procedural morbidity. Symptom control is important,
and centres should have access to specialist palliative
care teams. Data on interventions and patient
outcome should be collected prospectively with a
view to obtaining long-term follow-up data.
Patients with oligometastatic disease (more than
one distant metastatic site) should be considered for
systemic chemotherapy versus synchronous or staged
R0 resection of the sites. In the case of staged resections,
the order in which these are undertaken is important.
Despite the absence of high-quality data, patients with
resectable oligometastatic disease are increasingly
being considered for staged surgery. Finally, there is
a role for local ablative techniques in treating lung
and liver metastases. These include thermal devices
(radiofrequency, cryo-, or microwave ablation),
non-thermal devices (brachytherapy and external
beam high precision radiotherapy), embolisation
(radioembolisation with selective internal radiation
therapy or transarterial chemoembolisation) and
locally delivered chemotherapy.
Locally advanced primary and
recurrent rectal cancer
‘Locally advanced primary rectal cancers’ are defined
in this chapter as primary rectal cancers beyond
the total mesorectal excision plane (PRCbTME), a
term coined by the ‘Beyond TME Collaborative’.11
These lesions range from being just beyond the
circumferential resection margin of a TME (T4a)
to infiltrating adjacent organs (T4b). ‘Recurrent
rectal cancer’ in this chapter is defined as local
recurrence following previous mesorectal excision.
Whilst both groups potentially require multivisceral
surgery beyond the traditional mesorectal excision
(TME) planes to achieve an R0 resection, it should
be noted that only 50% of recurrent rectal cancer
cases are selected for surgery, either because an R0
margin cannot be obtained, the patient is unfit for
multivisceral resectional surgery, or the morbidity
is unacceptable to the patient.12 It is therefore very
important to appropriately counsel the patient and
set realistic expectations. Data on outcomes from
specialist centres suggest that in selected cases, R0
rates of around 86% can be achieved for locally
advanced primary rectal cancer, with 5-year overall
survival rates of 62%.13 For recurrent rectal cancer
these figures are lower, with R0 rates of over 60%
and 55% 3-year disease-free survival. R1 and R2
resections are associated with a very poor prognosis.
14
Radiotherapy
Patients should be considered for neoadjuvant
chemoradiotherapy prior to surgery.
An established regime is 45 Gy in 25 fractions with
concurrent fluoropyrimadine-based chemotherapy.
The optimal timing of subsequent re-staging and
surgery after completion is debatable. Whilst some
have suggested re-staging at 6–8 weeks,11 it is
recognised that tumour regression can occur up to
12weeks.
A number of established groups including the
author’s institution re-stage at 10weeks, with surgery
undertaken at 12–14weeks.
Localised radiotherapy may have a role in the
treatment of recurrent rectal cancer, although
outcome data are scarce. Options include:
• Intraoperative radiotherapy at the time of surgery
as either intraoperative electron beam radiotherapy
or high-dose-rate brachytherapy at surgical sites
where the resection margin is threatened.
• Stereotactic body irradiation therapy
(CyberKnife system) delivering multiple
beams to well-defined targets in few fractions.
Indications include irresectable pelvic sidewall
and pre-sacral recurrences.
15
12
12
16
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Perineal excision
Extralevator (ELAPE) Ischio-anal resection
For low rectal cancers, the concept of 'extralevator
abdominoperineal excision' (ELAPE) with a
cylindrical specimen has gained acceptance.
However, it is important to note that in the context
of locally advanced primary low rectal cancers,
there may be a need for an extended excision of the
ischio-anal fat akin to ‘salvage’ surgery for recurrent
anal cancers after chemoradiotherapy. Figure 8.2
illustrates the difference in these two procedures.
Pelvic multivisceral exenteration
Organs that may require removal with the rectum
in locally advanced primary and recurrent rectal
cancers include anterior structures (bladder,
prostate, seminal vesicles, urethra, uterus, vagina),
posterior structures (pre-sacral fascia and sacrum)
and lateral structures (ovaries and associated
structures, ureters and pelvic sidewall vessels, nerves
and musculoskeletal tissue).
Patterns of rectal cancer recurrence
Classification systems describing the patterns of
recurrence in rectal cancer have been proposed, but
standardisation of this nomenclature has not been
achieved. A simplified version has been described by
Renehan12 as:
• Central recurrence (Fig.8.3) most commonly
arising at a previous rectal anastomotic site or
in the residual mesorectum. These can go on to
involve the anterior urogenital structures and can
also extend posteriorly up to the sacral fascia or
Advanced and recurrent colorectal cancer
Figure8.3 • MRI demonstrating central recurrence in a
rectal stump following previous Hartmann’s procedure (A)
with associated cystic cavity (B).
periosteum but not the bone. Both may be resected
en bloc for an R0 resection without sacrectomy.
• Sacral recurrence (Fig.8.4) where bony invasion
is present and an R0 resection is only possible
with a sacral resection through a two-stage
combined abdominosacral approach.
• Lateral recurrence (Fig.8.5) involves the lateral
pelvic sidewall, encasing iliac vessels, pelvic
autonomic nerves and ureter and can extend
through the greater sciatic foramen with or
without invasion of the sciatic nerve. Of all the
types of recurrence, this is the most difficult
T4
T3
tumour
Figure8.2 • Approaches to perineal excision. (a) Standard extralevator abdominoperineal excision approach. (b) A wider
ischio-anal approach for low, locally advanced T4 rectal cancers.
tumour
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Chapter 8
Figure8.4 • MRI demonstrating sacral recurrence
(arrows) extending up to the level of S3.
Figure8.5 • Lateral recurrences of the left pelvic side-
wall involving left internal iliac vessels and ureter (left scan,
arrow) or abutting left internal iliac artery branches (right
scan, arrow).
in which to achieve an R0 resection, and is
therefore associated with the poorest prognosis.
Techniques to achieve clear lateral margins
involving en bloc resection of the iliac vessels
and other sidewall structures17 and extended
lateral pelvic sidewall excision18 have been
described in order to achieve an R0 resection
with promising early results.
Types of pelvic clearance
Pelvic clearance (exenteration) surgery needs to be
tailored to include:
Figure8.6 • MRI demonstrating locally advanced
rectal cancer (A) with anterior perforation and associated
abscess cavity (B) adjacent to bladder (C). The patient
required total pelvic clearance.
has an end colostomy and an ileal conduit as the
most common urinary reconstruction technique.
• Anterior pelvic clearance involves removal of
the distal ureters, bladder, prostate and seminal
vesicles in a male, and in females also the uterus,
ovaries, fallopian tubes and vagina as required.
It is not a commonly performed operation for
rectal cancer and reserved mainly for tumours of
the upper rectum and rectosigmoid that invade
into anterior structures. This operation is more
commonly used for the treatment of advanced
urological and gynaecological tumours. The distal
rectum is spared and may be re-anastomosed. An
ileal conduit is required for urinary reconstruction.
• Posterior pelvic clearance is a procedure
performed in women, involving the removal
of the rectum and uterus, required part of the
vagina, ovaries and fallopian tubes. This may be
with or without removal of the anus (perineal
excision). The bladder is spared.
In the lateral dissection of the pelvic sidewall,
surgery may be undertaken in three planes of
dissection to get R0 clearance (Fig.8.7):
• Total pelvic clearance (TPC) involves removal
of the rectum, sigmoid colon, bladder, draining
lymph nodes, pelvic peritoneum and lower
ureters. In males the prostate and seminal
vesicles are also excised (Fig.8.6). In females
the uterus, ovaries, fallopian tubes and required
part of the vagina can be removed. The patient
• Mesorectal fascial plane – a continuation of the
standard TME plane.
• Ureteric plane – deep to the lateral peritoneum
where the ureter lies.
• Bony plane – lateral to internal iliac vessels
along the obturator internus and piriformis
muscles in the lateral pelvic compartments.
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