Download Oncological and functional outcome of intersphincteric resection and

FACULTY OF MEDICINE AND
HEALTH SCIENCES
Academic Year 2014 - 2015
Oncological and functional outcome of intersphincteric
resection and coloanal anastomosis for very low rectal
cancer
Benjamin DEPUYDT
Promotor: Prof. Dr. Wim Ceelen
Dissertation presented in the 2nd Master year
in the programme of
Master of Medicine in Medicine
“The author and the promotor give the permission to use this thesis for consultation and to
copy parts of it for personal use. Every other use is subject to the copyright laws, more
specifically the source must be extensively specified when using results from this thesis.”
Date
Benjamin Depuydt
Prof. Dr. Wim Ceelen
II
1 Foreword
The process of writing this thesis was not as easy as I thought it would be and without the
support of a lot of people I could not have accomplished this work. Therefore, I would like to
take the opportunity to thank these people.
First and foremost, I would like to express my gratitude to my promotor Prof. Dr. Wim Ceelen
for giving me the opportunity to work on this very interesting topic and for giving me the
necessary time and space to bring this work to a good end. I also want to thank him for giving
me the necessary advice when needed.
I also want to thank Elke Bruneel, Delphine Lambrecht, Sander Lefere, Koen Maes, David
Menmadala and Jentel Vincke for rereading this work and giving me constructive feedback.
It goes without saying, I would also like to thank my parents for giving me the opportunity to
start with this fascinating study and for all the support they have given me in the last seven
years.
Last of all, I want to thank my friends for the necessary support and the countless motivational
talks over the past years.
Depuydt Benjamin
Gent, 6 April 2015
III
2 List of abbreviations
APPEAR
anterior perineal plane for ultra-low anterior resection
APR
abdominoperineal resection
AR
anterior resection
CAA
coloanal anastomosis
CEA
carcinoembryonic antigen
CRC
colorectal cancer
CRM
circumferential margin
CRT
chemoradiotherapy
CSS
cancer-specific survival
CT
computed tomography
DFS
disease-free survival
DRE
digital rectal examination
DRM
distal resection margin
EGFR
epidermal growth factor receptor
EUS
endorectal ultrasound
FDG
fluorodeoxyglucose
Gy
Gray (unit of absorbed ionizing radiation in a particular mass)
ISR
intersphincteric resection
ISV
initial (anal) sensory volume
LAP
laparoscopic surgery
LAR
low anterior resection
LARS
low anterior resection syndrome
LFR
local failure rate
LR
local recurrence
LRFS
local relapse-free survival
MRI
magnetic resonance imaging
MSP
maximal (anal) squeeze pressure
MSV
mean (anal) sensory volume
MTV
mean/maximum (anal) tolerable volume
OpS
open surgery
OS
overall survival
PESR
partial external sphincter resection
IV
PET
positron emission tomography
Qol
quality of life
R0
complete removal of all tumor
ROB
robotic surgery
RP
(anal) resting pressure
RT
radiotherapy
Rx
X-ray
SR
systemic recurrence
TAE
transanal excision
TAMIS
transanal minimally invasive surgery
TEM
transanal endoscopic microsurgery
TME
total mesorectal excision
TNM
classification of malignant tumours (tumor, lymph nodes, metastasis)
ULAR
ultra-low anterior resection
VEGF
vascular endothelial growth factor
95% CI
95% confidence interval
V
3 List of figures
Figure 1
Sagittal view of the anal canal and rectum
Figure 2
Anatomy of the anal canal and the sphincter complex
Figure 3
Distribution of sporadic colorectal cancer
Figure 4
Total mesorectal excision (TME)
Figure 5
Low anterior resection (LAR)
Figure 6
Abdominoperineal resection (APR)
Figure 7
APPEAR-procedure
Figure 8
Types of coloanal anastomosis
Figure 9
Differentiation between the LAR, ULAR and ISR technique based on height
and method of anastomosis
Figure 10
ISR: an abdominal and perineal approach
Figure 11
ISR: the perineal approach
Figure 12
ISR: anal pull-through
Figure 13
ISR: hand-sewn coloanal anastomosis
4 List of tables
Table 1
TNM classification
Table 2
Subgrouping of localized rectal cancer assessed by MRI and recommended
primary treatment
Table 3
General study, patient and tumor characteristics of the included studies
Table 4
Mortality, morbidity and postoperative complications after ISR
Table 5
Oncological outcomes after ISR
Table 6
Functional outcomes after ISR
Table 7
Manometric results before, and 3, 6, 12 months after ISR
Table 8
Quality of life after ISR: EORTC QLQ-C30
Table 9
Quality of life after ISR: EORTC QLQ-CR38
VI
5 Table of Contents
1
Foreword ........................................................................................................................III
2
List of abbreviations ...................................................................................................... IV
3
List of figures ................................................................................................................. VI
4
List of tables .................................................................................................................. VI
6
Abstract .......................................................................................................................... 1
6.1
English .................................................................................................................... 1
6.2
Nederlands .............................................................................................................. 2
7
Introduction .................................................................................................................... 4
8
Background .................................................................................................................... 6
8.1
Anatomy and physiology of the rectum .................................................................... 6
8.1.1
Anatomy ........................................................................................................... 6
8.1.1.1
Rectum ..................................................................................................... 6
8.1.1.2
Anal canal ................................................................................................. 7
8.1.1.3
Muscles and spaces .................................................................................. 8
8.1.1.4
Arterial, venous and lymphatic system ...................................................... 8
8.1.1.5
Innervation ................................................................................................ 8
8.1.2
Physiology........................................................................................................ 9
8.2
Prevalence of colorectal cancer..............................................................................10
8.3
Pathophysiology and risk factors of colorectal cancer ............................................10
8.4
Symptoms ..............................................................................................................11
8.5
Diagnosis and preoperative staging .......................................................................12
8.5.1
Diagnosis ........................................................................................................12
8.5.2
Staging ............................................................................................................12
8.6
8.5.2.1
Evaluation of local invasion of the primary tumour (T) ..............................12
8.5.2.2
Evaluation of regional lymph node involvement (N) ..................................15
8.5.2.3
Evaluation of distant metastasis (M) .........................................................15
Therapy ..................................................................................................................15
8.6.1
Preoperative treatment ....................................................................................16
8.6.1.1
Radiotherapy ............................................................................................16
8.6.1.2
Chemotherapy..........................................................................................19
8.6.2
Surgery ...........................................................................................................19
8.6.2.1
History of rectal cancer surgery ................................................................19
8.6.2.2
Total mesorectal excision (TME) ..............................................................21
8.6.2.3
Distal resection margin (DRM) .................................................................22
8.6.2.4
Current surgical options for low rectal cancer ...........................................23
8.6.2.4.1 Resection options .................................................................................23
8.6.2.4.1.1 (Ultra-) low anterior resection ((U)LAR) ..........................................23
8.6.2.4.1.2 Intersphincteric resection (ISR) .......................................................24
VII
8.6.2.4.1.3 Local excision .................................................................................24
8.6.2.4.1.4 Abdominoperineal excision .............................................................25
8.6.2.4.1.5 Anterior perineal plane for ultra-low anterior resection (APPEAR) ..27
8.6.2.4.2 Coloanal anastomosis (CAA) and neorectum reconstruction.................28
8.7
9
General functional outcome and quality of life after rectal cancer surgery ..............29
What is ISR? .................................................................................................................31
10
Purpose of this thesis.................................................................................................32
11
Methods .....................................................................................................................33
11.1
Search strategy ......................................................................................................33
11.2
Study selection .......................................................................................................33
11.3
Data collection and statistical analysis....................................................................33
12
Results ......................................................................................................................34
12.1
Literature search ....................................................................................................34
12.2
Study and patient characteristics ............................................................................37
12.3
Indications for ISR ..................................................................................................38
12.4
Surgical procedure .................................................................................................38
12.5
Mortality, morbidity and postoperative complications ..............................................41
12.6
Oncological outcome ..............................................................................................43
12.7
Functional outcome ................................................................................................45
12.8
Quality of life ..........................................................................................................47
13
Discussion .................................................................................................................49
13.1
What are good indications for ISR? ........................................................................49
13.2
Preoperative treatment and surgical technique.......................................................49
13.3
Mortality, morbidity and anastomotic leakage after ISR ..........................................52
13.4
Is the ISR procedure safe from the oncological point of view? ................................52
13.5
How are the functional outcomes and quality of life after ISR? ...............................53
13.6
Strengths and weaknesses of this thesis ................................................................56
14
Conclusion .................................................................................................................57
15
References ................................................................................................................58
VIII
6 Abstract
6.1 English
Background: Abdominoperineal resection (APR) has long been the only surgical option in the
treatment of distal rectal cancer. However, the evolution towards better surgical techniques,
better understanding of locoregional tumor spreading and the introduction of preoperative
chemoradiotherapy have led to more sphincter-saving surgery. The intersphincteric resection
technique (ISR) was developed by Schiessel et al. in the early nineties as a sphincter-preserving
alternative for the APR procedure with its permanent colostomy. Since the first description of
this surgical procedure, various institutions published their experience with this technique.
Purpose: The aim of this thesis was to evaluate the current evidence regarding the short- and
long-term oncological and functional outcomes in patients who have been treated with ISR with
hand-sewn coloanal anastomosis in the treatment of distal rectal cancer. The indications for ISR
and the surgical technique were also discussed.
Methods: Systematic literature research, for literature published between 1960 and January
2015 was performed, using Web of Science, Pubmed and the Cochrane Library. Only free
available original studies published in the English language which mentioned oncological
and/or functional outcome after ISR with handsewn coloanal anastomosis were included.
Results: The literature search retained 82 articles, 20 of them were included for further
exploration. A total of 1535 patients (67.2% men) with a mean age of 60.8 year were analyzed.
The mean mortality rate within 30 days after surgery was 0.4% (95% CI: 0-0.8%). Mean
morbidity was 24.8% but varied widely among the different studies (range: 7.5%-64.5%). Most
common complication following ISR was anastomotic leakage (mean: 7.8%; 95% CI 0.6-15%).
R0 resection was achieved in 97.7% of the cases. Local recurrence was seen in 6.1% of the
patients (95% CI: 2.6-9.6%). The mean 5-year overall and disease-free survival were 85.9%
(95% CI: 82.5-89.3%) and 78.5% (95% CI: 73.2-83.8%), respectively. Functional outcomes
were not reported consistently. The mean number of bowel movements per day after ISR was
2.9 (95% CI: 2.4-3.4). Perfect continence was seen in 53.3% (range: 29.6%-86.3%) of the
patients whereas 46.6% (range: 5.8%-84.0%) of the patients needed to wear a pad. The mean
Wexner score was 8.8 (95% CI: 6.5-11.1).
Conclusion: ISR can be a good alternative for APR in the treatment of very low rectal cancer
when patients are chosen carefully. Oncological outcomes are good and comparable with those
after LAR and APR. Functional outcomes following ISR are suboptimal but acceptable.
1
6.2 Nederlands
Achtergrond: Abdominoperineale resectie (APR) is lange tijd de enige chirurgische optie
geweest in de behandeling van zeer laag gelegen rectumcarcinoom. De evolutie naar betere
chirurgische technieken, betere inzichten in de locoregionale tumoruitbreiding en de introductie
van preoperatieve chemoradiotherapie hebben echter geleid tot meer sfincter-sparende
ingrepen. De intersfincterische resectie techniek (ISR) is in de vroege jaren negentig ontwikkeld
door Schiessel et al. als een alternatief voor de permanente colostoma verbonden met de APR
procedure. Sinds de eerste beschrijving van deze techniek hebben reeds verschillende instituten
hun ervaring met deze techniek gepubliceerd.
Doelstelling: Het doel van deze thesis was om de huidige evidentie rond de korte- en
langetermijnresultaten op oncologisch en functioneel vlak te evalueren bij patiënten behandeld
met ISR en manuele colo-anale naad. De indicaties voor ISR en de chirurgische techniek
werden ook besproken.
Methode: De literatuur, van 1960 tot januari 2015, werd systematisch doorzocht gebruik
makend van Web of Science, Pubmed en the Cochrane Library. Enkel vrij verkrijgbare artikels
gepubliceerd in de Engelse taal die vermelding maakten van de oncologische en/of functionele
resultaten na ISR met manuele colo-anale naad werden geïncludeerd.
Resultaten: De literatuurstudie weerhield 82 artikels, waarvan er 20 werden weerhouden voor
verdere exploratie. Een totaal van 1535 patiënten (67.2% mannen) met een gemiddelde leeftijd
van 60.8 jaar werden geanalyseerd. De gemiddelde mortaliteit binnen 30 dagen na de operatie
was 0.4% (95% BI: 0-0.8%). De gemiddelde morbiditeit was 24.8% maar kende een grote
variatie tussen de verschillende studies onderling (range: 7.5%-64.5%). Met een gemiddelde
van 7.8% was lekkage van de colo-anale anastomose de meest voorkomende complicatie na
ISR (95% BI: 0.6-15%). Een R0 resectie werd bereikt in 97.7% van de gevallen. Lokaal recidief
werd gezien in 6.1% van de patiënten (95% BI: 2.6-9.6%). De gemiddelde globale en ziektevrije
5-jaarsoverleving waren respectievelijk 85.9% (95% BI: 82.5-89.3%) en 78.5% (95% BI: 73.283.8%). Functionele resultaten werden niet consequent gerapporteerd. Het gemiddeld aantal
keren stoelgang per dag na ISR was 2.9 (95% BI: 2.4-3.4). Een perfecte continentie status werd
gezien bij 53.3% (range: 29.6%-86.3%) van de patiënten terwijl 46.6% (range: 5.8%-84.0%)
van de patiënten een maandverband nodig hadden om zich te beschermen tegen lekkage. De
gemiddelde Wexner score was 8.8 (95% BI: 6.5-11.1).
2
Conclusie: Wanneer patiënten zorgvuldig worden uitgekozen kan ISR een goed alternatief zijn
voor APR in de behandeling van zeer laag gelegen rectumkanker. Oncologische resultaten zijn
goed en vergelijkbaar met deze na LAR en APR. Functionele resultaten na ISR zijn suboptimaal
maar acceptabel.
3
7 Introduction
In Europe, colorectal cancer (CRC) is the second most common cancer after breast cancer with
a yearly incidence of 447,000 new diagnoses. Colorectal cancers make up for 13.0% of all
cancer cases (1). Approximately 30% of the colorectal cancers are located in the rectum, making
rectal cancer a significant health problem worldwide (2).
Surgery has always been the most important aspect in the treatment of rectal cancer. It is the
best way to achieve healing of the patient and to obtain local control of the disease.
The traditional surgical approach to tumors located in the distal one-third of the rectum is the
abdominoperineal resection (APR) technique first reported by Miles in the early 20th century
(3)
. This procedure proved its effectiveness in obtaining high survival and low recurrence rates,
although many patients suffered from the psychological and social limitations associated with
the inevitable permanent colostomy.
The development of better surgical techniques such as the low and ultra-low anterior resection,
the total mesorectal excision (TME), combined with the development of better anastomotic
techniques and the possibility to construct a neorectum after excision of the rectum led to a
greater focus on sphincter-preserving surgery. The better understanding of locoregional tumor
spreading and the evolution to preoperative chemoradiotherapy were other important factors in
this evolution.
In 1994, Schiessel et al. described the intersphincteric resection (ISR) technique. ISR is a
surgical technique that extends the rectal resection into the space between the internal and
external sphincter, known as the intersphincteric space. It is performed by a synchronous
abdominoperineal approach with TME and excision of the entire or part of the internal
sphincter, followed by a handsewn coloanal anastomosis (4). This procedure makes it possible
to treat rectal tumors within 2 cm of the sphincter complex without the need of a permanent
colostomy, which is an unavoidable consequence of the APR procedure.
However, this procedure is not without risk. Since the internal anal sphincter is responsible for
resting anal continence; excision of the internal anal sphincter can compromise the sphincter
function and result in anal incontinence
(5)
. In addition, other common rectal cancer surgery
complications such as anastomotic leakage or stricture, pelvic sepsis, wound infection and even
death can occur. Another potential disadvantage of the ISR procedure is the possibility of
incomplete removal of the tumor (R0 resection) when the tumor is located too close to the
sphincter complex, resulting in an increased local recurrence rate.
4
Since the invention of the ISR technique by Schiessel in 1994, many studies were published to
evaluate this procedure on functional and oncological outcomes.
The aim of this thesis was to evaluate the current evidence regarding the short- and long-term
oncological and functional outcomes in patients with low rectal cancer who have been treated
with ISR and handsewn coloanal anastomosis.
5
8 Background
8.1 Anatomy and physiology of the rectum
8.1.1 Anatomy
8.1.1.1 Rectum
The rectum is the terminal segment of the gastrointestinal tract and is located in the pelvis. It is
preceded by the sigmoid colon (= pelvic colon) and it ends with the anal canal at the anus. The
transition between sigmoid colon and rectum can be marked by noting where the adventitial
taeniae bands have coalesced to form outer longitudinal muscle
(5, 6)
. The rectum follows the
concavity of the sacrum after which it bows dorsal to the anus (7). The total length of the rectum
is approximately 12 to 18 cm. The bladder and prostate are located anterior to the rectum. The
anterior upper two-thirds and the lateral upper one-third are covered by the peritoneum. The
ventral lower one-third of the rectum is coated by the endopelvic fascia, also known as the
Denonvilliers fascia. The rectum is attached to the ventral surface of the sacral bone by the
Waldeyer's fascia. Within its lumen the rectum has 2 or 3 plicae transversales, also known as
valves of Houston (5).
Figure 1: Sagittal view of the anal canal and rectum (6)
6
8.1.1.2 Anal canal
The anal canal, the last part of the rectum, begins at the level of the levator ani muscle and
opens to the anal verge and is approximately 2.5 to 5 cm in length. The anal canal is surrounded
by the internal and external anal sphincter muscle. The internal sphincter muscle is an extension
of the inner circular smooth muscle layer of the rectum. The striated external anal sphincter
encircles the internal sphincter. The external anal sphincter is a part of the puborectalis muscle,
in turn part of the levator ani muscle (5).
Histologically, the anal canal can be divided into 3 parts: the zona columnaris (columnar
epithelium), the zona intermedia (columnar, transitional, or stratified squamous epithelium) and
the zona cutanea ( stratified squamous epithelium) (5). The border between the zona intermedia
and the zona cutanea is called the dentate (pectinate) line, it is located 2 cm above the anal verge
(6)
. Above the dentate line, parallel to the length of the anal canal, there are folds in the mucosa:
the columns of Morgagni. The anal crypts, that drain the anal glands are located between these
colums (5).
Figure 2: Anatomy of the anal canal and the sphincter complex (6)
7
8.1.1.3 Muscles and spaces
The levator ani muscle consists of 3 muscles: the iliococcygeal muscle, the pubococcygeal
muscle and the puborectalis muscle. The main function of the levator ani muscle is supporting
the viscera of the abdomen and assisting defaecation
(5)
. The puborectalis muscle creates the
angulation between the rectum and the anal canal: the anorectal angle (6).
Perianal and perirectal spaces are spaces filled with loose areolar tissue or fat between the
rectum and the surrounding muscles or between two muscles mutually (5). One of these spaces
is located between the internal and external anal sphincter: the intersphincteric space. This space
is used in intersphincteric surgery to separate the internal from the external anal sphincter.
8.1.1.4 Arterial, venous and lymphatic system
The rectum and anal canal are irrigated by 3 arteries: the superior rectal artery, the middle rectal
artery and the inferior rectal artery. The superior rectal artery arises from the inferior mesenteric
artery (this is the last branch of the aorta before its bifurcation) and provides the rectum and the
upper third of the anal canal. The distal rectum and proximal anal canal are supplied by the
middle rectal arteries. These middle rectal arteries originate from the internal iliac arteries. The
sphincter muscles are provided by the inferior rectal arteries. These arteries arise from the
internal pudendal artery, which is a branch of the internal iliac artery (5).
The venous drainage of the rectum follows the arterial system. Most of the blood from the
rectum drains into the portal circulation using the superior hemorrhoidal (rectal) veins. The
other portion drains into the internal iliac veins directly through the middle rectal veins and the
inferior rectal veins (5).
The dentate line plays a key role in the two different systems of lymphatic drainage. Lymph
from above the dentate line drains to the inferior mesenteric and internal iliac nodes. The
superficial inguinal lymph nodes receive lymph from below the dentate line (6).
8.1.1.5 Innervation
The rectum is innervated by sympathic nerves, parasympathic nerves and the pudendal nerve.
The sympathic nerves arise from the first 3 lumbar segments (5). They join the preaortic plexus
anterior to the abdominal aorta and extend toward the mesenteric plexus. At the level of the
aorta bifurcation the inferior mesenteric nerve bifurcates into two hypogastric nerves (6). These
two hypogastric nerves join the pelvic plexi at the lateral sides of the rectum.
8
The parasympathic innervation originates from the 3 caudal sacral nerve roots (S2,S3 and S4)
(5)
. After exiting the sacral foramina, they form the pelvic nerves, also known as the nervi
errigentes
(6)
. These nerves are joined by the hypogastric nerves, forming the pelvic plexi.
Damage to these nerves during surgery can result in incomplete erection, lack of ejaculation,
retrograde ejaculation or complete impotence (5).
The pudendal nerve arises from S2-S4. This nerve is important for the motor innervation of the
pelvic floor muscles and the external anal sphincter
(6)
. The internal anal sphincter shares the
same sympathetic and parasympathetic innervation as the rectum.
The area between the dentate line and 0.3 cm to 1.5 cm above that line is sensitive to touch,
pinprick, heat and cold. The rectum proximal to this region is only sensitive to distension. These
sensory stimuli are transmitted by the inferior rectal branch of the pudendal nerve (6).
8.1.2 Physiology
The main functions of the rectum are anal continence and defecation. Anal continence means
having voluntary and involuntary control over fecal discharge. It relies upon the ability of the
anorectum to discriminate between the states of fecal matter (solid, liquid or gas) and the ability
to storage faeces. The anal sensations include touch, pain, cold, pressure, tension and friction.
Nonetheless, these sensations are thought to play a minor role in discrimination between the
states of fecal matter. The reservoir function of the rectum is determined by the adaptive
compliance of the rectum, difference in pressure patterns and angulations between the rectum
and the anal canal (puborectalis muscle). The internal sphincter is primarily responsible for
resting anal continence. The external anal sphincter has also continuous tonic activity at rest
and even during sleep which is unique because other striated muscles are electrically silent at
rest. The resting tone of the external anal sphincter increases to prevent unintentional defecation
when the intra-abdominal pressure increase (sneezing, couching, Valsalva maneuver) (5).
The process of defecation will start as soon as the rectal reservoir is distended. In response to
this distention the internal sphincter relaxes. To maintain continence the external sphincter
contracts. The pelvic floor descends when the pressure of a Valsalva maneuver overcomes the
resistance of the external sphincter. The fecal bolus can only pass if the external anal sphincter
relaxes after receiving inhibiting signals. The timing of defecation results from the balance of
environmental factors acting through cortical inhibition and basic reflexes of the anorectum (5).
9
8.2 Prevalence of colorectal cancer
Colorectal cancer is the second most common cancer in Europe after breast cancer which
respectively make up for 13,0% and 13.5% of all cancer cases. Approximately 447000 new
patients were diagnosed with colorectal cancer in 2012. CRC is responsible for 12,2% of all the
cancer deaths, only lung cancer causes more deaths (approximately 20%). In men, CRC is the
third most common cancer (13,2%) after prostate cancer (22,8%) and lung cancer (15,9%). In
women, CRC is the second most common cancer (12,7%) after breast cancer (28,8%); lung
cancer follows CRC with 7,7%. In both men and women CRC is the second leading cause of
cancer related death (11,6% and 13,0%) after respectively lung (26,1%) and breast cancer
(16,8%) (1).
8.3 Pathophysiology and risk factors of colorectal cancer
Most of the colorectal cancers are adenocarcinomas that usually occur sporadic (75-85%) (2, 8).
However a hereditary susceptibility to CRCs is not rare (5-10%). Familial adenomatous
polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome)
are the most frequently seen hereditary CRCs
(8)
. Both inherit in an autosomal dominant way.
A third group of patients with colorectal cancer consists of patients with a first degree family
relative affected by colorectal cancer (2).
Most of the diagnosed colorectal tumours are located in the left-sided colon, approximately
30% of all CRCs are located in the rectum (6).
Risk factors to develop colorectal cancer are age (>50 years), diet (too much red and processed
meat, saturated fatty acids, proteins and alcohol, low dietary fibre, sugar), lack of exercise,
obesity and smoking
(2, 8)
. In addition, the use of non-steroidal anti-inflammatory drugs
(NSAIDs), hormone replacement therapy (HRT), statins and oral contraceptives have been
associated with an increased risk of CRC. Inflammatory bowel diseases (colitis ulcerosa and
Crohn’s disease), diabetes or colorectal polyps are pre-existing conditions, resulting in a higher
risk of developing colorectal cancer (2). A family history of CRC and increasing age are the two
most common risk factors for CRC. Fish, calcium and milk, fibre and vegetables play a
protective role in the development of CRC (2)(9).
10
Figure 3: Distribution of sporadic colorectal cancer (9)
8.4 Symptoms
A big challenge in diagnosing colorectal cancer is that patients in an early stage are often
asymptomatic. In the occasion they do have symptoms, these vary depending on the size and
location within the large bowel. When located on the right side the complaints tend to be nonspecific, including malaise, weight loss, vague abdominal pain or even a self-detected mass in
the abdomen. Left-sided colonic and rectal lesions are more likely to cause obstructive
symptoms. In which case the patient presents with change in bowel habit with constipation and
more frequent diarrhea with or without abdominal pain. Rectal bleeding, usually upon
defecation is more typical for rectal and sigmoid cancers. When distally located tumours invade
the anal canal, a more pronounced pain is often perceived. Tenesmus and symptoms of iron
deficiency anaemia from occult bleeding of the tumour (fatigue, headaches, faintness,
breathlessness, angina, intermittent claudication and palpitations) are other clinical signs of
colorectal cancer. Moreover, locally spread CRC can cause faecal incontinence (infiltration of
the anal sphincters), back pain (infiltration of the sacral plexus), urinary infection, a rectovesical
fistula or renal failure (infiltration of the renal tract) (10).
11
8.5 Diagnosis and preoperative staging
8.5.1 Diagnosis
Along with the typical symptoms of rectal cancer and physical examination of the patient, the
diagnosis of rectal cancer is usually based on digital rectal examination (DRE) or
coloscopy/rectoscopy. When a coloscopy is performed, it is possible to take a biopsy of the
tumour immediately. Histopathological examination of the biopsy can confirm the diagnosis of
rectal cancer, but it has only a slight impact on the treatment decision
(11)
. The probability of
sphincter-preservation, fixation and involvement of the sphincter complex, the distance from
the anorectal ring and the size of the tumour can be examined by DRE. Considering the overall
accuracy of DRE is only 65%, other imaging modalities are necessary for the staging of rectal
cancer (12).
8.5.2 Staging
The TNM staging system is by far the most used staging tool for rectal cancer. The depth of
local invasion of the primary tumour (T), the extension of regional lymph node involvement
(N) and the presence of distant metastasis (M) are the key parameters of this system
(12)
. With
this system, it is possible to divide patients into groups with similar prognosis and similar
therapeutic interventions. These days, there is a preference for the 5th version (1997) of the
TNM staging system
(13)
. To distribute the patients into this stages (I, II, III and IV) different
imaging modalities are used such as endorectal ultrasound (EUS), X-ray (Rx), (endorectal)
magnetic resonance imaging (MRI), computed tomography (CT) and positron emission
tomography - computed tomography (PET-CT).
8.5.2.1 Evaluation of local invasion of the primary tumour (T)
Endorectal ultrasound (EUS) is considered the most ideal imaging tool for staging superficial
rectal tumours. EUS can accurately evaluate the depth of tumor penetration into the rectal wall
to differentiate T1 from T2 rectal tumours (2, 14). The sensitivity and specificity from EUS for
muscularis invasion and perirectal tissue invasion are respectively 94 % and 86% and 94% and
69% (15). Because ultrasound is observer dependent, the values of sensitivity and specificity can
differ strong between different centers (2). It is better not to use EUS for the staging of large,
locally invasive or desmoplastic tumours because it is difficult to distinguish true tumour
infiltration from tissue reaction; resulting in overstaging (12).
12
Prognosis (5TNM
Stage
Extension to
year overall
survival)
Carcinoma in situ:
Tis N0 M0
0
intraepithelial or invasion
of lamina propria
T1 N0 M0
I
Submucosa
T2 N0 M0
I
Muscularis propria
T3 N0 M0
IIa
Substaging
>90%
Subserose/perirectal
tissue
T3a
Less than 1 mm
T3b
1-5 mm
T3c
5-15 mm
T3d
15+ mm
60%-85%
Perforation into visceral
T4 N0 M0
IIb
peritoneum; or invasion
to other organs
T1-2 N1 M0
IIIa
T3-4 N1 M0
IIIb
T1-4 N2 M0
IIIc
T1-4 N1-2
M1
IV
1-3 regional nodes
involved
1-3 regional nodes
involved
4 or more regional nodes
involved
Distant metastases
55%-60%
35%-42%
25%-27%
5%-7%
Table 1: TNM classification (version 5, 1997) with subclassifications and stage-specific
survival (11, 12)
13
The accuracy of EUS after preoperative radiotherapy is decreased due to an increased
echogenicity of the rectal wall
(12)
. EUS cannot be used in patients with high or stenotic
circumferential rectal tumours (2). All things considered, the accuracy of EUS for T staging is
about 80% to 95% (12).
Endorectal MRI has the same accuracy as EUS in T1 and T2 tumours but has the advantage
that it also can be used in high located or stenosing cancers and it is less observer-dependent (2,
12)
. However, endorectal MRI is not the first choice because of its high costs. It is also a
technically more demanding imaging tool and it is a less comfortable procedure to undergo for
the patients (2).
In T3 tumours, EUS can be considered equally accurate to endorectal MRI. Both MRI and EUS
have difficulties in the differentiation between T2 and borderline T3 lesions which can result in
overstaging and suboptimal therapy choice (2). MRI can assess the depth of extramural spread
of T3 rectal tumours as accurately as histology (2). For tumours located in the lower third of
the rectum MRI is superior to EUS when high resolution sequences with scans perpendicular
to the anal canal and coronal scans of the sphincter complex are used (2, 14). In the evaluation of
local invasion of lower rectal tumours, CT remains inferior to EUS and MRI because it cannot
differentiate between the layers of the rectal wall and the inherent soft tissue planes
(2, 12)
. For
the evaluation of high rectal tumours CT is useful to show the relationship of the tumour to
pelvic structures (12).
For advanced rectal cancer (T3 and T4 tumours), only phased array MRI has a high accuracy
in the evaluation of local infiltration (2).
To evaluate the circumferential resection margin (CRM), which is important for the substaging
of T3 tumours, phased array MRI is the imaging modality of choice
(2, 14)
. Endoscopic
ultrasound, endorectal MRI and conventional CT have no place in the evaluation of the CRM
(2)
.
Digital examination (DRE) is a good way to evaluate the height of the tumour in the rectum (12).
This examination is highly accurate for mid-rectal and lower rectal tumours. In contrast to rigid
proctoscopy, flexible endoscopy is not always reliable to locate the tumour. The distance
between the anorectal junction and the distal part of the tumour as well as the length of the
tumour are usually measured with a phased array MRI. CT can also be used to determine the
distance of the tumour to the anal sphincter complex (2).
Tumor infiltration of the internal or external sphincter can be accurately evaluated by digital
rectal examination, EUS, phased array or endorectal MRI (2).
14
8.5.2.2 Evaluation of regional lymph node involvement (N)
Currently, characterising lymph nodes into malignant or non-pathologically enlarged lymph
nodes remains an important radiological challenge. Nodes larger than 8 mm are considered as
malignant on CT, MRI and EUS. EUS is considered better than MRI and CT for nodal staging
except for nodes located in the mesorectum (2). However, the size criteria is not a good predictor
for malignancy (14). The best way to indicate malignant lymph nodes is based on morphological
features such as the presence of mixed signal intensity within the lymph node and/or irregularity
of the borders of the lymph node. The best way to describe these morphological alterations is
by using high resolution MRI scan techniques. The use of FDG PET is not recommended in the
search for malignant lymph nodes (2).
8.5.2.3 Evaluation of distant metastasis (M)
About 50-60% of all rectal cancer patients will develop distant metastasis after treatment. These
metastases are usually found in the liver (20-25%), the lungs (10-20%), bone (6-10%) and less
common in the brain (3%). The finding of distant metastasis has important implications on the
choice of treatment (12).
In search for distant disease, the investigations generally used are chest X-ray, thoracic and
abdominal CT or MRI. FDG-PET and MRI are superior to helical CT in the detection of hepatic
metastases. Bipat et al. showed us that FDG-PET had a significantly higher sensitivity on a perpatient basis, but not on a per-lesion basis. The sensitivity per lesion basis for MRI using liverspecific contrast agents was significantly superior to that for helical CT
(2, 16)
. When clinical
symptoms - such as bone pain or neurological dysfunction - occur, a bone and brain scan can
be performed in search of distant metastasis.
8.6 Therapy
The only way to cure cancer is to remove or destroy every malignant cell in the entire body.
Radical removal of the primary tumour and prevention of local recurrence form the main
principles in general cancer treatment. As with most types of cancer, surgery is the most
effective way to accomplish this. When surgery cannot insure a complete removal of the tumour,
preoperative therapy can be performed to improve surgical conditions. Preoperative therapy
consists of radiotherapy (RT) and/or chemotherapy.
15
Based on a study from Smith and Brown, Blomqvist and Glimelius divided rectal cancers into
three groups with a different preoperative management: “the good, the bad and the ugly”(17).
The distribution into these groups is based on the position of the tumour into the TNM
classification, the location of the tumour in the rectum and the status of the circumferential
resection margin before surgery (negative or positive for malignant cells) (18). Other factors that
play a role in the decision making concerning preoperative therapy, such as size of the
mesorectum, anterior or posterior location of the tumour and extramural vascular invasion were
not included in this algorithm (11).
The “good” group of rectal tumours shows no bad prognostic factors on MRI nor a risk of local
or systemic failure. Therefore, surgery for “good” tumours does not need to be preceded by
preoperative treatment. Rectal cancer with an increased risk for distant metastases is classified
in the “bad” group; those cancers are usually treated with short-course RT followed by
immediate surgery. The “ugly” group consists of tumours with features suggesting high risks
for local recurrence and distant metastases. It is recommended to treat these patients with
chemoradiotherapy before delayed surgery (18).
8.6.1 Preoperative treatment
8.6.1.1 Radiotherapy
The use of radiotherapy is of great importance in the treatment of rectal cancer. The main
purposes of radiotherapy are reducing local recurrence and obtaining a better survival rate
(8)
.
A variety of treatment modalities, distinguishable by preoperative, intraoperative, postoperative
application, with or without chemotherapy and duration are used around the world.
Before the 1990s, researchers from the United States investigated postoperative RT while
European researchers did the same with preoperative RT. Several studies showed the
superiority of preoperative RT versus postoperative RT
(19, 20)
. The main advantage of
preoperative RT compared to postoperative RT is its downstaging effect on the tumor which
results in better surgical options (8). There are more sphincter-saving procedures performed after
preoperative RT and this technique is less toxic than its postoperative variant
(8, 11)
. However,
when a second biopsy is performed to evaluate the histopathological response after
radiotherapy, pathological details such as margins, depth of bowel wall penetration and
histological features can be hard to investigate due to tissue destruction (2).
16
Rectal cancers
Favourable “good”
group
Intermediate “bad” group
Advanced “ugly”
group
mid/ upper rectum
T1-3b
lower rectum T1-2, T3a
N0
mid/upper rectum
T3c/d
lower rectum also includes
T3b
T4 with peritoneal or vaginal
involvement only
N1/N2
T4 with overgrowth to
prostate, seminal
vesicles, base of
urinary bladder, pelvic
side walls or floor,
sacrum positive lateral
lymph nodes
CRM clear
CRM clear
CRM positive
5yr LFR 2) <10%
5yr LFR 2) 10-20%
5yr LFR 2) 20 - 100%
Primary surgery (TME) 3)
Preop 5 x 5 Gy with
immediate surgery
Preop CRT or 5 x 5 Gy
with delayed surgery 4)
1) The algorithm does not primarily address the risk of systemic disease, although this risk
also increases with the presence of many of ‘the risk factors’, however, not necessarily parallel
to the local failure rate (LFR).
2) Calculated in the group of patients planned for surgery, i.e. irrespective of the surgical
outcome. The figures are valid if the surgeon is an experienced rectal cancer surgeon and no
pre-treatment is given.
3) A local procedure is possible in a few (chiefly pT1, sm1 + 2, N0).
4) CRT means chemoradiotherapy to 50.4 Gy in 1.8 Gy fractions with 5-fluorouracil. 5 x 5
Gy with delayed surgery is used in patients not fit for CRT. The relative antitumour efficacy
of conventionally fractionated RT or the short-course schedule is not known with any greater
certainty.
Table 2: Subgrouping of localized rectal cancer assessed by MRI and recommended primary
treatment (11, 18)
17
Of course, this does not apply for postoperative RT. Postoperative radio(chemo)therapy can be
an alternative treatment option when the patient with comorbidity refuses radical surgery while
adverse prognostic factors such as involved margins, poorly differentiated tumours and
lymphovascular invasion are absent (2).
Short-course irradiation, most commonly used in the “bad” group, consists of a dose of 25 Gy
over 1 week (5 x5 Gy) with surgery within 10 days after the first radiation fraction. Long-course
RT at the other hand consisting a dose of 50.4 Gy in 1.8 Gy/ fraction and followed by surgery
after a 6–8 week gap is mostly used in the “ugly” group of rectal cancers (11).
Preoperative radiotherapy should be planned using a four-field plan, with shielding of normal
tissue to reduce toxicity. The primary tumor with the mesorectum and lymph nodes (those most
at risk) outside the mesorectum should get the highest irradiation dose (11).
As shown in Table 2, radiotherapy is indicated especially in the intermediate “bad” and
advanced “ugly” group of rectal tumours. In most cases early localized cancers (favourable
“good” group) require no further therapy besides surgery
(11, 18)
. After the introduction of the
total mesorecal excision (TME) technique, the local recurrence rates were reduced dramatically
even without preoperative RT
(12)
. Because TME already achieves a low recurrence rate,
preoperative radiotherapy is not recommended in the “good” group of rectal cancers
(11)
.
Exceptionally, when the medical condition of the patient does not allow a surgical procedure
or if the patient refuses radical surgery, radiotherapy alone can be performed (2).
In the intermediate “bad” and the advanced “ugly” group of rectal cancers preoperative
radiotherapy is performed standard even in combination with the TME technique
(2, 11, 14, 18)
.
The Dutch CKVO 95-04 trail examined the outcome of preoperative RT with the TME
technique versus TME surgery alone in 1805 patients who had a resectable rectal cancer.
Preoperative radiotherapy with TME had an overall 5-year local recurrence rate of 6% while
TME alone had a rate of 12%
(12, 21)
. An alternative option is initial surgery followed by
postoperative CRT if the tumor is T3 and/or N1-2 (22).
The interval between preoperative CRT and surgery is longer (6-8 weeks = long-course RT) in
the locally advanced rectal cancers than in the group of the “bad” rectal cancers (< 10 days after
the first radiation fraction = short-course RT). The longer period between preoperative
irradiation and surgery provides an increased downstaging of the tumour without noxious effect
on toxicity. However, this delay after CRT did not result in a significant difference in long-term
local control or survival (23). It is important to know that short-course RT does not downstage
the tumour. For this reason, short-course RT is only indicated when the circumferential
18
resection margin (CRM) is free of cancer based on preoperative MRI. When the CRM is
threatened by the tumour, downstaging long-course CRT is indicated (24).
Currently, with the eye on organ preservation, some institutions restage the tumour after
preoperative CRT; when no viable tumour cells are found, no further therapy is delivered and
the patient is monitored for at least 5 years (11, 25). This approach can only be performed in some
early cases of rectal cancer (26).
MRI and FDG-PET can be used in the evaluation of response after preoperative CRT, but it is
not recommended to modify the extent of surgery based on the findings of these examinations.
It is uncertain that the results of these imaging tools are reliable predictors of tumor
downstaging after RT (11).
8.6.1.2 Chemotherapy
Currently, chemotherapy is typically used in combination with radiotherapy. In contrast to
colon cancer, the evidence of the use of chemotherapy in rectal cancer is not well investigated.
Therefore, the evidence about the use of chemotherapy in colon cancer is generally used in the
treatment of rectal cancer (12).
A combination of 5- fluorouracil (5-FU), leucovorin and oxaliplatin (= FOLFOX) is considered
to be the current standard choice of adjuvant chemotherapy (12).
When the rectal tumour is not treated with neoadjuvant CRT, adjuvant chemotherapy is usually
reserved for stage III tumours. However, when the tumour, already treated with CRT, is located
in the stage II or III group, the use of adjuvant chemotherapy is recommended and this for
approximately 6 months (12).
Other agents used for chemotherapy are capecitabine (oral prodrug of fluorouracil), irinotecan,
cetuximab and panitumumab (EGFR inhibitors) and bevacizumab (VEGF inhibitor). Most of
these chemotherapeutic agents are still under investigation.
8.6.2 Surgery
8.6.2.1 History of rectal cancer surgery
Prior to preceding to the current sphincter-saving procedures, surgery for lower rectal cancer
evolved over a long period of time. Before the 18th century rectal cancer was a disease that
could only be recognized. It was considered incurable until Giovanni Morgagni first suggested
removing the entire rectum in the management of rectal cancer. In 1739, Jean Faget (France)
was the first one who performed a rectal resection. The result of this attempt was an
19
“uncontrollable sacral anus” which was difficult to control. The patient did not survive. The
first colostomy was also executed in France by Henri Pillore in 1776; also this patient did not
survive the procedure (27).
The first successful excision of the rectum was performed by Jacques Lisfranc in 1826. Via a
perineal approach he could remove a few centimeters of the distal rectum
(28)
. The functional
result of such an operation could be compared with a perineal colostomy. Because of the lack
of anesthesia and hemostasis at that time, patients did not survive the procedure due to excessive
hemorrhage. So only five of the nine resections he performed were successful (27).
In 1874, Theodor Kocher introduced the posterior approach. After closure of the anus, in order
to minimize the risk of spillage and infection, he removed the entire coccyx and a part of the
sacrum to enhance the accessibility to the rectum. When the rectum was removed he performed
an anastomosis between the colon and the anus. Simultaneously, Paul Kraske developed a
technique similar to that of Kocher (resection of the coccyx and a piece of the left wing of the
sacrum). The main disadvantage of the perineal and sacral approach was the limited vision of
the surgical field compromising chances for complete tumour removal (28).
In the same century, Carl Gussenbauer performed the first abdominal resection with
intraperitoneal closure of the distal rectum while J. Hochenegg developed a “pull through”
technique by everting the anus and rectum, then excising the tumor and finishing with a rectoanal anastomosis. In 1884, Vincent Czerny was the first surgeon performing a combined
abdominal and perineal resection when it was impossible to remove the tumour via the sacral
approach (27).
A review of 1500 rectal resection cases carried out before 1900 showed an operative mortality
of 20.9% and a recurrence rate of 80%
(27)
. Due to these high recurrence rates, Ernest Miles
started postmortem examinations on patients who died from cancer recurrence after rectal
surgery. He found recurrences in the pelvic peritoneum, the mesocolon, and the lymph nodes
situated at the bifurcation of the left common iliac artery. In 1908, he concluded that lymphatic
spread occurred in all directions (upward, lateral and downward) and that these involved lymph
nodes were responsible for the development of locally recurrent disease (28). Miles suggested to
remove the tumour, the rectosigmoid (and its blood supply), the mesorectum and associated
lymph nodes en bloc through a combined abdominal and perineal approach. He also performed
a wide perineal resection with removal of the levator ani muscle and created an abdominal
colostomy afterwards. The abdominoperineal resection (APR) was born
(27)
. In 1923, Miles
reported a mortality and recurrence rate of 31% and 29.5% respectively. Mortality was mainly
caused by blood loss and infection (28).
20
However, Miles procedure did not become the golden standard because others claimed the
procedure was too risky for patients over the age of sixty with comorbidities. Furthermore,
Miles procedure was considered too radical and was accompanied with a high morbidity:
genitourinary dysfunction, permanent colostomy and psychosocial implications. Consequently,
most surgeons continued to perform perineal resections
(27)
. With the advent of blood
transfusion and improved anesthetics the outcome improved with a decrease of mortality from
36% to 9%. Since then, Miles’s radical APR became the standard procedure for all rectal tumors
(27, 28)
.
To eliminate the need of a colostomy and to spare the sphincter Donald Balfour was the first
surgeon who described the anterior resection procedure. He dissected the tumor through an
abdominal approach and constructed a primary end-to-end anastomosis. Later in 1948, Claude
Dixon demonstrated the safety of sphincter-saving surgery and reported a mortality rate of 2.6%
and a 5-year survival rate of 64%
(28)
. Because of its sphincter-saving nature, the anterior
resection procedure became the golden standard for tumors in the middle- and upper third of
the rectum. However, it did not become the golden standard for tumors of the distal third of the
rectum because of the standard minimal distal resection margin of 5cm in that period (28). Until
the 1970s, the abdominoperineal resection technique remained the surgical treatment modality
of choice for low rectal tumors.
With the development of the low anterior resection (LAR) technique by Alan Parks (1972),
where the anastomosis of the colon and the anus is done peranal via a pull-through technique,
it was possible to resect also low-lying tumors without the need of a permanent colostomy (27).
From then on, LAR was chosen over APR because of its sphincter-saving characteristics.
8.6.2.2 Total mesorectal excision (TME)
In the 1980s studies disclosed that more than a quarter of the resected rectum specimens had
lateral wall margins that were positive for tumor cells. Local pelvic recurrence occurred in 85%
of these cases. In response to this data, Richard Heald developed the total mesorectal excision
technique which is based on the embryologic development of the hindgut
(27)
. In order to
minimize the chance of positive lateral margins he excised the tumor and mesorectum en bloc
to the level of the levator muscles through sharp dissection of the avascular plane between the
mesorectum and the surrounding tissues under direct vision (27, 28). To preserve a good urinary
and sexual function after surgery, it is important to protect the surrounding structures (ureter,
deferent duct, bladder) and the autonomous nerves while excising the mesorectum (29).
21
His technique led to decreased positive lateral margins and decreased local recurrence rates (a
decrease of ±7%) in combination with good functional postoperative results (12, 27-29).
TME has become a standard surgical procedure for middle and lower rectal tumours. For
tumours of the upper one-third of the rectum TME is still controversial (29).
(B)
(A)
(C)
Figure 4: Appropriate planes for total mesorectal excision (dashed line); (A) anterior view, (B)
lateral view man and (C) lateral view woman (30)
8.6.2.3 Distal resection margin (DRM)
The ideal length of the distal resection margin is still a controversial issue in rectal cancer
surgery. Traditionally, a length of 5 cm was taken between the DRM and the edge of the tumor.
Better understanding of the distal spread of rectal cancer and preoperative CRT led to
shortening of this distance. Currently a distal margin of 2 cm is considered as the standard for
all rectal cancers
(12, 31)
. To permit a sphincter-saving procedure, a distal margin of 1 cm is
accepted for low rectal cancers because distal intramural spread occurs over 1 cm in only 410% of the cases (31, 32).
Two recent systematic reviews showed a slightly higher local recurrence rate (+-1%) in the
group with a DRM of ≤1cm compared with the >1cm group. However, this data was not
statistically significant (P = 0.175 and 0.600) and therefore they both concluded that a DRM
of ≤ 1cm was not associated with an increased risk for local recurrence. Both studies could not
22
even approve significant higher recurrence rates in the group with a DRM of ≤ 5mm
(32, 33)
.
This data calls the current ‘2-or 1-cm rule’ into question.
8.6.2.4 Current surgical options for low rectal cancer
Nowadays, the two main surgical procedures in rectal cancer surgery to choose from are the
low anterior resection (LAR) and the abdominoperineal resection (APR) techniques. With a
ratio of 1:3 or 1:4, the sphincter-saving LAR technique is the most used one
(34)
. The local
excision techniques and the APPEAR procedure are still in development, further research is
necessary to learn their full potentials.
8.6.2.4.1 Resection options
8.6.2.4.1.1 (Ultra-) low anterior resection ((U)LAR)
Low or ultra-low anterior resection is the surgical procedure of choice for low rectal cancers
who do not invade the sphincter complex and where the rectal dissection proceeds below the
pelvic floor
(35)
. This procedure consists of a total or near-total excision of the rectum, with
TME, in combination with a coloanal anastomosis after a complete mobilization of the splenic
flexure of the colon
(3)
. The main advantage of the LAR technique is the conservation of the
intestinal continuity and anal sphincter complex (31). For this reason patients choose it above the
abdominoperineal procedure, which is associated with a permanent colostomy, even though
there is a risk of fecal incontinence after LAR
(36)
. LAR can be performed via an open
(abdominal) or laparoscopic approach.
Sometimes, to improve the healing of the coloanal anastomosis, a temporary diverting colo- or
ileostomy is constructed. The meta-analysis from Tan WS et al. showed lower rates of clinical
anastomotic leakage (RR = 0.39; P < 0.001) and reoperation (RR = 0.29; P < 0.001) in the stoma
group compared with the group without a protective stoma
(37)
. LAR is associated with low
local (LR) and systemic (SR) recurrence rates. Kim C. et al compared the oncological outcome
of LAR with APR in lower rectal cancers and found a LR rate of 4.5% and SR of 14.9% in the
LAR group (402 patients) and 9.5% and 22.6% in the APR group (402 patients).
These results were comparable to those reported in other studies
(31, 34)
. At present, there is
strong evidence that LAR and APR have comparable long-term oncological results when
appropriate surgical margins can be assured (31).
23
Figure 5: A,B: low anterior resection; C: coloanal anastomosis; D: neorectum construction
(J-pouch) (http://www.hopkinscoloncancercenter.org/)
8.6.2.4.1.2 Intersphincteric resection (ISR)
See section: What is ISR?
8.6.2.4.1.3 Local excision
Local excision of rectal tumors is still a controversial topic in rectal surgery. Local excision can
be an option in selected early stage rectal cancers, more advanced tumors in combination with
CRT and for tumors in patients who are unable to undergo transabdominal surgery (3, 30). Small
(<3cm), mobile, node-negative pT1 tumors with favorable histology would be ideal candidates
for local excision (30, 31). However, none of these factors can be preoperatively determined with
certainty by means of EUS or MRI (30).
Currently there are two main techniques for local excision: the most widely used transanal
excision (TAE) and the transanal endoscopic microsurgery (TEM). TEM can be used for tumors
up to 20 cm from the anal verge while TAE can only be used for tumors within the distal 8 cm
of the rectum (31). Transanal minimally invasive surgery (TAMIS) can be used for endoluminal
tumor resections when TEM is not suitable (30).
Although there are still only a few studies available, the local excision techniques seem to be
relatively safe, with less anorectal and genitourinary dysfunction and better quality of life
compared with radical surgery, on condition of careful patient selection (2, 31).
24
A recent systematic review by Ung et al. demonstrated a median overall survival, diseasespecific and disease-free survival of respectively 75% (range: 66-80.6%), 89% (range: 7593.3%) and 74% (range: 64-85.2%) for T1/T2N0M0 rectal tumors treated with local excision
and (neo)adjuvant chemoradiotherapy. Median local, distant and overall survival were 75%
(66–80.6%), 89% (75–93.3%) and 74% (64–85.2%), respectively
(38)
. The local excision
procedures seem to become an attractive option for well selected early rectal cancer cases.
8.6.2.4.1.4 Abdominoperineal excision
Since the invention of the abdominoperineal resection technique by Miles in the early 20th
century, it has long been the standard treatment for most of the tumors of the middle and lower
rectum. Hence the name, the rectum is removed via an abdominal and a perineal approach. The
APR technique is inevitably combined with a definitive left iliac colostomy since the entire
sphincter complex is excised with the rectum (31, 39). The perineal skin is closed afterwards.
Because of the progress of other surgical sphincter-saving techniques, decreased distal resection
margins, the possibility of making low colo-anal anastomoses and the introduction of
neoadjuvant therapy, the indications to choose for APR are decreased significantly. Currently,
the indications for APR in low rectal cancer are limited to advanced (T3/T4) tumors involving
the external sphincter or pelvic floor and tumors with a circumferential margin, estimated
preoperatively, to be less than 1 mm. APR can also be a solution in patients where anterior
resection is not an attractive option because of sphincter incompetency, fear of poor functional
outcome and poor colonic vascularization which can compromise a colorectal/ coloanal
anastomosis (30, 39).
Various studies show that the classic APR procedure is associated with poor postoperative
functional and oncological outcome compared to the anterior resection technique. For example,
How et al. summarized in their review of twenty four studies comparing APR with anterior
resection (AR) results relating to circumferential resection margin (CRM), tumor perforation
rates, local recurrence, overall survival (OS), cancer-specific survival (CSS) and disease-free
survival (DFS). APR was associated with higher local recurrence rates in 8 out of 19 studies.
Nine of these 19 studies did not find any significant difference between the two procedures. All
studies comparing DFS, OS and CSS between both procedures showed a decreased survival
associated with APR (40). This worse oncological outcome, is most probably a result of the fact
that most APRs are performed for large, more advanced low-lying rectal tumors with a poor
prognosis where the risk of CRM involvement and intraoperative perforation is increased (30, 39,
25
40)
. This theory is supported by the results of a multivariate analysis by Kim et al. in which no
linked-association was found between LR, OS and DFS and APR. When looking in the APR
group, LR was associated with adjacent-organ or perineural invasion, CRM+ and advanced
stage (P = 0.003-0.04), DFS with LR, systemic recurrence (SR), CRM+ and infiltrating tumor
(P < 0.001-0.05) and OS with LR, SR, elevated s-CEA and lymphatic vessel invasion (P <
0.001-0.05) (34).
Figure 6: Abdominoperineal resection (dashed lines are the resection margins)(30).
(http://www.hopkinscoloncancercenter.org/)
26
8.6.2.4.1.5 Anterior perineal plane for ultra-low anterior resection (APPEAR)
Very recently Williams et al. created the Anterior Perineal PlanE for ultra-low Anterior
Resection (APPEAR) technique. Just like APR, the APPEAR procedure is done via an
abdominal and perineal approach. Via the abdomen the rectum is mobilized and transected, via
the perineum (incision between the anus and the vagina or base of the scrotum) a
rectovaginal/rectoprostatic plane is created. The entire sphincter complex is preserved and a
coloanal anastomosis is made. So, APPEAR is a sphincter-saving procedure (30, 41).
Currently there are still few studies discussing oncologic and functional outcomes of the
APPEAR procedure. The initial results from Williams et al., however, seem promising. Of the
14 (from which 7 had rectal cancer) patients who had undergone this procedure no one died and
no one developed LR. All patients were continent to solid and liquid stool. Quality of life preand postoperative seemed to be comparable. The only disadvantage was the high rate (50%) of
perineal sepsis and subsequent colonic/ileoanal pouch perineal fistulation (41).
Further research is necessary to evaluate this technique.
Figure 7: APPEAR-procedure. A) incision line between anus and scrotum. B) initial dissection
to expose the distal rectum. C) fully mobilized rectum before transecting the bowel above the
external anal sphincter (41)
27
8.6.2.4.2 Coloanal anastomosis (CAA) and neorectum reconstruction
Restoration of bowel continuity through coloanal anastomosis is possible in most of the lower
rectal cancers. The coloanal anastomosis can be accomplished in 2 ways: handsewn or stapled.
Distal CAA are most commonly done through a double cross stapled technique using a circular
intraluminal stapling instrument which is introduced transanally.
Irrigation of the rectum with a tumoricidal fluid prior to the stapling procedure is needed in
order to avoid implantation of disseminated tumor cells (42).
Nowadays, a hand-sewn coloanal anastomosis is mainly used in combination with the pullthrough technique in intersphincteric resection, in obese patients with a narrow pelvis or in
patients where the stapled anastomosis failed (42). It is generally known that functional outcome,
such as the ability to maintain continence and frequency of defecation, are worse when the
anastomosis is located lower to the anal verge (42-44).
The three main options to accomplish this coloanal anastomosis are the straight end-to-end, the
colonic J-pouch or the transverse coloplasty anastomosis. Because the reservoir function of the
rectum is lost when performing a straight end-to-end anastomosis, this technique is associated
with higher rates of frequency of defecation, fecal urgency and incontinence. This combination
of defecation related symptoms is called the ‘low anterior resection syndrome’(42, 43).
To improve bowel function and quality of life after rectal resection, neorectum reconstruction
techniques, such as the colonic J-pouch and the transverse coloplasty, were developed.
Construction of a neorectum has the ability to increase the volume of stool that can be stored.
The colonic J-pouch consists of a J-shaped reservoir of 6-7 cm. Larger reservoirs are associated
with more evacuation problems
(3, 42, 43)
. Heriot et al. found in their meta-analysis that the
colonic J-pouch had better functional results compared to the straight end-to-end anastomosis.
The J-pouch showed lower rates of stool frequency and there were less complaints of urgency
up to one year after surgery (44).
The transverse coloplasty can be an alternative in patients where construction of a colonic Jpouch is not possible due to technical (narrow pelvis, bulky anal sphincters, diverticulosis,
insufficient colon length or pregnancy) or non-technical (complex surgery or distant metastasis)
issues. Coloplasty has a smaller volume compared to the colonic J-pouch but has comparable
functional results (43, 44).
28
(B)
(A)
(C)
Figure 8: A) Straight end-to-end anastomosis; B) Colonic J-pouch and C) Transverse
coloplasty (42)
8.7 General functional outcome and quality of life after rectal cancer surgery
Functional outcome after rectal cancer surgery is influenced by many factors including the
patients characteristics, (neo)adjuvant CRT, surgical technique and the method and level of
anastomosis (30).
A significant number of patients (10-50%) who were treated with sphincter-saving surgery
frequently experience altered bowel function. This disorder is called the ‘(low) anterior
resection syndrome ((L)ARS)’. It includes multiple bowel symptoms like urgency (12-45%),
fecal incontinence (10-71%), obstructed defecation and constipation (16-74%). This syndrome
has a significant adverse effect on quality of life (QoL), especially when it is associated with
urinary and sexual dysfunction. Important factors that contribute to the development of LARS
are perioperative damage to the sphincter complex or its innervation and postoperative factors
such as shortened intestinal length, a more distally located coloanal anastomosis, a reduced
rectal reservoir and higher volumes of more liquid stool delivered in a smaller neorectum
(30,
45)
.
Mobilization of the rectum and to extensive TME during surgery can cause injury of the
hypogastric and sacral splanchnic nerves which can result in urinary and sexual dysfunction.
Sexual function includes the ability to engage sexual intercourse, to have a normal erection or
ejaculation for men and the ability to obtain vaginal lubrication and orgasm in women. Ho et
al. stated in their review that sexual dysfunction rates after rectal surgery varied from 23-69%
in men and 19-62% in women
(46)
. Less than 5% of the patients reported having urinary
complications (incomplete emptying, urgency, leakage, dysuria, post-micturition dribbling)
after surgery
(43, 47)
. Most of the urinary complaints seems to disappear over time
(43)
. Risk
factors for sexual and urinary dysfunction are increasing age, pre-operative RT, APR and TME
29
which fails to respect the mesorectum
(46, 47)
. Well-designed studies using validated surveys,
knowing pre-operative sexual and urinary function and have good data quality are scarce.
Studies comparing the ‘Quality of life’ (QoL) before and after rectal surgery are rare as well.
Quality of life after sphincter-saving surgery compared with that after permanent colostomy is
better investigated. In the meta-analysis of 11 studies by Cornish et al. there was no difference
in overall QoL between patients with or without colostomy
(48)
. Fourteen trials (from the 35
included studies) from another meta-analysis performed by Pachler et al. also showed no
difference. However, 18 studies showed that QoL in patients with a stoma was significantly
impaired in one or more QoL sub-scales (49).
Further and better research is necessary to better understand the influence of the different
options in rectal cancer treatment on QoL, sexual and urinary functionality after surgery.
30
9 What is ISR?
Traditionally, rectal tumors located close to the sphincter complex were treated with the APR
procedure, even when the internal or external sphincter were not infiltrated by malignant cells.
With the knowledge of the cephalic lymphatic spread into the mesorectum and the limited distal
spread of rectal cancer, Rudolf Schiessel, an Austrian colorectal surgeon, developed the
intersphincteric resection (ISR) technique in 1994 as an alternative for the APR procedure in
the treatment of distally located rectal cancer. However, since intersphincteric resection of the
rectum already existed in the treatment of inflammatory bowel disease (since 1977), the ISR
technique developed by Schiessel and colleagues can be considered more as a modification of
an existing technique than a real invention (50, 51).
This technique, based on the existence of the with fat-filled intersphincteric space between the
internal and external anal sphincter, consists of an excision of the rectum in combination with
TME and a total or partial resection of the internal sphincter followed by a hand-sewn coloanal
anastomosis. The operation is carried out in two stages: an abdominal and a perineal part. The
surgical technique will be described in detail in the results of this thesis.
In contrast to APR with its permanent colostomy, ISR is a sphincter-saving procedure that
preserves the gastrointestinal continuity.
Based on the distal resection line, which depends on the distance from the tumor to the anal
verge, ISR can be divided into three subtypes: total-, subtotal- or partial-ISR. When the entire
internal sphincter is excised we speak of a total-ISR, the resection line is then located at the
intersphincteric groove. For subtotal- and partial-ISR the resection line is lying respectively at
or above the dentate line and between the dentate line and the intersphincteric groove (see
Figure 9). The upper one-third of the internal sphincter is removed when performing a partialISR and the upper two-third when performing a subtotal-ISR (50, 52). The choice between these
three options depends primarily on the location of the tumor and the size and depth of invasion
and the decision should ideally be made prior to surgery.
Currently, many variations are made on the original ISR procedure as described by Schiessel,
such as ISR with mechanical stapler anastomosis, full abdominal ISR procedures or ISR with
partial resection of the external sphincter (PESR) when the intersphincteric space or external
anal sphincter is suspected for tumor invasion.
Ultra-low anterior resection (ULAR) with hand-sewn coloanal anastomosis, as described by
Parks, is often thought to be a variation of the partial-ISR technique. However, since the internal
31
sphincter is almost completely preserved performing ULAR, it cannot be classified as a subtype
of ISR (50).
Figure 9: Differentiation between the LAR, ULAR and ISR technique based on height and
method of anastomosis. The arrows show the distal resection line for each technique.
Abbreviations: PR peritoneal reflection, LAM levator ani muscle, ISS intersphincteric space,
IS internal sphincter, DL dentate line, ES external sphincter, ISG intersphincteric groove, SbES
subcutaneous part of the external sphincter, DST double stapling technique, CAA coloanal
anastomosis (50)
10 Purpose of this thesis
Today, because of the evolution of distal rectal cancer surgery towards more sphincter
preservation, the ISR procedure with hand-sewn coloanal anastomosis has become a more
attractive alternative for the otherwise inevitable permanent colostomy associated with the APR
technique. Since its development by Schiessel et al. in 1994, various trials have been launched
to evaluate the oncological safety and functional outcomes of this operation in the treatment of
distal rectal cancer.
The purpose of this thesis was to investigate the current evidence regarding the short- and longterm oncological and functional outcomes in patients who have been treated with ISR with
hand-sewn coloanal anastomosis, as described by Schiessel, in the treatment of distal rectal
cancer. The indications for ISR and the surgical technique were also discussed.
32
11 Methods
11.1 Search strategy
A systematic literature search using Web of Science, PubMed and the Cochrane Library
between 1960 and January 2015 was performed. Following search terms and their combinations
were used: “cancer OR adenoca* OR carcinoma OR tum*”, “rect*”, “low OR distal”,
“intersphinct* OR inter-sphinct*”, “funct*” and “oncol*”. To further explore for other trials
the ‘related articles’ function of Pubmed was used and the reference list of the selected original
articles and reviews were searched for other available trials.
11.2 Study selection
Only free available original studies published in the English language which mentioned
oncological and/or functional outcome after intersphincteric resection (ISR) with hand-sewn
coloanal anastomosis , as described by Schiessel et al., were included. This means that articles
which investigated ISR with stapled anastomosis were excluded. Other factors which have led
to exclusion were: ISR with partial excision of the external sphincter (PESR), non-typical ISR
procedures and lack of information about the method of anastomosis. For articles who
compared the ISR with handsewn anastomosis with another technique (LAR, APR), only the
data of the ISR procedure was retained. When there was more than one study found from the
same institution, only the most recent one was retained to avoid double counting of patients.
There were no restrictions on the size of study population, follow-up duration and method of
ISR procedure (open surgery, laparoscopy or robot).
11.3 Data collection and statistical analysis
The selected trials were searched for relevant data about the indications for ISR, preoperative
staging, the surgical technique, morbidity and mortality and long-term oncological and
functional outcomes and quality of life (QoL) after ISR.
The information about the general characteristics of the studies and data about short- and longterm oncological and functional outcomes were then summarized into five tables (see section
results). These tables include basic descriptive statistics such as simple counts, percentages or
weighted means which were provided by the included trials. When not reported, the percentages
were calculated when the required simple counts were given.
33
To summarize all this data, total counts, average weighted means, ranges and 95% confidence
intervals were calculated with the data from the included studies wherever possible.
12 Results
12.1 Literature search
Eighty two articles were retained for further Search strategy on Web of Science
(103 results), Pubmed (205 results)
exploration after the application of the initial and Cochrane Library (8 results)
exclusion criteria (irrelevant title or abstract,
double articles, studies not published in the
Exclusion:
- Titel & abstract
- Double articles
- Not English
- No full article available
English language and articles without free
full-text). Another 61 articles were excluded
because they did not meet the inclusion
criteria: no original article (17), stapled 82 studies
anastomosis (10), PESR (8), non-typical ISR
Exclusion:
- No original articles (17)
- Stapled anastomosis (10)
- PESR (8)
- Non typical ISR technique
(4)
- No data about method
anastomosis (4)
- No data about functional/
oncological outcome (10)
- Other procedure (3)
- More recent article (4)
- No adenocarcinoma (1)
- Other (1)
technique (4), no data about method of
anastomosis
(4),
functional/oncological
no
data
about
outcome
(10),
description of another procedure (3) or nonadenocarcinoma (1). Four studies were
excluded from this review because there
were more recent trials available with the
same patient population. One article who
met the inclusion criteria was still excluded
because it was difficult to extract the useful
20 studies included
data since they reported their results in two
different periods with different and lower number of patients (53).
Overall, the data of the 20 remaining articles which did not meet the exclusion criteria and
contained enough details about the oncological and/or functional outcome after ISR with handsewn coloanal anastomosis were included in this review (4, 52, 54-71).
The general characteristics of the included articles are represented in Table 3.
34
Reference
Patients
Year
(n)
Operation
type
Mean age
M/W (n)
(years)
T-staging (n)
pT1 (10); pT2
pI (20); pII
(17); pT3 (49);
(25); pIII (32)
pT4 (1)
pT1(4); pT2 (25);
pT3(7)
pTis (3); pT1
p0 (3); pI (24);
(22); pT2 (11);
pII (0); pIII (10)
pT3 (1)
T0 (4); T1 (7); T2
(10); T3 (10); T4
(0); unknown (2)
Koyama et al. (54) 2014
77
Open
surgery
56/21
63
Cong et al. (55)
2014
38
Laparoscopy
21/17
60,3
Shiomi et al. (56)
2013
37
Laparoscopy
17/20
66
Konanz et al. (57) 2013
33
Open
surgery
26/7
63,1
14
Open
surgery (11)
and
laparoscopy
(3)
9/5
61
cT1 (3); cT2 (4);
cT3 (7); cT4 (0)
124
Open
surgery
77/47
65
pT1 (20); pT2
(37); pT3 (64);
pT4 (3)
65
Open
surgery
45/20
64
-
110
Laparoscopy
72/38
64
-
Dumont et al. (58) 2013
Akagi et al. (59)
2013
Laurent et al. (60) 2012
Gong et al. (61)
2012
43
Open
surgery
27/16
53
Park et al. (62)
2011
80
Open
surgery
53/27
59,1
130
Laparoscopy
88/42
60,9
Median
Pathological Neoadjuvant Adjuvant tumor height
TNM staging
treatment treatment
from anal
(n)
(%)
(%)
verge (mm ±
SD (range))
cT1 (26); cT2
(17)
cT1 (14); cT2
(32); cT3 (33);
cT4 (1)
cT1 (13); cT2
(40); cT3 (73);
cT4 (4)
DRM
(mm
(range))
Positive
CRM
(<1mm)
(%)
R0
resection
(%)
Neorectum Diverting
Method of
construction ileostomy
ISR (n)
(n)
(%)
9
-
37,1 ± 13,1
(20-50)
-
-
-
-
JP(29); TC(5);
SCA(3) (37/
77 patients)
9
13,2
-
20 ± 7(*)
-
-
-
pISR (15);
stISR (23)
-
100
0
-
40 (10-50)
12 (5-22)
0
100
-
SCA (37)
100
58
21,2
-
-
-
-
-
-
-
-
71,5
71,5
40 (25-55)
-
0
-
pI (43); pII
(41); pIII (40)
0
46,8
30 (10-40)
-
2,4
-
84,6
53,8
40 (20-50)
20
(10-30)
6,2
-
93,6
50,9
35 (10-60)
18 (5-40)
15,5
-
0
-
-
-
-
100
1,3
-
47 ± 8
14 ± 11
5
7,7
-
36 ± 13
15 ± 9
100
-
34 ± 10
(10-50)
88,5
-
pI (27); pII
(21); pIII (17)
pI (53); pII
(23); pIII (34)
pI (24); pII
(20); pIII (32);
pIV (4)
pI (40); pII
(36); pIII (42);
pIV (12)
p0 (14); pI
(45); pII (28);
pIII (24)
pI (14); pII (2);
pIII (9)
stISR and
JP(12); SCA(2)
tISR
SCA(124)
100
JP or SCA
100
JP or SCA
100
pISR (43)
SCA
0
-
-
SCA (80)
7,5
2,3
-
-
SCA (130)
10,7
13 ± 11
(5-45)
13,7
100
pISR (106);
tISR (5)
SCA (111)
100
35 (25-50)
13,6
(1-45)
13,3
-
Lim et al. (63)
2011
111
Laparoscopy
86/25
60,1
-
Kuo et al. (64)
2011
26
Open
surgery
16/10
51,1
-
Yamada et al. (52) 2009
107
Open
surgery
76/31
59,4
-
pI (48); pII
(24); pIII (35)
0
55,1
-
-
-
100
Weiser et al. (65) 2009
44
Open
surgery
25/19
54
uT1-2N1 (6);
uT3N0 (12);
uT3N1 (26)
p0 (11); pI
(16); pII (12);
pIII (5)
100
89
50 (30-60)
10 (9-13)
5
92
-
100
pISR (39);
tISR (26)
pISR (80);
tISR (30)
pISR or
SCA (26)
stISR
pISR (71);
JP(102);TC(2);
stISR (16);
SCA(3)
tISR (20)
-
JP (21); TC (6);
SCA (17)
100
100
-
35
Reference
Patients
Year
(n)
Operation
type
Mean age
M/W (n)
(years)
T-staging (n)
Han et al. (66)
2009
40
Open
surgery
24/16
62
Akasu et al. (67)
2008
120
Open
surgery
92/28
57
Chamlou et al. (68) 2007
90
Open
surgery
59/31
58,9
Hohenberger et
al. (69)
65
Open
surgery
-
61
-
60
83/38
63,6
pT1 (37); pT2
(45); pT3 (37)
17/14
60
60,8
Yoo et al. (70)
2006
2005
29
Schiessel et al. (4) 2005
121
Köhler et al. (71)
31
Total/ Weighted
mean
Range
2000
1535
Open
surgery (20)
and
laparoscopy
(9)
Open
surgery
Open
surgery
Open
surgery
(1097) and 969/472
laparoscopy
(438)
Median
Pathological Neoadjuvant Adjuvant tumor height
DRM
TNM staging
treatment treatment
from anal
(mm
(n)
(%)
(%)
verge (mm ± (range))
SD (range))
cT1-2N0 (18);
cT1-2N1 (22)
-
Positive
CRM
(<1mm)
(%)
R0
resection
(%)
Neorectum Diverting
Method of
construction ileostomy
ISR (n)
(n)
(%)
2,5
55
15 (5-50)(*)
-
0
100
pISR(35);
tISR (5)
JP (7); SCA
(33)
27,5
pI (50); pII
(21); pIII (46);
pIV (3)
ypT0 (7); pT1
pI (37); pII
(12); pT2 (35); (16); pIII (25);
pT3 (32); pT4 (4)
pIV (5)
yp0 (3); pI
T1-T2
(28); pII (13);
pIII (21)
0
22,5
30 (10-50)
12 (3-40)
3,3
96,7
pISR (103);
tISR (17)
SCA (120)
90
41
4,4
35 (22-53)
12 (5-35)
4,4
94,4
pISR (63);
stISR (27)
JP (90)
100
-
-
-
17,5
-
-
-
JP or SCA
100
pTis (1); pT1 (8);
p0 (1); pI (15);
pT2 (11); pT3
pII (5); pIII (9)
(10)
0
20,6
40 (20-60)
-
6,8
-
pISR (31)
SCA (31)
100
-
0
31,6
30 (10-50)
-
-
96,7
-
SCA(121)
100
pT1 (7); pT2
(16); pT3 (8)
-
0
35,4
13 ± 9 (323)(*)
16 ± 8 (626)
-
-
pISR and
stISR
SCA (31)
100
T1 (201);
T2 (330);
T3 (410);
T4 (13)
p0 (32);
pI (484);
pII (287);
pIII (381);
pIV (24)
29
40,1
35,6
14,5
6,1
97,7
pISR (586),
stISR(66),
tISR (103)
JP (261);
TC(13);
SCA (869)
76,4
(0 - 100)
(4,4 - 89,0)
(10 - 60)
(1 - 45)
(0 - 15,5)
(92 - 100)
pT1 (25); pT2
(46); pT3 (49)
(51,1 - 66)
(0 - 100)
Table 3: General study, patient and tumor characteristics.
M male, F female, SD standard deviation, DRM distal resection margin, CRM circumferential resection margin, R0 complete removal of the entire tumor
without microscopic cancer involvement of the margins, cT clinical T-stage, pT pathological T-stage, uT ultrasound T-stage, yp0 complete pathological
response after preoperative chemoradiation therapy, (*) distance from the dentate line, pISR partial ISR, sbISR subtotal ISR, tISR total ISR, JP colonic Jpouch, TC transverse coloplasty, SCA straight coloanal anastomosis.
36
12.2 Study and patient characteristics
General study and patient characteristics are shown in Table 3.
Most of the studies that met the inclusion criteria were from Asian (Japan (6), China (3), Korea
(2) and Taiwan (1)) and European (Germany (3), France (3) and Austria (1)) institutions with
respectively 12 and 7 included articles. There was only one article from the USA (65).
The total number of patients analyzed in this review was 1535. The mean age at the moment of
surgery was 60.8 years (range: 51.1-66 years). Most of the patients who underwent ISR were
males with 67.2% of the cases (969 men and 472 women). According to three studies, ISR is
predominantly performed in males because of the higher prevalence of a narrow pelvis, the less
mobile pelvic floor musculature and obesity which are unfavorable factors for the use of a
stapling device when performing a LAR (65, 69, 70).
The median distance from the tumor to the anal verge was reported in 13 articles. The weighted
mean distance was 35.6 mm (range: 10-60 mm). Three studies reported the median distance to
the dentate line with an average of 16.2 mm (range: 3-50 mm) (55, 66, 71).
Fifteen of the 20 studies reported the pathological TNM staging. The majority (95.4%) of the
rectal tumors were categorized as TNM stage I-III with respectively 40.1%, 23.8%, 31.5% of
the tumors. The other 4.6% consisted of carcinomas in situ and metastatic rectal cancers.
In order to enhance the possibility of sphincter preservation, neoadjuvant treatment was
performed in 29% of the ISR cases (range: 0-100%). Indications for administration of
preoperative chemoradiation therapy were locally advanced rectal cancer (T3 and T4) and
lymph node involvement (N+). Two studies reported a treatment of all included patients with
preoperative CRT
(63, 65)
. Adjuvant treatment was performed in 40.1% of the patients (range:
4.4-89%).
The intersphincteric resection was either carried out by open surgery or by laparoscopy.
Thirteen studies used only the open technique, 3 only the laparoscopic technique and 4 studies
reported the use of both techniques. The open technique was used in 71.5% of the patients
(n=1097). The minimally invasive laparoscopic technique became a more popular option in the
more recent articles and was performed in 438 cases (28.5%). None of the included trials made
use of robotic surgery.
The method of ISR subtype was only well documented for 755 patients. The majority of the
patients underwent partial ISR (77.6%). Subtotal and total ISR was performed in 8.7% and
13.6% of the cases respectively.
37
12.3 Indications for ISR
Clinical features which have led to the inclusion or exclusion of patients for the ISR procedure
were stated in 19 of the included studies.
Frequently mentioned indications for ISR were:

Tumors located less than 5 - 6 cm from the anal verge (55, 59-61, 67, 69)

T1-T3 tumors (4, 56, 59, 66, 69)

Good or moderately differentiated rectal cancers (4, 55, 59, 66)

Mobile tumors (59, 71)

Impossibility to obtain an adequate distal resection margin for conventional (U)LAR
with stapled anastomosis (54, 65, 67, 70)
All authors agreed that rectal cancer invading the levator ani muscle or the external anal
sphincter was a major contraindication for ISR. None of the studies mentioned involvement of
the internal sphincter as a contraindication. Most of them also stated that a good sphincter
function and good fecal continence were essential prior to surgery
(4, 52, 55, 56, 59, 62, 63, 65-69, 71)
.
Other frequently mentioned contraindications were T3-4 or bulky tumors, poorly differentiated
tumors, untreatable distant metastasis, significant comorbidity, inadequate distal margin,
massive obesity and the existence of an anal stricture.
The majority of the included trials mentioned the use of digital examination, pelvic MRI,
thoracic and abdominal CT, endorectal ultrasound, colonoscopy, biopsy or a combination of
these to evaluate the location of the tumor, its relationship to the anal sphincter complex, and
the presence of local and distal spread. In order to make an objective assessment of the
preoperative anal sphincter function, 6 articles made use of anal manometry
(4, 59, 61, 66, 68, 71)
.
Other less-used technical examinations were barium enema, determination of the serum
carcinoembryonic antigen (CEA) concentration and PET scan.
12.4 Surgical procedure
When neoadjuvant treatment was administered, ISR surgery was initiated 6-8 weeks after
completion in most of the studies. One trial reported a shorter interval of 3 weeks between
preoperative treatment and surgery (55).
All the articles made use of the ISR procedure as described by Schiessel et al. in 1994. As
mentioned above, the ISR procedure is done in two stages: the rectal dissection via a
transabdominal and the intersphincteric resection via a transperineal approach. The majority of
the surgeons of the included articles started with the abdominal part followed by the perineal
38
part as suggested by Schiessel. Two authors mentioned that they first started with the perineal
approach (69, 70).
The use of the Lloyd-Davis or lithotomy position allows surgeons to perform both stages
without the need to reposition the patient during surgery (4, 70).
The abdominal part of the operation can
be
carried
out
by
open
surgery
(laparotomy) or by laparoscopy. After
exploration of the entire abdomen, the
first step is ligation of the inferior
mesenteric artery (and vein) close to its
origin
at
the
aorta
followed
by
mobilization of the left colon. When the
left colon appears to be relatively short,
the splenic flexure of the colon is also
dissected.
mesorectal
Subsequently,
excision
the
total
(TME),
with
preservation of the hypogastic nerves
Figure 10: ISR is a 2-step procedure. The
and pelvic plexuses, is performed up to
abdominal part consists of a dissection of the
the pelvic floor as distal as possible in
rectum (with TME) down to the pelvic floor
order to make the perineal part of the
(upper
procedure easier. Six Asian studies
resection via the perineal route (lower arrows)
performed
a
lateral
lymph
node
arrows)
and
the
intersphincteric
(93)
dissection when lateral lymph node
metastases were present or suspected (52, 54, 56, 59, 67, 70). The intersphincteric plane can already be
entered through the abdominal approach when the anatomy of the pelvis is favorable; and if a
sufficient distal margin (± 1-2 cm) can be obtained, even the intersphincteric dissection can be
performed via the abdominal way (68).
In the majority of the cases this is not possible by which the perineal part of the ISR procedure
can be initiated. Most surgeons use the Lone Star retractor in order to achieve maximal access
to the anus and anal canal. After infiltration of the anal skin with an epinephrine solution to
minimize blood loss, the mucosa and internal anal sphincter were circumferentially incised up
to the intersphincteric space. Most authors decided to start the dissection at least 1 cm from the
lower edge of the tumor.
39
(a)
(b)
(c)
Figure 11: Perineal approach. (a) Circumferential incision of the anal mucosa up to the
intersphincteric plane after placing the Lone Star retractor and injection of the epinephrine
solution. (b) Dissection of the intersphincteric space in the direction of the pelvis in order
to connect with the abdominal dissection. (94)
Three studies reported the use of a distal resection margin of at least 2 cm (54, 66, 70). The internal
sphincter can be recognized as a 3 mm thick white band-like structure and the external sphincter
as a thick red structure with an avascular space between them
(66)
. The level of the distal
resection line with respect to the dentate line determines whether a partial, subtotal or total ISR
is performed (see section: ‘What is ISR’). Thereafter, the intersphincteric space is dissected
upwards to connect with the pelvic dissection from the abdominal approach.
To minimize the risk of tumor cell dissemination into the pelvis, the rectum and pelvic cavity
can be irrigated with a cytocidal fluid (4, 52, 56, 61, 66-68, 70) and the dissected distal rectum can be
closed by hand suturing (52, 56, 58, 60, 62, 65, 67, 68, 70) or with a clamp (66, 71) prior to removal of the
rectum. To exclude cancer positive cut
margins, histopathological examination
of the distal resection line with frozen
section analysis was performed during
surgery in three institutions (55, 65, 69).
When the rectum is detached from the
adjacent organs (urethra, prostate or
vagina), the tumor bearing rectum is
usually pulled through the anus and the
proximal dissection is performed at the
rectosigmoid transition. Laurent and
Figure 12: Anal pull-through after cytocidal
wash-out and/or closure of the rectum (94)
40
Chamlou et al. reported removing the rectum through the abdominal incision (60, 68).
After removal of the rectum, the intestinal continuity is restored with the construction of a handsewn coloanal anastomosis with single sutures. If the remaining colon is long enough and the
pelvis is not too narrow, a colonic pouch can be constructed. The majority (76%) of the coloanal
anastomoses, in the included studies, were straight end-to-end anastomoses. J-pouch and
transverse coloplasty anastomoses represented respectively 22.8% and 1.3% of the CAA (table
3).
Figure 13: Hand-sewn coloanal anastomosis with single sutures (94)
A protective ileo- or colostomy was created in order to give the anastomosis time to heal. A
total of 76.4% of the patients received a protective stoma (table 3). Indications for the
construction of a protective stoma differed among the included studies. Thirteen out of the 20
included studies created a defunctioning stoma routinely in all patients. Gong et al. reported not
to use a diverting ileostomy in any of the patients
(61)
. Other authors constructed only an
ileostomy in selected cases such as patients with preoperative CRT, poorly prepared bowels,
significant comorbidity, anastomosis under tension or major intraoperative adverse events
(54,
62)
. The majority of the institutions reversed the stoma 6 to 8 weeks after surgery.
12.5 Mortality, morbidity and postoperative complications
Fifteen out of twenty articles reported figures for mortality, morbidity, and postoperative
complications (see Table 4).
The mean mortality rate within 30 days after surgery was 0.4% (range: 0-3.1% and 95% CI: 00.8%). Overall morbidity varied widely from 7.5 to 64.5% among to the different institutions.
An average of 24.8% of the patients suffered from postoperative complications (95% CI: 16.133.5%).
41
Reference
Type of
surgery
Mortality
(%)
Morbidity
(%)
Anastomotic Anastomotic Haemorrhage
Fistula (%)
leakage (%) stricture (%) (%)
Urinary
Bowel
Wound
Pelvic sepsis
tract
obstruction complications
(%)
infection
(%)
(%)
(%)
Neorectal
mucosal
prolapse (%)
Shiomi et al. (56)
0
-
5,4
5,4
-
-
-
24,3
5,4
5,4
5,4
Konanz et al. (57)
-
48
-
-
-
-
-
15
9
-
-
Akagi et al. (59)
0
12
5,6
-
-
-
-
-
-
-
-
Open surgery
0
53,8
-
-
-
-
20
-
-
-
-
Laparoscopy
0
40,9
-
-
-
-
25,5
-
-
-
-
0
-
11,6
-
-
-
-
-
-
-
-
Open surgery
1,3
17,5
6,2
1,3
-
1,3
-
2,5
-
-
-
Laparoscopy
0
13,1
3,8
2,4
-
1,5
-
1,5
-
-
-
Lim et al. (63)
0
21,6
1,8
6,3
-
0,9
2,7
4,5
-
-
1,8
Yamada et al. (52)
0
14,9
4,7
8,4
0
0
-
3,7
3,7
0,9
3,7
Weiser et al. (65)
0
39
4,5
16
-
4,5
-
-
6,8
-
-
Han et al. (66)
0
7,5
2,5
0
-
0
0
0
5
-
-
0,8
33
15
-
-
-
-
-
-
-
-
0
18,8
8,8
-
2,2
1,1
5,5
2,2
1,1
-
-
Hohenberger et al. (69)
3,1
24,6
-
-
-
-
-
-
-
-
-
Schiessel et al. (4)
0,8
17,1
-
9,4
0,8
5,1
-
0,8
-
-
-
Köhler et al. (71)
0
64,5
48,3
9,7
3,2
19,3
0
3,2
6,4
-
-
Weighted mean
0,4
24,8
7,8
6,2
1,1
2,5
11
3,9
4,4
2,1
3,1
(0 - 16)
(0 - 3,2)
(0 - 19,3)
(0 - 25,5)
(0 - 24,3)
(1,1 - 9)
(0,9 - 5,4) (1,8 - 5,4)
[2,9 - 9,5]
[-0,3 - 2,5]
[2,5 - 6,3]
[-2,3 - 6,5] [1,1 - 5,1]
Laurent et al. (60)
Gong et al. (61)
Park et al. (62)
Akasu et al. (67)
Chamlou et al. (68)
Range
(0 -3,1)
95% CI
[0 - 0,8] [16,1 - 33,5] [0,6 - 15]
(7,5 - 64,5) (1,8 - 48,3)
[-1,5 - 6,5] [2,2 - 19,8] [-0,9 - 8,7]
Table 4: Mortality, morbidity and postoperative complications after ISR.
CI confidence interval
42
Commonly reported short-term complications after surgery were anastomotic leakage,
haemorrhage, fistula, pelvic sepsis, bowel obstruction, wound complications and urinary tract
infection. Anastomotic stricture and neorectal mucosal prolapse are rather late complications.
Anastomotic leakage and stricture are the most frequent complications after ISR with
respectively 7.8% (range: 1.8-48.3%; 95% CI 0.6-15%) and 6.2% (range: 0-16%; 95% CI 2.99.5%) of the cases. The management of anastomotic leakage may consist of a conservative
approach with antibiotic therapy and/or delayed conversion of the temporary ileostomy (4, 52, 61,
63, 66-68, 71)
; or reoperation with reconstruction of the anastomosis or application of a definitive
colostomy
(56, 63, 65, 67, 68)
depending on the severity of the leakage. Anastomotic stricture is
usually resolved with perianal dilatation or by construction of a permanent colostomy (52, 56, 65,
71)
. The figures, weighted averages and 95% confidence intervals of the other postoperative
complications are given in Table 4.
12.6 Oncological outcome
Early postoperative oncological outcome after ISR is defined by the length of the distal
resection margin, the infiltration of the circumferential margin and the number of R0 resections
(see Table 3). The rate of R0 resections after ISR, as provided by 9 studies, was high with an
average of 97.7% (range: 92-100%). According to 10 studies, the mean distal resection margin
was 14.5 mm and ranged from 1 to 45 mm. The circumferential resection margin was
considered to be positive for tumor infiltration when it was located less than 1mm from the
tumor. The CRM was positive in 6.1% of the patients (range: 0-15.5%).
Data about the long-term oncological outcome after ISR could be extracted from 17 of the 20
studies (see Table 5).
The median follow-up time ranged from 20 to 94 months. Local recurrence (LR) is defined as
any recurrence of the tumor into the pelvic cavity, perineum, anastomosis or regional lymph
nodes independent of the presence of distant metastasis outside the pelvis. LR occurred in 6.1%
of the included patients (range: 0-31%; 95% CI: 2.6-9.6%). Systemic recurrence was seen in 0
to 24% of the cases with an average occurrence of 13.6% (95% CI: 10.4-16.8%). The mean 5year overall and disease-free survival rates were mentioned by 12 trials and were respectively
85.9% (range: 76.4-97%; 95% CI: 82.5-89.3%) and 78.5% (range: 65.7-93.5%; 95% CI: 73.283.8%). Five of the included studies reported the 3-year overall and disease-free survival. The
mean 3-year overall survival rate was 89.2% (range: 81.6-95%; 95% CI: 84-94.4%) and the 3year disease-free survival rate was 80.3% (range: 73-93.1%; 95% CI: 74.9-85.7%) (56, 62-64, 67).
43
Reference
Type of
surgery
Median
follow-up
(months)
Local
Distant
recurrence metastasis
(%)
(%)
3-year
3-year
5- year
survival
survival
survival
(disease
(overall) (%) (overall) (%)
free) (%)
5-year
survival
(disease
free) (%)
Koyama et al.
(54)
69,0
7,8
19,5
-
76,4
-
93,5
Shiomi et al. (56)
33,6
0,0
5,4
-
-
93,1
-
Akagi et al. (59)
65,0
4,8
10,5
-
81,7
-
-
Open surgery
53
2
19
-
82
-
71
Laparoscopy
53
5
24
-
85
-
70
20
0
0
-
-
-
-
Open surgery
37
7,7
18,8
81,6
-
77
-
Laparoscopy
32,5
2,6
10,8
86,6
-
82,1
-
Lim et al. (63)
29,4
5,4
20,7
92,8
-
73
-
Kuo et al. (64)
55
7,7
15,3
83
83
82
76
Yamada et al.
(52)
41,0
2,5
8,4
-
91,7
-
85,2
Weiser et al. (65)
47
0
16
-
96
-
83
Han et al. (66)
43
5
2,5
-
97
-
86
42,0
6,7
13
95
91
83
77
56,2
6,6
8,8
-
82,0
-
75,0
70
22,7
-
-
-
-
-
Yoo et al. (70)
57,0
31,0
10,3
-
86,2
-
65,7
Schiessel et al.
(4)
94
5,3
-
-
87
-
-
Köhler et al. (71)
82
9,7
9,7
-
79
-
-
Weighted mean
52
6,1
13,6
89,2
85,9
80,3
78,5
(20 - 94)
(0 - 31)
(0 - 24)
(81,6 - 95)
(76,4 - 97)
Laurent et al.
(60)
Gong et al. (61)
Park et al. (62)
Akasu et al. (67)
Chamlou et al.
(68)
Hohenberger et
al. (69)
Range
95% CI
(73 - 93,1) (65,7 - 93,5)
[2,6 - 9,6] [10,4 - 16,8] [84,0 - 94,4] [82,5 - 89,3] [74,9 - 85,7] [73,2 - 83,8]
Table 5: Oncological outcomes after ISR.
CI confidence interval
44
12.7 Functional outcome
Fifteen of the 20 articles discussed the functional outcomes after ISR. Results are listed in Table
6. The Jorge and Wexner continence score was the most frequently used tool to assess the
postoperative bowel function. The Wexner score provides a good assessment of the continence
status of the patient based on 5 questions: incontinence for solid stool, liquid stool and gas, need
to wear a pad and alteration of lifestyle. Each question gets a score from 0 to 4 based on the
frequency of the symptoms (0 = never, 1 = rarely, 2 = sometimes, 3 = usually and 4 = always
present). When these scores are added together, a score from 0 to 20 is obtained wherein 0
means perfect continence and 20 means complete incontinence
(54)
. The Wexner score varied
from 0.4 to 12.9 in eight of the included articles. The mean Wexner score was 8.8 (95% CI:
6.5-11.1). The mean number of bowel movements per 24 hours was 2.9 according to 12 studies
(range: 0.2-10; 95% CI: 2.4-3.4). Perfect continence is seen in approximately half (53.3%) of
the patients undergoing ISR surgery (range: 29.6-86.3%; 95% CI: 37.3-69.3%). On the other
hand, 28% of the patients suffered from faecal soiling and 46.6% of the patients needed to wear
a pad. Faecal urgency was experienced by 42.3% of the patients (range:19-58.8%: 95% CI:
30.8-53.8%). Incontinence to flatus, stool fragmentation and the inability to discriminate flatus
from faeces was considered to be a problem in respectively 20.7%, 61.1% and 54.9% of the
cases. About a quarter (25.8%) of the patients complained of constipation and antidiarrheal
medication was necessary in 27.2% of the patients. Three studies analyzed the postoperative
sphincter function by using anal manometry
(4, 61, 71)
. Gong et al. compared the preoperative
resting pressure, maximal squeeze pressure, initial sensory volume and maximum tolerable
volume of the neorectum with those 3, 6, and 12 months after surgery. They found that each of
these factors were significantly decreased 3 months after surgery. During the first year they
observed a gradual improvement of all these parameters with resting pressure and maximal
squeeze pressure approaching the initial preoperative level after one year. The postoperative
initial sensory volume and maximum tolerable volume, however, were significantly lower
compared with the values prior to surgery (61). Köhler et al. found that the resting pressure was
significantly reduced and that the squeeze pressure slowly recovered to its preoperative value
7 years after ISR
(71)
. The results of the anal manometry after ISR by Schiessel et al. were
comparable with those of Köhler (4). The study of Akagi et al. was the only one who mentioned
the postoperative urogenital dysfunction rate. Of the 124 included patients, only 2 (1.6%) of
them suffered from urogenital dysfunction (59).
45
Reference
Type of
surgery
Koyama et al. (54)
Functional tool
Bowel
movements
Perfect
per day
Urgency (%) continence
(mean(+-SD
(%)
or range))
Stool
Faeces-flatus
Incontinence
Constipation
Faecal
fragmentation
discrimination
to flatus (%)
(%)
soiling (%)
(%)
(%)
Need to
wear a pad
(%)
Antidiarrheal Wexner-score
medication (%) (mean(+-SD))
Wexner
3,7 ± 2,2
57
-
-
-
-
43,2
-
84
11
8,1 (± 4,8)
Saito function
questionnaire;
Wexner
3,4 ± 1,9
39,5
-
-
57,9
47,4
42,1
-
65,8
47,4
7,3 (± 3,8)
Shiomi et al. (56)
Kirwan score
4 (0,5-10)
-
37,9
6,9
-
-
-
51,7
-
-
-
Konanz et al. (57)
Wexner
-
-
-
-
-
-
-
-
-
-
12,9
Dumont et al. (58)
Wexner
-
-
-
-
-
-
-
-
-
-
11
Open
Wexner
2 (0,2-8)
40,9
-
-
77,3
40,9
68,2
-
-
-
12
Laparoscopy
Wexner
2 (0,3-7)
58
-
-
81,1
24,7
72,8
-
-
-
11
Gong et al. (61)
Kirwan score,
Wexner
2,9 (± 1,1)
-
-
11,6
-
-
-
-
23,3
-
4 (± 3,6)
Lim et al. (63)
Wexner
-
-
-
-
-
-
-
-
-
-
7,5 (± 2,7)
Kuo et al. (64)
Wexner
4,7 (1->6)
19
-
-
38,1
-
-
-
19
28,6
2,8
Wexner, Kirwan
3,7 (2-7)
-
42,3
29,8
-
15,4
-
27,9
-
-
-
Kirwan score
2,6
31,4
42,8
28,5
42,8
31,4
85,7
28,5
-
40
-
Wexner
2,3 (±1,3)
19
41
-
41
-
25,3
-
46
26,5
-
5 (2-9)
58,8
-
17,6
-
-
-
58,9
5,8
-
-
2,2 (1-9)
-
86,3
-
-
-
-
13,7
-
-
-
3,5 (3-4)
-
29,6
11,1
-
0
-
26
26
-
-
2,9
42,3
53,3
20,7
61,1
25,8
54,9
28
46,6
27,2
8,8
Cong et al. (55)
Laurent et al. (60)
Yamada et al. (52)
Han et al. (66)
Chamlou et al. (68)
Yoo et al. (70)
Schiessel et al. (4)
Köhler et al. (71)
Cleveland Clinic
incontinence
score
Williams and
Johnston
classification
-
Weighted mean
Range
(0,2 - 10)
(19 - 58,8) (29,6 - 86,3) (6,9 - 29,8)
(38,1 - 81,1)
(0 - 47,4)
(25,3 - 85,7) (13,7 - 58,9) (5,8 - 84,0)
(11 - 47,4)
(0,4 - 12,9)
95% CI
[2,4 - 3,4] [30,8 - 53,8] [37,3 - 69,3] [13 - 28,4]
[45,9 - 76,3]
[12 - 39,6]
[36,6 - 73,2] [14,3 - 41,7] [25,8 - 67,4]
[15 - 39,4]
[6,5 - 11,1]
Table 6: Functional outcomes after ISR.
SD standard deviation; CI confidence interval
46
Manometric
factor
Preoperative
3 months
6 months
12 months
44,3 (5,7)
19,8 (2,7)
30,2 (4,5)
42,4 (5,6)
MSP
181,4 (19,6)
132,0 (15,4)
174,1 (19,5)
178,9 (21,2)
ISV
101,2 (11,8)
44,8 (6,0)
63,1 (7,3)
80,2 (10,7)
MTV
164,9 (21,1)
55,7 (7,9)
95,0 (14,8)
112,4 (16,2)
RP
Table 7: Manometric results before, and 3, 6, 12 months after ISR (n=43)
Mean value (SD). RP resting pressure (mmHg); MSP maximal squeeze pressure (mmHg); ISV
initial sensory volume (ml); MTV maximum tolerable volume (ml)(61)
12.8 Quality of life
Only 3 of the included studies contained data about the quality of life (QoL) after ISR (54, 57, 58).
To assess the quality of life, Konanz and Dumont et al. used the European Organization for
Research and Treatment in Cancer (EORTC) QLQ-C30 questionnaire and its colorectal cancer
module QLQ-CR38 (57, 58).
The EORTC QLQ-C30 and QLQ-CR38 questionnaires respectively consists out of 6 and 4
functional scores and 9 and 7 symptom/problem scores. Each score is expressed on a scale of 0
to 100. A score of 0 suggests the worst outcome and 100 suggests the best outcome on the
functional scores. For the symptom scores it is the other way around (0 = never present and 100
= always present).
The results about the QoL after ISR by Konanz and Dumont are given in Table 8 and Table 9.
The QLQ-C30 table was extended with the results of healthy German and colorectal cancer
population to have a better idea about the observed values (57). The QLQ-C30 functional scale
results between the 2 studies were comparable and were significantly lower than those for the
healthy population. The obtained functional scale results were similar to the results of the
colorectal cancer population. The outcomes of the symptom scale of the QLQ-C30 and QLQCR38 questionnaires differed strongly between both studies.
Koyama et al. evaluated the QoL by using the modified fecal continence QoL (mFIQL) score
in which 0 points represents the best possible score and 100 points represents the worst fecal
incontinence. In the study of Koyama et al. 73% of the 37 included patients had a mFIQL score
of less than 50 after ISR. The mean fecal continence score was 34.3 (SD: ± 31.1) (54).
47
EORTC QLQ-C30
Mean reference
Konanz et al. Dumont et al. scores healthy
(57)
(58)
population
Subscales
Mean reference scores
colorectal cancer
population - all stages
n = 33
n = 14
(%)
(%)
(%)
(%)
Global health and quality of life
58,1
66,7
70,8
60
Physical functioning
82,2
84,1
90,1
79,2
Role functioning
63,6
93,6
88
70,4
Cognitive functioning
80,3
71,8
91,2
85,2
Emotional functioning
70,7
78,7
78,7
68,9
Social functioning
59,6
65,4
91
76
Dyspnea
18,2
96,1
9,1
17,4
Pain
22,7
66,7
15,4
24
Fatigue
25,9
66,7
17,1
34,7
Insomnia
24,2
66,7
16,4
30,5
Appetite loss
7,1
92,3
5,4
19,1
Nausea and vomiting
4,6
100
2,8
7,3
Constipation
20,2
100
3,6
15,8
Diarrhea
45,5
49,8
2,8
16,6
Financial difficulties
22,2
91,7
6
13,6
Functional scales
Symptom scales
Table 8: Quality of life after ISR: EORTC QLQ-C30 (57, 58)
CR38
Konanz et al.
(57)
Subscales
Dumont et al.
(58)
n = 33
n = 14
(%)
(%)
Body image
72,7
53,4
Future perspectives
52,5
39,7
Sexual functioning
44,4
16,7
Sexual enjoyment
75,9
36,5
Male sexual problems
53,6
40,5
Female sexual problems
33,3
0
30
72,2
Chemotherapy side effects
16,5
86,1
Gastrointestinal symptoms
37,8
74,1
Defecation problems
44,7
57,1
Weight loss
11,1
100
Functional scales
Symptom scales
Micturition problems
Table 9: Quality of life after ISR: EORTC QLQ-CR38 (57, 58)
48
13 Discussion
A complete removal of the tumor has always been the main objective in rectal cancer surgery.
For a longtime postoperative functional outcomes remained of secondary importance to the
oncological outcome. However, with the introduction of preoperative CRT and improvement
of several surgical techniques in the last two decades, the focus on sphincter-saving surgery and
good quality of life with acceptable functional results gained importance in the treatment of
low rectal cancer. Where formerly APR was the procedure of choice for most of the tumors in
the lower one-third of the rectum, sphincter-preserving techniques, such as LAR and ISR, has
become more popular.
This essay systematically reviewed the current literature about the oncological and functional
outcomes after ISR with hand-sewn coloanal anastomosis. The surgical technique and
indications for ISR and were also discussed.
13.1 What are good indications for ISR?
Patients diagnosed with good or moderately differentiated (T1-T3), mobile rectal cancers within
5-6 cm from the anal verge, which are not eligible for (U)LAR with stapled anastomosis, and
perfect preoperative anal function seem to be good candidates for the ISR procedure. Gong et
al. demonstrated that, when the inclusion criteria for ISR are chosen carefully, local and distal
recurrence are low, even without pre- and postoperative chemoradiotherapy (61).
13.2 Preoperative treatment and surgical technique
Nowadays, neoadjuvant CRT is frequently used in the treatment of rectal cancer. Because of its
downsizing and downstaging effect, neoadjuvant therapy is thought to increase the chance of
performing sphincter-saving surgery. However, two recently published systematic reviews
could not demonstrate a significant benefit of neoadjuvant CRT on the rate of sphincterpreserving surgery. Therefore, they concluded that the increased number of sphincter-saving
surgery was rather a result of the development of new technologies and changes in surgical
techniques, such as the TME and the possibility of performing very low anastomosis (31, 72, 73).
The advantageous effect of neoadjuvant CRT on the oncological outcome after rectal cancer
surgery is well documented (see further). Several studies have reported worse functional
outcomes after preoperative CRT compared with surgery alone. Parc et al. for example, found
49
that the mean number of daily bowel movements, urgency and the use of antidiarrheal
medication were significantly higher in irradiated patients compared to the non-irradiated
patients. They also found that sexual function was significantly worse after preoperative
radiotherapy (74). Canda et al. found that the maximal anal squeeze pressure was significantly
lower and the Wexner score was significantly worse after neoadjuvant CRT in comparison with
the surgery-alone group
(75)
. It is important to inform patients, suitable for ISR, about the
additional risk for functional imperfections when neoadjuvant treatment is indicated.
Most of the ISR procedures were performed using open surgery. In the last decade, however,
there is a tendency towards minimally invasive surgery. This trend is also noticeable for ISR
surgery, as more and more surgeons opt for laparoscopic and even robotic surgery. Several
studies investigated the clinical outcomes of open versus laparoscopic ISR. Park et al. compared
the surgical and oncological outcome of 130 patients who underwent laparoscopic (LAP) versus
80 patients undergoing open ISR surgery (OpS). There was no significant difference between
both techniques in terms of complication rate (LAP 5.4% vs OpS 3.8%; P=0.428), local
recurrence rates (LAP 2.6% vs OpS 7.7%; P=0.184) and 3-year disease-free survival (LAP
82.1% vs OpS 77.0%; P=0.523). Nevertheless, laparoscopy was associated with a shorter
hospital stay and a shorter time to bowel movement compared with the group treated with open
surgery. The group who had laparoscopic surgery had less intraoperative blood loss
(62)
. The
duration of surgery of the laparoscopic ISR procedure seems to be significantly longer in
comparison with the open approach (76, 77). The study from Park also found that rectal tumours
were located significantly more distally in the laparoscopic group than those from the open
approach. The better visibility obtained through laparoscopy in the deep pelvic floor was given
as an explanation for this result
(62)
. The study from Laurent et al. also could not show a
significant difference in postoperative mortality (LAP = OS = 0%) and morbidity ( LAP 23%
vs OpS 28%; P=0.410), 5-year LR (LAP 5% vs OpS 2%; P=0.349) and 5-year DFS (LAP 70%
vs OpS 71%; P=0.862). Functional outcomes and Wexner scores ( LAP 11 vs OpS 12;
P=0.675) were also not significantly different (60). Currently there are still only few studies that
describe short- and long-term outcomes after robotic ISR surgery. Kuo et al. made a comparison
between robot-assisted (ROB) and the laparoscopic ISR procedure. The mean operating time
was significantly longer in the robotic group (ROB 485.8 min, LAP 374.3 min; P<0.001) and
significantly more patients received a diverting stoma in the laparoscopic group (ROB 19.4%,
LAP 46.4%; P = 0.021). There was no difference in estimated blood loss, length of
postoperative hospital stay, time to first bowel movement, R0 resections, mean DRM, CRM
involvement and mean number of lymph nodes between the robotic and laparoscopic patients
50
(78)
. Baek et al. found that the short-term oncological results after laparoscopic and robotic ISR
were comparable as they could not show any difference in local recurrence, 3-year overall
survival and 3-year disease-free survival between the two procedures (79). This data shows that
open, laparoscopic and robotic surgery are both feasible and safe surgical options for ISR.
Oncological and functional outcomes after laparoscopic ISR are comparable with those of the
open approach. The outcomes for robotic ISR are promising, but further research is needed.
Since the first description of the ISR procedure by Schiessel et al., several institutions made
modifications to the technique. Some surgeons complete the coloanal anastomosis with a
mechanical stapling device instead of with a hand-sewn suture. Cong et al. investigated the
safety and feasibility of stapled versus hand-sewn coloanal anastomosis in patients who
underwent laparoscopic ISR and found that anastomotic leakage and stricture formation were
significantly lower in the stapled anastomosis group. Other anastomotic complications, such as
fistula formation, bleeding and neorectal prolapse, functional outcomes and Wexner scores
were equivalent in both groups
(55)
. However, Neutzling et al. could not demonstrate any
superiority of the stapled over the hand-sewn coloanal anastomosis technique in their systematic
review of 9 randomized controlled trials with 622 patients with stapled and 611 with hand-sewn
CAA
(80)
. In this thesis, studies who mentioned the use of partial excision of the external
sphincter (PESR) or puborectal muscle were excluded for further analysis. However, several
authors combine the ISR with a PESR when it is impossible to obtain sufficient safety margins
for tumors that are suspected of invading the intersphincteric space or external sphincter. They
do this in order to avoid a permanent stoma associated with the otherwise indicated APR
procedure. Akagi et al. evaluated the oncological and functional outcome of 25 patients who
underwent ISR + PESR. There was no operative mortality and postoperative morbidity was
seen in 40% of the patients. R0 resection was achieved in 92% of the patients and the LR rate
was 8%. Functional outcome was assessed using the Wexner and Kirwan scores. Eighty percent
of patients had Kirwan grade I or II (I = no incontinence; II = incontinence to flatus) and the
Wexner score after 24 months was 5.2 ± 4.6
(81)
. Saito et al. showed that the 7-year overall,
disease-free and local relapse-free survival after ISR + PESR were significantly worse
compared with the ISR-alone group (respectively: OS 47% vs 77.4%; DFS 42.9% vs 67.3%
and LRFS 62.5% vs 81.4%). The higher positive CRM rate in the ISR + PESR group was given
as explanation for these inferior results
(82)
. Further research is needed to better evaluate the
outcomes after ISR + PESR compared with ISR-alone and APR.
51
13.3 Mortality, morbidity and anastomotic leakage after ISR
Mortality within one month after ISR was very low in all of the included studies (average: 0.4%,
range: 0-3.1%). Results about the morbidity after ISR varied widely between different
institutions with a range from 7.5% to 64.5% and an average of 24.8%.
With an average incidence of 7.8% (95% CI: 0.6-15%), anastomotic leakage is the most
common complication reported after ISR. Similar rates of leakage (range: 3-15%) were found
after anterior resection with stapled anastomosis
(83)
. It is of great importance to keep the
anastomotic leakage rate as low as possible since it is associated with postoperative anastomotic
stricture, cancer recurrence, poor postoperative bowel function and increased operative
mortality (83). Rullier and Akasu et al. made a multivariate analysis to determine the risk factors
for anastomotic leakage. They found that male sex, the level of anastomosis, obesity,
intraoperative blood transfusion, pulmonary disease and a colonic J-pouch were independently
associated with anastomotic leakage (84, 85). Neoadjuvant CRT and smoking are also considered
to be risk factors for leakage. Complete bowel preparation, elective surgery by surgeons
specialized in colorectal cancer surgery, pelvic drainage and a defunctioning stoma have been
found to be beneficial for reducing anastomotic leakage
(84)
. In general, we can conclude that
ISR is associated with a low operative mortality and an acceptable complication and
anastomotic leakage rate.
13.4 Is the ISR procedure safe from the oncological point of view?
With a median local recurrence rate of 6.1% (95% CI: 2.6-9.6%) and a mean 5-year overall
and disease-free survival of respectively 85.9% (95% CI: 82.5-89.3%) and 78.5% (95% CI:
73.2-83.8%), oncological outcome seems to be good and comparable with those for LAR and
APR. Koyama et al. compared the local recurrence rates and the 5-year overall and disease-free
survival of ISR with the LAR and APR technique. They found that the local recurrence did not
significantly differ between the three procedures (ISR 7.8%, LAR 11.7% and APR 12.1%;
P=0.668). Kuo, Weiser, Akagi and Saito et al. could neither demonstrate a significant
difference in local recurrence rate between ISR and APR (59, 64, 65, 86).
To identify the risk factors for local and distant recurrence, Akasu and colleagues made a uniand multivariate analysis of 120 patients who underwent ISR surgery. The univariate analysis
showed that the pT, pathological stage, focal dedifferentiation, microscopic resection margins
and preoperative serum CA19-9 level were significantly associated with local recurrence.
Multivariate analysis of these factors demonstrated that positive microscopic resection margin,
52
positive focal dedifferentiation and preoperative CA 19-9 level of >37U/ml were independently
associated with a high local recurrence rate
(67)
. The pathological stage and the distal and
circumferential resection margins can be positively influenced by the tumor shrinking effect of
neoadjuvant CRT. A recent meta-analysis, investigating the effectiveness and safety of
neoadjuvant radiotherapy in the management of rectal cancer, showed that local recurrence was
significantly lower after neoadjuvant radiotherapy compared with the surgery alone (resection
+ TME) group (hazard ratio (HR) 0.59; 95% CI 0.48–0.72). However, overall survival was just
not significantly better after neoadjuvant radiotherapy (HR 0.93; 95% CI 0.85–1.00). They also
demonstrated an advantage of preoperative CRT on local tumor control compared to RT alone.
There were no differences between neoadjuvant CRT and RT-alone in terms of overall and
disease-free survival (87). This benefit of (neo)adjuvant therapy on locoregional recurrence was
also reported by Hohenberger et al.. They found that the LR rate was significantly higher when
no neo-/adjuvant CRT was administered compared with those who did receive CRT (LR of
respectively 46.5% versus 14.2%; P=0.0200) (69).
The study from Koyoma et al. showed that the 5-year overall survival was significantly worse
after APR compared with the ISR procedure; there was no difference with the LAR procedure
(ISR 76.4%, LAR 80.7%, APR 51.2% P=0.0008) (54). This lower 5-year overall survival rate
after APR was also observed in other studies
(64, 65, 86)
. Koyama, Saito and Hohenberger et al.
claimed that the 5-year disease-free survival after ISR was similar with that of the APR
procedure (54, 69, 86). Kuo and Weiser, however, found also a significant difference in the diseasefree survival. They found that APR was associated with significantly more positive
circumferential margins (Kuo: ISR 13.3% versus APR 31.6% P=0.026 and Weiser: ISR 5%
versus APR 13%). The higher rate of bulky, more poorly differentiated tumors who are often
less responsive to chemoradiotherapy in the APR group, and not surgery dependent factors, are
most frequently given as explanations for these lower survival rates (64, 65).
13.5 How are the functional outcomes and quality of life after ISR?
Most studies assessed the functional outcome using institution specific questionnaires and
continence scores such as the Wexner and Kirwan classification score. In contrast to the
oncological outcomes, the functional results are not reported consistently. It is notable that
functional symptoms such as urgency, incontinence to flatus, stool fragmentation, constipation,
faecal soiling, the need to wear a pad and the use of antidiarrheal medication varied widely
among the different studies (see Table 6). The combination of two or more of these symptoms
53
is better known as the ‘anterior resection syndrome’ and it is typically seen after sphincterpreserving rectal surgery. Since a part or the whole internal sphincter is resected during the
procedure and knowing that the internal sphincter is responsible for 55% of the anal resting
pressure it is not surprising that the functional outcome is significantly reduced after ISR. The
mean number of bowel movements per day after ISR was 2.9 (range 0.2 -10; 95% CI 2.4-3.4)
and the mean Wexner score was 8.8 (range 0.4-12.9; 95% CI 6.5-11.1).
Only a few studies compared the functional results between LAR and ISR. Koyama et al. found
similar results in terms of bowel movements per day (ISR 3.7 ± 2.2; LAR 3.2 ± 2.2; P=0.399),
urgency (ISR 57%; LAR 47%; P=0.644), ability to distinguish flatus from faeces (ISR 58%;
LAR 64%; P=0.391) and antidiarrheal medication usage (ISR 11%; LAR 8%; P=0.516).
However, the need to wear a pad (84% vs 33%; P<0.001) and the mean Wexner incontinence
score (8.1 vs 4.9; P=0.004) were significantly higher in the ISR group compared with those in
the LAR group
(54)
. Yoo et al. also found very comparable functional outcomes between ISR
and LAR; only nocturnal soiling was significantly more present in the ISR group (76.5 % vs
26.7%; P=0.005) (70). Patients treated with the ISR procedure had significantly worse Wexner
score (ISR 10.8 vs LAR 6.9; P<0.001) and needed more antidiarrheal drugs (60% vs 35%;
P=0.04) in contrast to the patients who underwent LAR according to the trial of Bretagnol et
al.
(88)
. The Wexner score in the study from Konanz et al. was also worse after ISR in
comparison with LAR (ISR 12.9; LAR 9.5; P=0.0038) (57).
Inferior functional outcomes and fecal incontinence seem to improve over time (89-91).
Several studies tried to determine the clinical factors associated with inferior anal function after
ISR. Ito et al. found that total ISR and preoperative CRT were significantly associated with
worse Wexner scores
(91)
. The negative impact of preoperative radiotherapy on the functional
outcome was also demonstrated by Chamlou and colleagues
(68)
. According to the study of
Denost et al., only a tumor more distant than 1 cm from the anal ring and an anastomosis higher
than 2 cm from the anal verge were independent predictors of good continence after ISR
(90)
.
Yamada et al. found that also the patient’s age was significantly associated with postoperative
incontinence (52).
The subtype of ISR (partial-, subtotal- or total-ISR) seems to have little effect on the functional
outcome. Barisic et al. found more nocturnal leakage and more difficulty discriminating faeces
from flatus in patients treated with subtotal- and total-ISR compared with the partial-ISR group.
Total ISR was also associated with a higher use of pads. The Wexner score was also worse as
more of the internal sphincter was resected (partial-ISR 2.6; subtotal-ISR 4.26 and total-ISR
6.0) (89). A study from Yamada et al. showed a higher frequency of bowel movements in patients
54
who underwent total-ISR
(52)
. Since the subtype of ISR still has its repercussions on the
postoperative functional results it is important to make the decision prior to surgery so the
patient is well-informed about possible consequences.
As stated before, the colonic J-pouch and the transverse coloplasty are associated with better
functional results compared to the straight end-to-end anastomosis in patients who underwent
LAR
(44)
. However, Han et al. could not show any difference in functional outcome after 12
months between patients with (7 patients) and those without a J-pouch (28 patients) (66).
Some institutions evaluate the anal function using anal manometry. Köhler and Schiessel et al.
showed that the resting pressure (RP) was significantly reduced and maximal squeeze pressure
(MSP) slowly recovered to its preoperative value after ISR (4, 71). However, in the study of Gong
et al. the RP twelve months after ISR equaled the preoperative level (61). Barisic et al. measured
the mean RP, MSP, mean sensory volume (MSV) and mean tolerable volume (MTV) 12 months
after partial-, subtotal-, and total-ISR and found that the mean RP is significantly worse as more
of the internal sphincter is resected (partial-ISR 16.59 mmHg, subtotal-ISR 11.7 mmHg, and
total-ISR 7.0 mmHg; P=.004). MSP, MSV and MTV were not significantly different between
three ISR-subtypes after 12 months (89).
Since urinary complications and especially sexual complications occur relatively frequently
after rectal surgery it is very remarkable that only one of the included studies mentioned
urogenital outcome after ISR. Further research is necessary to explore the urogenital outcomes
after ISR.
Studies reporting quality of life (QoL) after ISR are also scarce. In general, it is thought that
patients who underwent APR have a worse QoL than those who underwent ISR or LAR because
of the permanent stoma. Konanz et al. compared the QoL of patients after LAR (n=41), ISR
(n=33) and APR (n=50) using the EORTC QLQ-C30 and -CR38 questionnaires and found no
difference in global QoL after the sphincter-saving procedures compared to APR. Physical
functioning was better in patients who underwent ISR compared to the APR group. The ISR
group had significantly more gastrointestinal symptoms and more defecation problems
compared to APR. Sexual functioning and enjoyment was found to be better after ISR compared
to respectively APR and LAR. Sexual function was remarkably worse in male patients who
underwent APR. A higher age of patients undergoing APR and a more extensive dissection of
the lower pelvis with a higher risk of damaging the pudendal nerve were given as possible
causes for this inferior outcome. Female sexual function was not significantly different between
the three surgical procedures
(57)
. Barisic et al. investigated whether the ISR-subtype affected
the quality of life using the EORTC QLQ-C30 questionnaire and the fecal incontinence quality
55
of life scale (FIQL). There was no significant difference in QoL between partial-, subtotal- and
total-ISR according to the QLQ-C30 questionnaire. However, the coping/behavior and
depression/self-perception scale of the FIQL-scale were significantly worse after total-ISR
compared with partial-ISR (89). Bretagnol et al. compared QoL between ISR and LAR and found
that patients treated with ISR had suffered significantly more from embarrassment than after
LAR. ISR patients more often leaked stools unknowingly and thus were more worried about
the smell (88).
It is important to inform patients extensively about the similarities and differences in functional
outcome and QoL between ISR, LAR and APR so they can decide whether a life with rather
unpredictable functional outcome or permanent colostomy is preferable.
13.6 Strengths and weaknesses of this thesis
Recently, three other systematic reviews about the outcomes after ISR were published. The
results for oncological and functional outcome of these reviews were highly comparable with
the results found in this paper (50, 83, 92). The main difference, as well as the advantage, of this
work with respect to these reviews is in its method of the study selection. This paper used
relatively strict exclusion criteria based on the surgical technique and modifications of the ISR
procedure. In order to reduce the heterogeneity of the studies, only articles who investigated
the outcomes of the original ISR technique as described by Schiessel et al. were included.
Factors such as PESR and stapled coloanal anastomosis led to exclusion in the present paper
but were not seen as confounding factors in the other systematic reviews.
Despite the rather strict exclusion criteria there is still a lot of heterogeneity among the included
articles in terms of preoperative treatment, ISR-subtype, type of coloanal anastomosis, presence
of diverting ileostomy,… . This fact makes it difficult to properly evaluate the effect of these
various modifications on the oncological and especially the functional outcomes and quality of
life after ISR. Studies with a more strict selection and segregation of study population are
needed to better evaluate the impact of these specific modifications on the postoperative
outcomes.
In contrast to the oncological outcomes, the functional outcomes and QoL were not reported
consistently. To have a better view on functional outcomes and QoL after ISR there is need for
a better reporting of these results. The use of equal and standardized functional questionnaires
among the different institutions could be a big step forward.
As mentioned before, there is a significant lack of results on urogenital function after ISR. It
would be an interesting outcome measure to study in future research.
56
14 Conclusion
Formerly, rectal tumors located at the distal one-third of the rectum were generally treated with
the abdominoperineal resection procedure. With the introduction of the intersphincteric
resection technique by Schiessel in the early 90s, another option for very low rectal cancers
became available.
This thesis reviewed the current evidence regarding the short- and long-term oncological and
functional outcomes in patients who have been treated with ISR with hand-sewn coloanal
anastomosis, as described by Schiessel, in the treatment of distal rectal cancer.
ISR with hand-sewn coloanal anastomosis can be a good alternative for the abdominoperineal
resection technique when sphincter-preservation is desirable in patients with pathologically
favorable tumours located within 5-6 cm from the anal verge and perfect preoperative anal
function.
Mortality following ISR is very low and morbidity is acceptable but there is a large variation
between studies. The rate of anastomotic leakage is comparable with that after LAR.
When the distal and circumferential resection margins can be kept tumor-free, oncological
outcomes such as the local recurrence rate, 5-year overall and disease-free survival after ISR
are good and comparable to those after LAR and APR.
Since a part or the entire internal sphincter is resected during ISR and in light of the important
role the internal sphincter plays maintaining anal continence, functional outcomes after ISR are
suboptimal but acceptable. However, continence seems to be worse after ISR when compared
to that after LAR.
Global quality of life following ISR is also comparable to that after LAR and APR.
Patients should be well informed about the potential advantages and disadvantage of the ISR,
LAR and APR procedures so they can decide whether a life with rather unpredictable functional
outcome or permanent colostomy is preferable to them.
Further research is needed to fully clarify the effects of different modifications (preoperative
CRT, ISR-subtype, type of coloanal anastomosis, PESR, stapled anastomosis,…) to the ISR
procedure on oncological and functional outcome and quality of life. Research of urogenital
function after ISR is also needed.
57
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