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Recent Advances
in the Treatment
of Colorectal Cancer
Hideyuki Ishida
Keiji Koda
Editors
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123
Recent Advances in the Treatment
of Colorectal Cancer
Hideyuki Ishida • Keiji Koda
Editors
Recent Advances in the

Treatment of Colorectal
Cancer
Editors
Hideyuki Ishida Keiji Koda
Department of Digestive Tract and Department of Surgery
General Surgery Teikyo University Chiba Medical Center
Saitama Medical Center Ichihara
Saitama Medical University Chiba
Kawagoe Japan
Saitama
Japan
ISBN 978-981-13-3049-0 ISBN 978-981-13-3050-6 (eBook)

https://doi.org/10.1007/978-981-13-3050-6
Library of Congress Control Number: 2018965168
© Springer Nature Singapore Pte Ltd. 2019

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Preface
The number of patients with colorectal cancer has been increasing worldwide, and
there is a high degree of concern among clinicians and investigators around the
globe. The level of colorectal cancer care in Japan is world-class.
Meticulous data has been compiled regarding the indications for endoscopic
therapy, and techniques and findings that have a global impact have been reported
from Japan. Recently, the standard lymph node dissection widely adopted in Japan
has been attracting the attention of colorectal surgeons everywhere. The treatment
strategies for rectal cancer in Japan and other countries differ greatly: in Japan, there
is a history of attaching importance to lateral lymph node dissection for lower rectal
cancer, and lateral lymph node dissection is considered one of the options for effec-
tive local treatment. The views in Western countries regarding perioperative chemo-
radiation therapy for lower rectal cancer also differ from those in Japan. Moreover,
the Japanese technique of sphincter preservation in lower rectal cancer has become
a world leader. Excellent oncological outcomes of laparoscopic surgery and robotic
surgery in the treatment of colorectal cancer have also been reported from Japan. In
the context of chemotherapy for colorectal cancer, Japan’s excellent results for
administering oral agents in combination with injection-based chemotherapy have
been widely used in Western countries. There is also a long history of research in the
field of hereditary colorectal cancer in Japan, and in recent years the findings
obtained using next-generation sequencing have also been reported to the world.
Japanese experts in diagnosing and treating of colorectal cancer have reviewed
this book, Recent Advances in the Treatment of Colorectal Cancer, and they have
added their own experience in 11 relevant areas and real-world clinical situations, as
well as added a discussion based on the foreign literature. We sincerely hope that
readers will peruse this book carefully, and that they will find it useful in the diag-
nosis and treatment of colorectal cancer in their everyday practice.
Saitama, Japan Hideyuki Ishida

Chiba, Japan Keiji Koda
v
Contents
Part I Endoscopic Treatment

1 Endoscopic Resection of Early Colorectal Cancer�� 3
Masayoshi Yamada, Yutaka Saito, Stefano Sansone, Hiroyuki
Takamaru, and Taku Sakamoto
2 Colonic Stent: Bridge to Surgery�� 17
Yoshihisa Saida
Part II Surgical Treatment

3 D3 Lymph Node Dissection for Colon and Rectal Cancers�� 27
Tatsuro Yamaguchi
4 Laparoscopic Surgery for Colorectal Cancer�� 39
Tetsuro Tominaga and Tsuyoshi Konishi
5 Robotic-Assisted Laparoscopic Surgery for Rectal Cancer�� 49
Tomohiro Yamaguchi and Yusuke Kinugasa
6 Intersphincteric Resection for Rectal Adenocarcinoma Near the Anus 59
Yoshito Akagi and Fumihiko Fujita
7 Chemoradiation for Rectal Cancer�� 71
Keiji Koda
Part III Chemotherapy
8 Adjuvant Chemotherapy�� 81
Toshiaki Ishikawa and Hiroyuki Uetake
vii
viii Contents
9 Chemotherapy for Metastatic Colorectal Cancer�� 101

Takeshi Yamada, Michihiro Koizumi, Seiichi Shinji, Akihisa
Matsuda, Yasuyuki Yokoyama, Goro Takahashi, Takuma Iwai,
Keisuke Hara, Masahiro Hotta, Kohki Takeda, Kohji Ueda, and
Hiroshi Yoshida
Part IV Hereditary Colorectal Cancer

10 Next-Generation Sequencing for Genetic Diagnosis of Hereditary
Colorectal Cancer and Polyposis Syndrome�� 115
Hidetaka Eguchi and Yasushi Okazaki
11 Clinical Management of Hereditary Colorectal Cancer�� 127
Kensuke Kumamoto and Hideyuki Ishida
Part I
Endoscopic Treatment
Chapter 1
Endoscopic Resection of Early
Colorectal Cancer
Masayoshi Yamada, Yutaka Saito, Stefano Sansone, Hiroyuki Takamaru,

and Taku Sakamoto
Abstract Endoscopic diagnosis and treatments have made considerable progress

in recent years. Endoscopic diagnosis aims to predict oncological characteristics of
a lesion based on endoscopic features and also differentiate between malignant and
benign tumors. Detailed inspection of lesions is required in order to pursue an accu-
rate endoscopic diagnosis. This can be achieved with image enhanced endoscopy.
Multiple strategies are available to achieve endoscopic resection of colorectal
lesions, including polypectomy, endoscopic mucosal resection, endoscopic mucosal
dissection, and full-thickness resection.
Each technique requires different skill-sets and has different frequency of com-
plications. Selection of the appropriate endoscopic treatment is based on oncologi-
cal indication and technical aspects of each strategy. All endoscopic procedures
require expertise which is achieved through adequate training and the availability of
appropriate equipment.
Keywords Endoscopic resection · Endoscopic submucosal dissection

Colorectal cancer
1.1 Introduction
With the development of new devices and technologies, both endoscopic diagnosis
and treatments have made considerable progress. Endoscopic resection is a proce-
dure to remove a lesion under direct vision using an endoscope and endoscopic
devices. Since it is a less invasive procedure than conventional surgery, endoscopic
resection has attracted attention as an alternative treatment with shorter in-hospital
M. Yamada · Y. Saito (*) · H. Takamaru · T. Sakamoto

Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
e-mail: masyamad@ncc.go.jp; ytsaito@ncc.go.jp; htakamar@ncc.go.jp; tasakamo@ncc.go.jp
S. Sansone
NIHR Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University
Hospitals NHS Trust and University of Nottingham, Nottingham, UK
e-mail: Stefano.Sansone@nuh.nhs.uk
© Springer Nature Singapore Pte Ltd. 2019 3

H. Ishida, K. Koda (eds.), Recent Advances in the Treatment of Colorectal
Cancer, https://doi.org/10.1007/978-981-13-3050-6_1
4 M. Yamada et al.
stays. In the late 1960s, Tsuneoka and Uchida firstly described a successful endo-
scopic resection of 43 gastric polyps using mechanical cutting with a looped wire.
Although the low retrieval rate (57%) of the resected specimen was recognized as
an issue, their report led to a breakthrough of endoscopic resection [1]. Subsequently,
the application of electrocautery has been introduced. Once the polyp stalk is cap-
tured with a looped wire (currently known as snare) coagulation can be delivered by
high-frequency electrical current from an electrosurgical generator. In addition to
pedunculated polyps, endoscopic resection has also been adopted for sessile, flat,
and depressed lesions by using an injection of saline into the submucosa under the
lesion. This procedure can lift the lesions up making them more amenable to snare
resection [2]. Currently, three types of endoscopic resection are mainly performed:
(1) polypectomy, (2) endoscopic mucosal resection (EMR), (3) endoscopic submu-
cosal dissection (ESD).
1.2 Treatment Selection
Endoscopic diagnosis plays a crucial role in determining treatment strategy

(Table 1.1). Treatment pathways are selected according to both oncological and
technical aspects. Endoscopic diagnosis aims to predict oncological characteristics
of a lesion based on endoscopic features, such as size, and also differentiate between
malignant and benign tumors. Endoscopic resection technique is dependent on the
endoscopist’s technical skill, with each technique requiring different skill-sets and
having different frequency of complications. Therefore, the decision-making pro-
cess should take into consideration these technical aspects.
Endoscopic treatment is only indicated for tumors with no lymph node metasta-
sis. Therefore, endoscopic resection is considered only for adenomas or invasive
tumors confined to the superficial layer of the submucosa (less than 1 mm in depth)
[3]. Cancers infiltrating the deeper submucosal layers carry a risk of lymph node
metastasis; therefore, a surgical intervention is required. Endoscopic treatment can
also be offered for rectal neuroendocrine tumors (carcinoid tumors).
Table 1.1 Strategy of endoscopic treatment in colorectum

Strategy
Endoscopic diagnosis Lesion size Polypectomy EMR ESD
Adenoma or low grade dysplasia <10 mm ◎a ○ ×
10~20 mm × ◎ ∆b
>20 mm × ○ ○
High grade dysplasia or adenocarcinoma ~10 mm × ◎ ×
(superficial submucosal invasion) 10~20 mm × ◎ ○b
>20 mm × ○c ◎
a
Including cold polypectomy
b
Recurrent lesion
c
If en-bloc resection is possible
1 Endoscopic Resection of Early Colorectal Cancer 5
Detailed inspection of colorectal lesions is required in order to pursue an accu-

rate endoscopic diagnosis. This can be achieved with image enhanced endoscopy
(IEE), which includes optical-digital methods such as narrow band imaging (NBI),
blue laser imaging (BLI), optical enhancement (OE), and chromoendoscopy (for pit
pattern diagnosis). Standard observation (white light image) is less effective at pre-
dicting histological subset [4]. The pit pattern classification, also known as Kudo’s
classification, defined the morphology of crypt opening observed on colonic muco-
sal surface with each histological subset. This classification was developed by Kudo
et al. and became widely adopted after the introduction of the optical zoom function
in 1990 [5]. Fu and colleagues reported a prospective comparative study between
endoscopic diagnosis with non-magnifying and magnifying observation by their pit
pattern in comparison with histological diagnosis. They concluded that reliability of
Kudo classification for differential diagnosis between neoplastic and non-neoplastic
lesions was higher with magnification than with non-magnifying observation
(95.6% vs. 84.0%) [6]. Matsuda and colleagues reported a prospective large-scale
study including a total of 4215 lesions and demonstrated that the diagnostic sensi-
tivity to submucosal deep invasive carcinoma using modified pit pattern (invasive
pattern) was 85.6% [7]. They concluded that invasive pattern is an effective diag-
nostic method to direct the decision of treatment strategy. Recently, Sakamoto and
colleagues performed an online survey comparing diagnostic performance of non-
magnifying white light endoscopy, magnifying NBI and pit pattern diagnosis. Pit
pattern diagnosis revealed significantly higher accuracy [8]. Pit pattern can differen-
tiate between malignant and benign lesions and also predict the degree of tumor
invasion and has been widely adopted as the gold standard method [9].
NBI, BLI, and OE highlight surface pattern and vessel pattern of the lesion aid-
ing endoscopic differential diagnosis. It can be used simply by pushing a button on
the endoscope and negates the need for dye. Some classifications using these meth-
ods have been reported including NICE (NBI International Colorectal Endoscopic)
classification and JNET (Japan NBI Expert Team) classification [10, 11]. Several
studies showed a high diagnostic accuracy for discriminating neoplasia and non-
neoplasia, or dysplasia and invasive cancer. Sano et al. first reported a prospective
comparative study and demonstrated that the diagnostic accuracy in discriminating
neoplasia and non-neoplasia was 95.3% [12]. Ikematsu and colleagues demon-
strated that by using disorganized meshed capillary patterns and a vascular or loose
vascular patterns enables discrimination between dysplasia/superficial submucosal
invasive cancer and deep submucosal invasive cancer [13]. McGill and colleagues
reported a meta-analysis on 28 studies (total of 6280 polyps) aiming to evaluate
diagnostic accuracy of NBI for polyps of 5 mm or less [14]. NBI showed excellent
diagnostic accuracy, 0.92 (95% confidence interval 0.90~0.94). However, consider-
ing the experience of the clinicians performing the colonoscopy, it is difficult to
extend the interpretation of data to daily practice. Indeed, Kuiper and colleagues
reported a prospective trial conducted at the general hospital (non-academic center)
in Amsterdam (DISCOUNT trial) [15]. The endoscopists involved in the study had
performed more than 2000 colonoscopies but did not routinely use NBI. Sensitivity
and specificity to the differential diagnosis for polyps up to 10 mm (high confidence)
6 M. Yamada et al.
were 77% and 79%, respectively. Nineteen percent of patients were assigned incor-
rect surveillance intervals. Ladabaum and colleagues also described similar results
[16]. NBI diagnosis is influenced by the expertise of the endoscopist and training is
required in order to acquire and maintain high diagnostic accuracy.
1.3 Endoscopic Treatment Strategy
1. Polypectomy
Polypectomy is indicated for lesions up to 10 mm, in particular lesions with
stalks resembling mushrooms. A metal loop called a “snare” is passed through
the working channel of the scope (Fig. 1.1a–c). This snare is then hooked on the
stalk and gently tightened (Fig. 1.1d). Then electrocautery is activated to coagu-
late and cut the stalk by using high-frequency electric current (Fig. 1.1e, f).
a b c
Prophylactic loop
snare in prevention
of bleeding
d e f
Loop snare Stalk of the
lesion
Snare
Lesion Snare
Stalk
Image c, d Image d, e
Fig. 1.1 Polypectomy. (a) A 20 mm sized pedunculated lesion in the descending colon, (b) stalk
of the lesion, (c) prophylactic endoloop, (d) snaring on the stalk, (e) excision site, (f) resected
specimen
Cold polypectomy is the removal of small non-pedunculated polyps without

electrocautery [17]. This is usually indicated for lesions less than 10 mm in
diameter without findings suggestive of high grade dysplasia or cancer. The main
advantage of this technique is the safety profile and similar efficacy to polypec-
tomy with coagulation. The risk of delayed bleeding is 0.1% which is the same
as routine biopsy. Cold polypectomy should be avoided in lesions with features
suggesting cancer because of insufficient submucosal resection. These features
include disappearing lobular appearance, depression, prominent redness or if the
lesion is depressed (0-IIc type in Parris classification).
2 . EMR
Lesions greater than 10 mm have a higher cancer risk (1.6–10.2%) and therefore
should be resected using EMR technique [18]. Similar to polypectomy, it
includes the use of a snare. However in order to reduce the risk of perforation,
saline is injected into the submucosal layer under the lesion before snaring
(Fig. 1.2a, b). After achieving appropriate lifting, snaring and coagulation is per-
formed (Fig. 1.2c–e). Considering its safety, curative ability and possibility of
tumor invasion into submucosal layer, EMR is routinely indicated for lesions
less than 20 mm [19–21].
a b c
d e
Injection
needle Snare
Lesion
Tie
Submucosal the
fluid injection snare
Image b Image c Image d
Fig. 1.2 EMR. (a) A 13 mm sized superficial lesion in the transverse colon, (b) appropriate lifting
by submucosal injection, (c) snare at the 6 o’clock position, (d) snaring, (e) excision site
8 M. Yamada et al.
3. ESD
ESD is used for lesions that are difficult to resect en-bloc via EMR. Similarly to
EMR, submucosal injection is performed under the lesion, but the lesion is
resected using an electric knife instead of the snare. First, the mucosal incision is
performed around the lesion (Fig. 1.3a, b). Then, the submucosal layer of the
lesion is dissected under direct vision (Fig. 1.3c, d). Using ESD even large
lesions, which would previously have been referred for surgery, can be treated
endoscopically with favorable long-term outcomes [22, 23]. High en-bloc resec-
tion rates (>90%) have been reported in Japan and other Asian countries [24, 25].
Although there is still technical gap in ESD skills between countries, this high
en-bloc resection rate allows detailed pathological diagnosis.
4. Endoscopic full-thickness resection
In recent years, an endoscopic full-thickness resection (EFTR) technique has
been developed using an over-the-scope clip (OTSC) [26]. It has been proven as
a safe and effective method to resect colorectal lesions. The procedural time is
similar to EMR and the resected specimen can be histopathologically evaluated
a b c
d e f
Injection
needle
Lesion Electric knife
Submucosal
fluid injection
Image b, c Image b, c, d Image e
Fig. 1.3 ESD. (a) A large (60 mm in diameter) superficial lesion in the ascending colon,
(b) mucosal incision around the lesion, (c) submucosal dissection under the direct vision,
(d) last cut, (e) excision site, (f) resected specimen
in detail as a full-thickness en-bloc specimen is obtained. The main limitation is

the difficulty assessing the lateral margin at the time of resection due to the
obscurement of visual field by the distal attachment. Laparoscopic endoscopic
cooperative surgery (LECS) can also lead to a full-thickness local resection by
means of combined use of laparoscope and endoscope [27, 28]. In 2008, Hiki
et al. reported seven gastrointestinal stromal tumors treated with LECS [27].
Because of potential risk of tumor cells seeding into peritoneal cavity, LECS
is mainly indicated for gastric submucosal tumors. Recently, LECS technique
has been modified to non-exposed endoscopic wall inversion methods, which
may be a good treatment alternative for difficult ESD cases [28]. Considering the
good function preservation after standard partial colectomy, the LECS may have
limited value and should be mainly reserved for technically difficult ESD cases.
Predictors for difficult ESD include: unstable scope maneuver, severe submuco-
sal fibrosis, non-lifting sign, and lesions located in the sigmoid colon or splenic/
hepatic flexures [29–33]. When present, these factors may indicate a possible
role for the EFTR.
1.4 T
reatment Outcomes and Indication of EMR,
Piecemeal EMR and ESD
The indications for EMR and ESD are still debated. The purposes of endoscopic
treatments are: (1) complete resection of the lesion and (2) pathological evaluation
of the resected specimen. Therefore, if a complete resection (en-bloc R0 resection)
can be obtained with EMR, this technique is preferable. A meta-analysis of 15 stud-
ies showed only 63% (95% CI: 51.50–73.52) of en-bloc resections using the EMR
technique to resect large (>2 cm) colorectal polyps (mean size of the polyps was
22.48 ± 4.52 mm) [34]. Furthermore, risk factors for recurrence after EMR include
large size (>40 mm), use of argon plasma coagulation, and piecemeal resection (>5
pieces) [35–38]. Notably, a meta-analysis showed no statistical difference between
EMR and ESD in the en-bloc resection rate of <20 mm lesions [39]. This data indi-
cates no need to perform ESD in lesion <20 mm.
When should piecemeal EMR be performed? Piecemeal EMR makes histopatho-
logical assessment difficult, if not impossible, with regard to depth of invasion and
evaluation of both lateral and vertical margins [40]. Therefore, when cancer is sus-
pected, piecemeal resection should be avoided. This requires detailed preoperative
endoscopic diagnosis, and there is no doubt that the pit pattern diagnosis using the
magnifying colonoscope is essential [19]. Considering the high submucosal inva-
sion rate in flat and depressed lesions (including non-granular type laterally spread-
ing tumor (LST-NG)), en-bloc resection by ESD should be performed in cases
where such lesions are >20 mm [19]. On the other hand, granular type LST (LST-G)
are associated with a low risk of submucosal invasion (3%) if they are smaller than
30 mm, without large nodules (>10 mm), and do not have depressed areas (Table 1.2,
10 M. Yamada et al.
Table 1.2 LST-G with no risk of submucosal invasion

LST-G (n = 414) SM invasion rate 95% CI
No large nodulea 12% (12/98) 7.1–20
No large nodulea, 4% (4/89) 1.7–11
No depressed area
No large nodulea, 3% (1/29) 0.7–17
No depressed area,
<3 cm
Nodule sized >10 mm
a
Fig. 1.4 Representative images of LST-G with no risk of submucosal invasion
Fig. 1.4). Indeed, Shigita and collages studied the clinical significance and validity
of the sub-classification of LST-G and reported that in the granule size group of
<5 mm (homogenous type) there was no submucosal invasion (0/154) [41]. We
believe that LST-G <30 mm, without a large nodule (>10 mm) and without a
depressed area can be a favorable candidate of piecemeal EMR. However, further
data is needed to clarify the indication for piecemeal EMR.
1.5 Complications
Two main complications are described in all strategies: bleeding and perforation
(Fig. 1.5a–f) [42]. Bleeding can be immediate if occurring during the procedure, or
delayed if occurring after several hours. The frequency depends on the size and the
morphology of the lesion. Pedunculated lesions have a relatively high risk of imme-
diate and delayed bleeding, reported as 3.1–12% in previous studies [43, 44]. This
bleeding rate is high compared to the delayed bleeding rate of EMR and ESD in
non-pedunculated lesions, which are reported as approximately 0.4–2% [45–47].
Several meta-analyses reported that there were no significant differences between
EMR and ESD with respect to delayed bleeding [39, 48, 49]. In the case of massive
bleeding, emergency endoscopic hemostasis should be performed.
Perforation can occur with both EMR and ESD. The colonic wall is thin, requir-
ing careful handling at the time of resection. Despite the ability to adjust the cutting
a b c
d e f
Fig. 1.5 Representative images of perforation during EMR and ESD. (a) EMR for 20 mm sized
lesion, (b) EMR, (c) large perforation (target sign) with active bleeding. (d) ESD for lesions on the
surgical anastomosis. Severe fibrosis can be observed, (e) perforation, (f) endoclip for closing the
perforation
depth in ESD, the perforation risk is three to five times higher than EMR based on
current meta-analyses [39, 48–50]. On the other hand, it is difficult to adjust the cut-
ting depth during EMR; therefore, if perforation occurs, it is usually larger than
ESD-related perforation. In most ESD cases, perforation can be treated conserva-
tively with endoscopic clip sutures, but emergency surgery may be required [47, 51].
Post-polypectomy electrocoagulation syndrome is another complication and
refers to the development of abdominal pain, fever, leukocytosis, elevated C-reactive
protein, and peritoneal inflammation in the absence of frank perforation after polyp-
ectomy with electrocoagulation. It results from electrocoagulation injury to the
colonic mucosa and the underlying muscularis layer, which causes transmural burns
with concurrent inflammation of the peritoneum without evidence of colonic perfo-
ration on imaging studies. This can be managed conservatively with medical
therapy.
1.6 Supportive Devices in Endoscopic Treatment
In order to improve the en-bloc R0 resection rate of EMR, a mucosal incision around
the lesion can be performed before proceeding to snare resection (Precutting EMR,
Hybrid EMR and ESD) (Fig. 1.6a–c). A traction device, such as S-O clip, can be
adopted to provide traction during ESD [52] (Fig. 1.6d, e). Also, if the endoscope is
unstable, ESD can be performed using an overtube (Fig. 1.6f) [53].
12 M. Yamada et al.
a b c
d e f
Fig. 1.6 Supportive devices for endoscopic treatment. (a) Hybrid EMR and ESD for LST-NG
lesion with non-lifting sign, (b) mucosal incision around the lesion, (c) en-bloc R0 resection by
snare resection, (d) S-O clip, (e) S-O clip adopted to provide traction during ESD, (f) overtube-
guided ESD
1.7 Conclusion
Selection of the appropriate endoscopic treatment is based on oncological indica-

tion and technical aspects of each strategy. All endoscopic procedures require
expertise which is achieved through adequate training and the availability of appro-
priate equipment.
An appropriate training program entails training sessions at a high-volume cen-
ter and participation in learning opportunities including conferences, live demon-
strations, and hands-on sessions.
Acknowledgement Funding: This paper partially funded by The National Cancer Center
Research and Development Fund (25-A-12, 28-K-1 and 29-A-13) and the JSPS KAKENHI Grant
Number 18K07925.
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Chapter 2
Colonic Stent: Bridge to Surgery
Yoshihisa Saida
Abstract Colonic stent (SEMS: self-expandable metallic stent) treatment for

malignant colonic obstruction is one of the standard endoscopic treatments and has
been available in Japan since 2012. In this review, the present conditions and future
prospects of the procedure are described based on data from the literature. The cur-
rent indication is malignant colorectal stenosis. Stent use in palliative treatment,
avoidance of colostomy, release of obstruction, shorter duration of hospitalization,
and better quality of life have been widely reported. Moreover, stent use can be a
bridge to surgery (BTS), enabling shorter duration of hospitalization and reduced
postoperative complications, colostomy rates, and mortality rates compared to
emergency surgery. However, the evidence concerning patients’ long-term progno-
sis is still lacking. Although the reported complication rate is low, adequate prepara-
tion and informed consent are important because complications can still occur.
Keywords Colonic stent · Colorectal obstruction · Palliative treatment · Bridge to

surgery · Colorectal Obstruction Scoring System
2.1 Introduction
Bowel obstruction due to colorectal cancer was previously described by the medical
term “colorectal cancer ileus” in Japan; however, ileus strongly signifies paralysis,
not obstruction. Accordingly, the recently applied term for such conditions is
“obstructive colorectal cancer” or “malignant large bowel obstruction” (MLBO).
Y. Saida (*)
Department of Surgery, Toho University Ohashi Medical Center, Tokyo, Japan
e-mail: yoshisaida@nifty.com

18 Y. Saida
2.2 E
pidemiological and Clinicopathological Characteristics
of Obstructive Colorectal Cancer
The incidence of bowel obstruction due to stenosis associated with colorectal can-
cer reportedly ranges from 10 to 20% for all colorectal cancers [1–4], and it is not
an uncommon complication with the currently increased incidence of colorectal
cancer.
The prognosis reportedly does not differ between obstructive and non-obstructive
cancers in stage-specific comparisons limited to patients undergoing curative resec-
tion [5]. However, obstructive colorectal cancers reportedly generally have a poorer
prognosis than non-obstructive cancers because far-advanced cases are more com-
mon, even for the same stage [6, 7]. On the other hand, more favorable outcomes
can be anticipated than for other advanced malignancies. Accordingly, there is a
vital need that therapeutic strategies for obstructive colorectal cancers pay close
attention to maintaining a balance for quality of life (QOL), which encompasses
outcomes and invasiveness.
2.3 Evaluation of Colonic Obstruction/Stenosis
The evaluation of colonic obstruction/stenosis lacks any formally established

method. The Japan Colonic Stent Safe Procedure Research Group have developed
the ColoRectal Obstruction Scoring System (CROSS) with a colon obstruction
score as a simple, generally applicable technique for assessing colonic obstruction
and stenosis. This scoring system has been published through the Research Group’s
home page (http://colon-stent.com/; Table 2.1) [8]. With the CROSS system, scores
are derived based on the state of oral intake and abdominal symptoms. Colonic
stents are indicated for palliative therapeutic use in patients with a CROSS score
between 0 and 3. A score between 0 and 1 is considered to indicate that stenting as
a bridge to surgery (BTS) is appropriate. The CROSS system enables understanding
of the decision-making regarding the therapeutic strategy for obstructive colorectal
cancers and facilitates evaluation of their efficacy.
Table 2.1 The ColoRectal Obstruction Scoring System: CROSS

Level of oral intake Score
Requiring continuous decompressive procedure 0
No oral intake 1
Liquid or enteral nutrient 2
Soft solids, low-residue, and full diet with symptoms of stricture 3
Soft solids, low-residue, and full diet without symptoms of stricturea 4
a
Symptoms of stricture contain abdominal pain/cramps, abdominal distension, nausea, vomiting,
constipation, and diarrhea which are related to gastrointestinal transit
2 Colonic Stent: Bridge to Surgery 19
2.4 Bridge to Surgery (BTS)
When an obstructive colorectal cancer is surgically curable, consideration must be

given to resolution of the bowel obstruction along with enhancement of surgical
safety and achieving a complete cure. Surgery for an obstructed bowel is regarded
as contaminated, and the risks of surgical complications or mortality are by no
means low [9]. There is a high risk of dehiscence and other postoperative complica-
tions after one-stage anastomosis. Colostomy is thus required in many cases, and a
negative impact on the patient’s QOL is unavoidable.
The ideal approach involves resolution of the bowel obstruction with conserva-
tive treatment avoiding emergency surgery and making a decision on elective sur-
gery after waiting for improvement in the patient’s general condition. However, the
ileocecal valve, which prevents reflux, may restrict decompression of the large
intestine into the small intestine when nasogastric or long ileus tubes are used.
Colonic stents have been implemented as a BTS to solve this problem since the
1990s; pre-operative decompression occurs through the anus as the bridge to elec-
tive surgery [10]. Currently, this transanal approach to pre-operative decompression
involves the use of colonic stents [10] or transanal drainage tubes [11].
Colonic stents and transanal drainage have been compared in only one study,
which had a two-group design and was not a randomized, controlled trial [12].
However, a comparison based on the current thinking is shown in Table 2.2.
Transanal drainage tubes have a narrower bore than colonic stents, and they
accordingly involve a longer time to resolve the bowel obstruction and difficulty in
initiating oral intake. They require frequent washing when used over consecutive
days due to the accumulation of warm fluid, which is indicative of the difficulties
faced in the medical management, as well as the negative impact on patient’s
QOL. Colonic stents are superior from the standpoint of examining lesions on the
oral side and the standpoint of patients’ QOL because they allow oral intake to be
initiated and are easier to manage.
Our current therapeutic strategy for obstructive colorectal cancers is shown in
Fig. 2.1. The standard approach is colonic stenting followed by laparoscopic sur-
gery irrespective of whether the obstruction is on the right side or the left side.
Table 2.2 Comparison between colonic stent and transanal drainage tube for BTS
Colonic stent Transanal drainage tube
Success rate Feasible Feasible
Decompression Fast Slow
Management Easy Difficult
Odor Non Yes
Oral intake Possible Difficult
QOL Good Poor
Influence to the tumor Invasive? Possibility of local recurrence?
Proximal site perforation Minimum 10%?
Long-term placement Possible Difficult
20 Y. Saida
Right side obstruction Left side obstruction
Colonic stent
Nasogastric or Long ileus tube Oral intake
Poor or failure Pre Op Exam
1-3 Weeks
Emergency surgery
Mechanical Prep.
2 Stage Op
Hartmann or Colostomy Elective surgery Primary Anastomosis
(Laparoscopic surgery)
Fig. 2.1 Strategy for Curative Obstructive Colorectal Cancers
2.5 Indications and Contraindications for Colonic Stents
Colostomies are required in many cases of obstructive colorectal cancer, and the
resultant negative impact on patient’s QOL is unavoidable. As a solution to this
problem, colonic stents were introduced in the early 1990s as a palliative measure
to decompress the large intestine in patients for whom curative resection was not an
option [13]. The indications for colonic stents have subsequently been expanded to
include pre-operative decompression as a BTS [10, 14]. In 2010, decompression
with colonic stents was recommended as a standard treatment in cases of malignant
colonic stenosis in the American Society for Gastrointestinal Endoscopy and World
Society of Emergency Surgery guidelines [15, 16].
Colonic stents were introduced into Japan in 2012. Currently, four types of
colonic stent manufactured in three countries are available in Japan (Fig. 2.2). Each
type of stent has a different extension and radial force, and their selection needs to
be made based on the patient’s condition. Currently, colonic stents are indicated as
a palliative treatment for malignant colonic conditions with stenosis. These condi-
tions (with malignant colonic stenosis) include recurrence at the anastomotic site
after colorectal cancer surgery, metastatic recurrence, and obstructive unresectable
cancers with unresectable conditions. Colonic stents are also indicated as a BTS for
avoiding emergency surgery for colorectal cancer patients with bowel obstruction
(pre-operative resolution of stenosis).
Colonic stents are contraindicated for benign stenosis or cases where elongated
or complex stenosis, hemorrhage, inflammation, or perforations are present. Pain
2012.1- WallFlex™ 2013.7- Niti-S Stent™
2017.10- Naturfit 2018.1- JentllyStent
Fig. 2.2 Colonic stent in Japan
Expanded colonic stent
Clip for marking

Expanded colonic stent
Fig. 2.3 Colonic stent for right side/proximal colon
and distress are likely when the stent margin approaches the pectinate line of the
anal canal; accordingly, colonic stents cannot be used when there is rectal stenosis
in the vicinity of the anal verge. Stents are mainly deployed on the left side of the
colon in Europe and North America, and there are few reports of the utility of
colonic stents with right-sided placement. However, right-sided stent placement is
relatively common in Japan (Fig. 2.3) [17], and reports of its utility are gradually
becoming more common [18].
22 Y. Saida
2.6 Outcomes with Colonic Stents
A systematic review by Watt et al. of colonic stents reported a median technical suc-
cess rate of 96.2% (range: 66.6–100%) and a median clinical success rate of 92%
(range: 46–100%) [19]. A report on multinational registries also showed satisfac-
tory outcomes, with technical and clinical success rates of 98% and 94%, respec-
tively, and an overall complication rate of 7.8% (perforation: 3%; deviation: 1.2%;
hemorrhage: 0.6%) [20]. Stents were compared with emergency surgery in a meta-
analysis based on eight studies and 601 patients. This meta-analysis showed that
stent insertion was associated with significantly lower colostomy and ICU admis-
sion rates, a significantly greater primary anastomosis rate, and significantly lower
surgical complication and anastomotic leakage rates, and colonic stents were shown
to have no adverse effect on mortality or long-term prognosis. Accordingly, BTS
colonic stents were concluded to have utility for left-sided, obstructive colorectal
cancers as a treatment enabling avoidance of colostomies and reduction of surgical
complications [21]. In Japan, a multicenter, prospective clinical study conducted by
the Japan Colonic Stent Safe Procedure Research Group reported technical and
clinical success rates of 97.9% and 95.5%, respectively, and a perforation rate of
2%, demonstrating that the colonic stents could be inserted safely [13].
Stent placement has generated some concerns over metastases or an adverse
effect on prognosis following direct invasion of the tumor (such as stent encroach-
ment into the tumor). However, in my view, there is no adverse effect on long-term
prognosis based on the results of a study performed with my colleagues [22] and the
study of Tilney et al. [23]. The meta-analysis by Zhang et al. also found no adverse
effects of stent placement on perioperative mortality or long-term prognosis [21].
On the other hand, stenting as a BTS was demonstrated to have a long-term adverse
effect in a study of 87 patients with left-sided malignant colonic obstruction in 2013
by Sabbagh et al. [24]. In that study, patients with stent insertion had significantly
poorer overall survival than patients undergoing surgery only. Five-year cancer-
specific mortality was 48% with stent placement against 21% for surgery. Those
results suggested that stents have a possible adverse effect on long-term prognosis
for colorectal cancer [24]. However, that was a retrospective study in which cancer
mortality rates were investigated; the prevalence of synchronous distant metastasis
was 37.5% in the stent placement group against 10.2% in the surgery-only group.
The success rate in the stent group was low, at 81%, and 5-year survival was
extremely low in patients without metastasis in the stent group, at 30%. Accordingly,
in my view, it is not possible to attach great importance to such results.
Nevertheless, stenting as a BTS is not recommended as the standard treatment
for symptomatic left-sided malignant colonic obstruction in the clinical guideline
issued by the European Society of Gastrointestinal Endoscopy (ESGE) since there
is a possible adverse effect on long-term prognosis [25]. However, the data from the
studies on which this guidance was showed a relatively poor success rate and high
complication rates, including for perforation, of colonic stenting, and poor colonic
stent placement might be related to poor long-term prognosis. Accordingly, the
“Japan Colonic Stent Safe Procedure Research Group’s Comments on the ESGE
Clinical Guidance” have now been published on the group’s web site. The counter-
argument stresses that the conclusion on BTS stents may be hasty due to the lack of
international studies conducted with an oncological primary endpoint and providing
a high level of evidence [8].
Colonic stents and emergency surgery were recently compared in a randomized,
controlled trial endorsed by the European Association for Endoscopic Surgery in
Italy [26]. No difference in long-term prognosis was found in that study; however,
the primary endpoint was a short-term outcome, and the study will seemingly not
produce a change in the above-stated ESGE guidance.
Against this background, the Japan Colonic Stent Safe Procedure Research
Group has initiated two multicenter clinical studies to produce fresh countering evi-
dence. These consist of a retrospective study, “A study on colonic decompression as
bridge to surgery for stage II/III obstructive colon cancer: retrospective multicenter
observational study” (the CODOMO study) and a prospective, randomized, con-
trolled trial, “Colonic stent for ‘Bridge to Surgery’ comparing treatment with non-
stenting surgery in stage II/III obstructive colon cancer” (the COBRA study) [8].
2.7 Conclusion
Among endoscopic and interventional radiology treatments, colonic stenting to

relieve stenosis can be expected to have dramatic efficacy; patients brought to hos-
pital by ambulance become capable of walking and oral intake soon after treatment.
However, much remains unclear about colonic stents; for example, the conditions of
patients with high perforation risk, the advisability of chemotherapy after stent
placement, and the effect on long-term prognosis. Approximately 30–40% of
patients with long-term stent placement experience some incidental symptoms, and
re-intervention or other surgical procedures such as the stent-in-stent procedure are
often needed. These details must naturally be explained to patients before stenting
is carried out, and the patient must be regularly monitored following stent place-
ment. It is vital that the endoscopic treatment team and the surgical team collaborate
in treatment and monitoring patient progress.
References
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2. Winner M, Mooney SJ, Hershman DL, et al. Incidence and predictors of bowel obstruction
in elderly patients with stage IV colon cancer: a population-based cohort study. JAMA Surg.
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3. Jullumstro E, Wibe A, Lydersen S, et al. Colon cancer incidence, presentation, treatment and
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4. Cheynel N, Cortet M, Lepage C, et al. Trends in frequency and management of obstructing

colorectal cancers in a well-defined population. Dis Colon Rectum. 2007;50:1568–75.
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Gastroenterol Surg. 2000;33:709–15 (in Japanese).
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bowel obstruction. Jpn J Gastroenterol Surg. 1993;26:76–81 (in Japanese).
7. Yang Z, Wang L, Kang L, et al. Clinicopathologic characteristics and outcomes of patients
with obstructive colorectal cancer. J Gastrointest Surg. 2011;15:1213–22.
8. Saida Y. A review of colonic stents. Gastroenterol Endosc. 2013;55: 3–11 (in Japanese).
9. Barillari P, Aurello P, De Angelis R, et al. Management and survival of patients affected with
obstructive colorectal cancer. Int Surg. 1992;77:251–5.
10. Saida Y, Sumiyama Y, Nagao J, et al. Stent endoprosthesis for obstructing colorectal cancers.
Dis Colon Rectum. 1996;39:552–5.
11. Lelcuk S, Ratan J, Klausner JM, et al. Endoscopic decompression of acute colonic obstruction.
Avoiding staged surgery. Ann Surg. 1986;203:292–4.
12. Li CY, Guo SB, Wang NF. Decompression of acute left-sided malignant colorectal obstruction:
comparing transanal drainage tube with metallic stent. J Clin Gastroenterol. 2014;48:e37–42.
13. Dohmoto M. New method: endoscopic implantation of rectal stent in palliative treatment of
malignant stenosis. Endosc Dig. 1991;3:1507–12.
14. Trompetas V. Emergency management of malignant acute left-sided colonic obstruction. Ann
R Coll Surg Engl. 2008;90:181–6.
15. ASGE Standards of Practice Committee, Harrison ME, Anderson MA, et al. The role of
endoscopy in the management of patients with known and suspected colonic obstruction and
pseudo-obstruction. Gastrointest Endosc. 2010;71:669–79.
16. Ansaloni L, Andersson RE, Bazzoli F, et al. Guidelines in the management of obstructing can-
cer of the left colon: consensus conference of the world society of emergency surgery (WSES)
and peritoneum and surgery (PnS) society. World J Emerg Surg. 2010;28:29.
17. Matsuzawa T, Ishida H, Yoshida S, et al. A Japanese prospective multicenter study of self-
expandable metal stent placement for malignant colorectal obstruction: short-term safety and
efficacy within 7 days of stent procedure in 513 cases. Gastrointest Endosc. 2015;82:697–707.
18. Amelung FJ, Consten ECJ, Siersema PD, et al. A population-based analysis of three treatment
modalities for malignant obstruction of the proximal colon: acute resection versus stent or
stoma as a bridge to surgery. Ann Surg Oncol. 2016;23:3660–8.
19. Watt AM, Faragher IG, Griffin TT, et al. Self-expanding metallic stents for relieving malignant
colorectal obstruction: a systematic review. Ann Surg. 2007;246:24–30.
20. Jimenez-Perez J, Casellas J, Garcia-Cano J, et al. Colonic stenting as a bridge to surgery in
malignant large-bowel obstruction: a report from two large multinational registries. Am J
Gastroenterol. 2011;106:2174–80.
21. Zhang Y, Shi J, Shi B, et al. Self-expanding metallic stent as a bridge to surgery versus emer-
gency surgery for obstructive colorectal cancer: a meta-analysis. Surg Endosc. 2012;26:110–9.
22. Saida Y, Sumiyama Y, Nagao J, et al. Long-term prognosis of preoperative “bridge to surgery”
expandable metallic stent insertion for obstructive colorectal cancer: comparison with emer-
gency operation. Dis Colon Rectum. 2003;46:s44–9.
23. Tilney S, Lovegrove RE, Purkayastha S, et al. Comparison of colon stenting and open surgery
for malignant large bowel obstruction. Surg Endosc. 2007;21:225–33.
24. Sabbagh C, Browet F, Diouf M, et al. Is stenting as “a bridge to surgery” an oncologically safe
strategy for the management of acute, left-sided, malignant, colonic obstruction?: a compara-
tive study with a propensity score analysis. Ann Surg. 2013;258:107–15.
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gency surgery for malignant colonic obstruction: results of a multicentre randomised con-
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Part II
Surgical Treatment
Chapter 3
D3 Lymph Node Dissection for Colon
and Rectal Cancers
Tatsuro Yamaguchi
Abstract Regardless of Western countries or Japan, surgical resection is the most

effective treatment for colorectal cancer. Therefore, the resection of the primary
tumor is recommended in the absence of distant metastasis. However, the concept
of colorectal surgery is quite different between Western countries and Japan. In
Western countries, the tumor is resected with wide margins in the direction of the
colonic axis based on the tumor location. In Japan, the extent of lymph node dissec-
tion depends on the degree of tumor progression, which is called D3 lymph node
dissection. According to the Japanese Society for Cancer of the Colon and Rectum,
regional lymph nodes are categorized into paracolic nodes (located around the mar-
ginal artery), intermediate nodes (located around the dominant artery corresponding
to the tumor location, such as the right colic artery), and main nodes (located around
the branching point of the dominant artery). For D3 lymph node dissection, com-
plete lymphadenectomy from the paracolic to main nodes is required. For lower
rectal cancer, D3 lymph node dissection includes dissection of the lateral lymph
nodes. Lateral lymph nodes are located outside the mesorectal fascia and are cate-
gorized into internal iliac nodes, common iliac nodes, obturator nodes, and external
iliac nodes. The internal iliac nodes are further categorized into proximal and distal
internal iliac nodes. In this chapter, we describe the Japanese criteria for D3 lymph
node dissection for colon and rectal cancers.
Keywords Colorectal cancer · D3 lymph node dissection · Lateral lymph node

dissection
T. Yamaguchi (*)
Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center
Komagome Hospital, Tokyo, Japan
e-mail: tatsuro@yamaguchi.email.ne.jp

28 T. Yamaguchi
3.1 Introduction
Colorectal cancer is the third most common malignant tumor (after lung and pros-
tate cancers) among men and the second most common tumor (after breast cancer)
among women. An estimated 1.4 million new cases of colorectal cancer were diag-
nosed across the world in 2012; this number is projected to increase to 2.4 million
new cases by 2035 [1]. Because surgical resection is the most effective treatment for
colorectal cancer, the resection of the primary tumor is recommended in the absence
of distant metastasis. Endoscopic resection is one of the treatment modalities for
early colorectal cancer; however, surgical resection with lymph node dissection is
recommended for lesions that have invaded submucosa or deeper layers [2]. The
purpose of surgical resection for colorectal cancer is to remove the primary tumor
as well as any lymph nodes with potential metastatic involvement.
In Western countries, the extent of colorectomy had been performed for colorec-
tal cancer. The tumor is typically resected with wide margins in the direction of the
colonic axis based on the tumor location [3] (e.g., right hemicolectomy for cecal
cancer and left hemicolectomy for descending colon cancer). In Japan, regional
lymph nodes are defined by the Japanese Classification of Colorectal Carcinoma
(the first edition was published in 1977) [4], and recommendations for lymph node
dissection are based on the Japanese Society for Cancer of the Colon and Rectum
(JSCCR) guidelines for the treatment of colorectal cancer (the first edition was pub-
lished in 2005) [2]. According to the JSCCR guidelines, the extent of lymph node
dissection depends on the degree of tumor progression. Accordingly, D3 lymph
node dissection is recommended for T3 or T4 tumors. Moreover, D3 lymph node
dissection for lower rectal cancer includes dissection of the lateral lymph nodes. In
this chapter, we describe the Japanese criteria for D3 lymph node dissection for
colon and rectal cancers.
3.2 D3 Lymph Nodes Dissection for Colon Cancer
3.2.1 J apanese Categorization of the Regional

Lymph Nodes of the Colon
Since the first publication of the Japanese Classification of Colorectal Carcinoma in

1977 [4], regional lymph nodes have been classified anatomically in Japan, while
the N status is classified numerically in TNM classification [5]. Regional lymph
nodes are categorized into the following three groups: (1) paracolic nodes (located
around the marginal artery); (2) intermediate nodes (located around the dominant
artery corresponding to the tumor location, such as the right colic artery); and (3)
main nodes (located around the branching point of the dominant artery).
3 D3 Lymph Node Dissection for Colon and Rectal Cancers 29
The range of the paracolic nodes is determined based on the positional relation-
ship between the dominant artery and tumor. For tumors located just under the
dominant artery, the paracolic nodes are ranged within 10 cm on both sides of the
tumor (Fig. 3.1a). For tumors located within 10 cm of the dominant artery, the
paracolic nodes are ranged from 5 cm on the opposite side of the tumor from the
dominant artery to 10 cm on the opposite side of the dominant artery (Fig. 3.1b).
For tumors located between two dominant arteries that are within 10 cm of the
tumor, the paracolic nodes are ranged from 5 cm on the opposite side of the tumor
from one dominant artery to 5 cm on the opposite side of the tumor from the other
dominant artery (Fig. 3.1c). For tumors located between two arteries that are
>10 cm away from the tumor, the nearest artery is considered the dominant artery,
and the paracolic nodes are ranged from 5 cm on the opposite side of the tumor
from the dominant artery to 10 cm on the opposite side of the dominant artery
(Fig. 3.1d).
a b
10 cm
10 cm T
<10 cm
T
5 cm
10 cm
Fig. 3.1 Schemas of the range of the paracolic nodes: (a) tumor located just under the dominant
artery, (b) tumor located within 10 cm of the dominant artery, (c) tumor located between two domi-
nant arteries, and (d) tumor located between two arteries that are > 10 cm away from the tumor
30 T. Yamaguchi
c d
10 cm
>10 cm
5 cm
<10 cm 5 cm
T
<10 cm
5 cm
Fig. 3.1 (continued)
3.2.2 D
efinition and Indications for D3 Lymph Node
Dissection for Colon Cancer
D1 dissection is defined as lymphadenectomy around the paracolic nodes, D2 as

lymphadenectomy from the paracolic to intermediate nodes, and D3 as complete
lymphadenectomy from the paracolic to main nodes. For D3 dissection, in addition
to high ligation, lymphadenectomy around the branching point of the dominant
artery is also required (Fig. 3.2).
According to the JSCCR registry [2], the frequency of metastatic involvement of
main nodes is 2.8% in colon cancer. The deeper the invasion, the more frequent is
the metastasis to the main nodes. The frequency of main node metastasis is >5.0%
in T4 tumors. Thus, D3 dissection is recommended for patients with T3 and T4
tumors. Currently, there is inadequate evidence to justify D3 dissection for T2
tumors; however, at least D2 dissection is necessary for these tumors. Nonetheless,
D3 dissection is an option in such cases because the frequency of metatstatic
involvement of the main nodes is <1.0% and preoperative assessment of the depth
of invasion is not very accurate.
Fig. 3.2 A schema of

range of Japanese D3
dissection for colon cancer
10 cm
10 cm
3.2.3 C
omplete Mesocolic Excision with Central
Vascular Ligation
Complete mesocolic excision (CME) was proposed as the standard surgical proce-
dure for colon cancer by Hohenberger et al. in 2009 [6]. It is defined as the separa-
tion of the mesocolic from parietal plane and true central ligation of the supplying
arteries and draining veins at their roots. In addition, Bokey et al. demonstrated the
32 T. Yamaguchi
importance of surgical resection using embryology in 2003 [7]. In the context of the
Japanese Classification, both surgical procedures correspond to D2 dissection as per
JSCCR as D3 dissection entails complete resection of the main nodes.
Until the introduction of CME, the standard criterion to determine the extent of
bowel resection was removal of the blood supply and lymphatics at the origin of the
primary feeding artery (Fig. 3.3) [8, 9]. A population-based study conducted by a
Danish group revealed longer disease-free survival after CME than that after conven-
tional colon cancer surgery, which indicated better prognosis in the CME group [10].
A study compared surgical outcomes of D3 dissection with those of CME with
central vascular ligation. The distance from the high vascular tie to the bowel wall
Fig. 3.3 A schema of the

range of complete
mesocolin excision
was comparable in the two groups; however, D3 dissection specimens were signifi-
cantly shorter and were associated with a smaller amount of harvested lymph nodes
compared with CME [11]. However, to date, no study has compared the prognosis
between D3 dissection and CME.
3.2.4 Longitudinal Resection Margin for Colon Cancer
Although the longitudinal resection margin for colon cancers is longer in Western
countries than in Japan [11], the range of regional nodes is not documented in the
TNM classification. The Guideline 2000 for Colon and Rectal Cancer Surgery [9]
recommends a longitudinal resection margin of >5 cm both proximally and distally.
However, the level of recommendation is grade D (i.e., it is backed by little or no
empirical evidence).
The evidence base to define optimal longitudinal resection margin from the
tumor is limited in the context of colon cancer. Hida et al. investigated the pericolic
spread of lymph node metastasis from colon cancer. They found that 96.9% of
lymph node metastasis was within 7 cm, while that beyond 10 cm was rare. They
recommended 7-cm proximal and distal margins for resection of T3 and T4 tumors
[12]. Hashiguchi et al. investigated pericolic spread of lymph node metastasis based
on accurate staging. They reported a 4.6% incidence of metastatic involvement of
lymph nodes located between 5 and 10 cm from the tumor. They found that addi-
tional removal of lymph nodes located >5 cm from the tumor did not improve the
staging accuracy or survival benefit [13]. To date, there is no evidence to suggest
any association between longitudinal resection margin and oncological outcomes
[14]. Increase in the longitudinal resection margin tends to increase the number of
harvested lymph nodes [11, 14]. Thus, considering the low frequency of lymph
node metastasis beyond 10 cm from the tumor, a 10-cm longitudinal resection mar-
gin seems adequate for T3 and T4 colon cancers. For cecal cancer, right hemicolec-
tomy is not necessarily required, and ileocecal resection may be adequate. Similarly,
for sigmoid colon cancer, left hemicolectomy is not necessarily required, and sig-
moidectomy may often be adequate.
3.3 D3 Lymph Nodes Dissection for Rectal Cancer
3.3.1 J apanese Categorization of Regional Lymph Nodes

That Drain the Rectum
According to the Japanese Classification of Colorectal Carcinoma, regional lymph

nodes for lower rectal cancer located below the peritoneal reflection include lateral,
pericolic, intermediate, and main nodes. Lateral lymph nodes are located outside
the mesorectal fascia and are categorized into the following four nodes: (1) internal
34 T. Yamaguchi
ObN
EIA
ObA
Ob-Nodes
CIA
DII-Nodes
PII-Nodes
CI-Nodes
IIA
Fig. 3.4 A schema of lateral lymph nodes for lower rectal cancer. CIA, common iliac artery;
CI-Nodes, common iliac nodes; DII-Nodes, distal internal iliac nodes; EIA, external iliac artery;
IIA, internal iliac artery; ObA, obturator artery; ObN, obturator nerve; Ob-Nodes, obturator nodes;
PII-Nodes, proximal internal iliac nodes
iliac; (2) common iliac; (3) obturator; and (4) external iliac. The internal iliac nodes
are further categorized into proximal and distal internal iliac nodes (Fig. 3.4).
3.3.2 M
esorectal Excision and Distal Margin
for Rectal Cancer
Since the proposal by Heald et al., total mesorectal excision is the standard surgical
procedure for rectal cancer in Western countries [15]. However, there is no clear
consensus on the need for TME for all rectal cancers. Shirouzu et al. investigated
distal spread of >600 rectal cancer specimens and found that 10% of all the speci-
mens and only 3.8% of curative surgery specimens showed distal spread; moreover,
the extent of distal spread was within 1 cm in most specimens [16]. In a study by
Ono et al., the distal spread was within 3 cm in upper rectal cancer and within 2 cm
in lower rectal cancer [17]. Therefore, TME is not necessarily required for rectal
cancer. Indeed, tumor-specific mesorectal excision is the typical approach to rectal
cancer surgery in Japan. The Japanese classification recommends 3- and 2-cm distal
margin for upper and lower rectal cancers, respectively.
3.3.3 I ndications for Lateral Lymph Node Dissection

for Rectal Cancer
D3 dissection entails complete lymphadenectomy of lateral lymph nodes as well as

main nodes. The local recurrence rate after rectal cancer surgery was reported to be
>30% since three decades or more [18, 19]. Local recurrence of rectal cancer typi-
cally causes severe pain and neurological disturbance, which impairs the quality of
life of the patient. Since the late 1960s, lateral lymph node dissection has been
performed in Japan to reduce the risk of local recurrence [18, 20, 21], while neoad-
juvant chemoradiotherapy followed by surgery is established as a standard treat-
ment strategy based on evidence from clinical trials in Western counties [15].
Currently, lateral lymph node dissection with autonomic nerve preservation is
widely performed for rectal cancer to achieve the twin objectives of curability and
functional preservation [22, 23].
The reported incidence of lateral lymph node metastasis in patients with lower
rectal cancer ranges from 10 to 25% (Table 3.1) [24–27], which is comparable with
that of intermediate node (inferior mesenteric artery nodes) metastasis [2]. However,
lateral lymph node metastasis is rarely observed in cases of upper rectal cancer in
Table 3.1 Published reports pertaining to lateral lymph node dissection

Lateral lymph 5-year survival Local recurrence Overall local
node metastasis rate in LLDM rate in LLDM recurrence rate
Author Year (%) (%) (%) (%)
Moriya Y et al. 1989 42/231 (18.9) 49 (DFS) 27/174 (15.5)
[21]
Sugihara K 1996 23/238 (10.6) 49.3 6/23 (26.1) 12/214 (5.6)
et al. [22]
Moriya Y et al. 1997 62/448 (13.8) 43 (DFS) 17/62 (27.4) 42/448 (9.4)
[24]
Hida J et al. 1997 25
[29]
Mori T et al. 1998 40/157 (25.5) 37.3 4/54 (7.4)
[23]
Ueno H et al. 2001 53/250 (21.2) 39.1 25/44 (56.8)
[30]
Shirouzu K 2001 47/303 (15.5) 12/152 (7.9)
et al. [31]
Shimoyama M 2003 9/66 (13.6) 38.9 2/9 (22.2) 6/66 (9.1)
et al. [32]
Ueno M et al. 2005 41/222 (18.5) 41.7 15/34 (44.1) 37/222 (16.7)
[33]
Sugihara K 2006 129/930 (13.9) 45.8 33/129 (25.6) 158/1977 (8.0)
et al. [26]
Kobayashi 2009 117/784 (14.9) 47.7 28/117 (23.9) 82/784 (10.5)
et al. [27]
36 T. Yamaguchi
which the lower border is located proximal to the peritoneal reflection and also in
≤T2 stage lower rectal cancer [26]. Therefore, the indication for lateral lymph node
dissection in Japan is T3-T4 rectal cancer, wherein the lower border is located distal
to the peritoneal reflection [2].
Recently, Japanese Clinical Oncology Group (JCOG) demonstrated the signifi-
cance of lateral lymph node dissection for lower rectal cancer. The JCOG0212 trial
was a randomized controlled trial to confirm that the results of mesorectal excision
alone are not inferior to those of mesorectal excision with lateral lymph node dis-
section. The incidence of lateral lymph node metastasis in the study population was
7% even in patients with lower rectal cancer who showed no signs of lateral lymph
node metastasis on preoperative evaluation. The trial failed to demonstrate the non-
inferiority of mesorectal excision alone over mesorectal excision with lateral lymph
node dissection [28]. Therefore, for lower rectal cancer with the lower border
located distal to the peritoneal reflection and the depth of tumor invasion being up
to mascularis propria or deeper, lateral lymph node dissection as part of D3 lymph
node dissection is recommended even in the absence of any signs of lateral lymph
node metastasis on preoperative evaluation [2]. However, several issues pertaining
to lateral lymph node dissection for lower rectal cancer need to be resolved. (1)
Comparison to neoadjuvant chemoradiotherapy: Randomized controlled trials to
compare lateral lymph node dissection and neoadjuvant chemoradiotherapy have
not been conducted. (2) Preoperative diagnosis of lymph node metastasis: Although
lymph nodes <10 mm were considered to have no metastasis in the JCOG0212 trial,
it is difficult to predict lymph node metastasis accurately based only on size. In
addition to size, use of diagnostic methods, such as MRI and PET-CT, to assess
lymph node metastasis should be investigated.
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16. Shirouzu K, Isomoto H, Kakegawa T. Distal spread of rectal cancer and optimal distal margin
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38 T. Yamaguchi
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Chapter 4
Laparoscopic Surgery for Colorectal
Cancer
Tetsuro Tominaga and Tsuyoshi Konishi
Abstract Laparoscopic surgery for colorectal cancer has become an established

alternative to open surgery. Multiple randomized controlled trials have demon-
strated potential advantages of laparoscopic surgery in short-term outcomes, includ-
ing lower blood loss, faster recovery of bowel movement, shorter length of hospital
stay, and lower postoperative complications. In colon cancer, long-term outcome of
laparoscopic surgery have been reported similar to open surgery. However, in rectal
cancer, potential disadvantage of laparoscopic surgery have been reported regarding
the quality of resected surgical specimen. Further evidences are needed whether
long-term outcomes are truly similar between laparoscopic and open surgery in
rectal cancer. In this chapter, evidences on laparoscopic colorectal surgery com-
pared to open surgery are reviewed, particularly focusing on differences between
Japan and other countries.
Keywords Laparoscopic surgery · Colorectal cancer · Randomized controlled

trial · Lateral pelvic lymph node dissection
4.1 Laparoscopic Surgery for Colon Cancer (Table 4.1)
In 1991, the first case report was published on right hemicolectomy for a colon
tumor [1]. Then, Jecobs et al. reported the series on 20 laparoscopic-assisted colec-
tomy (LAC) [2]. Since then, several large population studies and randomized clini-
cal trials (RCTs) have been reported that evaluated safety and feasibility of
laparoscopic surgery compared to open surgery for the patients with colorectal
cancer.
In colon cancer, the first RCT which compared LAC with Open Colectomy (OC)
was reported from Barcelona group in 2002 [3]. They randomized 219 patients with
colon cancer and evaluated short- and long-term outcomes. There was significant
T. Tominaga · T. Konishi (*)

Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation
for Cancer Research, Tokyo, Japan
e-mail: tetsuro.tominaga@jfcr.or.jp; tkonishi-tky@umin.ac.jp

Table 4.1 Evidences on laparoscopic versus open surgery for colon cancer
40
Disease-
Overall free
Operation Blood loss Hospital survival survival
time (min) (mL) stay (day) Complication (%) (%)
Cases LAC vs. LAC vs. LAC vs. (%) LAC vs. LAC vs.
(LAC, Primary Conversion OC, OC, OC, LAC vs. OC, OC, OC,
Trial Country Year OS) endpoint Results rate (%) p-value p-value p-value p-value p-value p-value
Barcelona Spain 1993– 219 CSS Met 11.0 142 vs. 105 vs. 5.2 vs.7.9, 28.7 vs. 10.8, 64 vs. 51, 72.7 vs.
1998 LAC 118, 193, p = 0.005 p = 0.001 p = 0.06 71.2,
111 p = 0.001 p < 0.001 p = 0.70
OC 108
COST USA 1994– 863 Time to Met 21.0 150 vs. 95, – 5.0 vs. 6.0, 21 vs. 20, 76.4 vs. 69.2 vs.
2001 LAC recurrence p < 0.001 p < 0.001 p = 0.64 74.6, 68.4,
435 p = 0.93 p = 0.94
OC 428
CLASICC England 1996– 794 3-year OS Met 16.0 180 vs. – 9.0 vs. 9.0, 8 vs. 8, NC 67 vs. 68, 66 vs. 68,
2002 LAC 3-year DFS 135, NC NC p = 0.35 p = 0.70
526 3-year LR
OC 268
COLOR Europe 1997– 1248 3-year DFS Failed 17.0 145 vs. 100 vs. 8.2 vs. 9.3, 21 vs. 20, 73.8 vs. 66.5 vs.
2003 LAC 115, 175, p < 0.001 P = 0.88 74.2, 67.9,
627 p < 0.001 p < 0.001 p = 0.50 p = 0.40
OC 621
ALCCaS Australia 1998– 601 5-year OS Met 14.0 158 vs. 100 vs. 9.5 vs. 37.8 vs. 45.3, 77.7 vs. 72.3 vs.
2005 LAC 5-year DFS 107, 100, 10.6, p = 0.06 76.0, 71.7,
299 5-year LR p < 0.001 p = 0.17 p = 0.06 p = 0.94 p = 0.82
OC 302
JCOG0404 Japan 2005– 1057 5-year OS Failed 5.4 211 vs. 30 vs. 85, 10 vs. 11, 7.5 vs. 25.1, 91.8 vs. 79.3 vs.
2012 LAC 159, p < 0.001 NC NC 90.4, 79.7,
533 p < 0.001 p = 0.51 p = 0.51
T. Tominaga and T. Konishi
OC 524
NC not calculated, CSS cancer-specific survival, OS overall survival, DFS disease-free survival, LR local recurrence
4 Laparoscopic Surgery for Colorectal Cancer 41
benefit for LAC group in terms of postoperative complications and hospital stay. In
addition, for the patients with stage III disease, both cancer-related survival and
overall survival were better in LAC group. This study is limited by relatively small
number of the harvested lymph node in both arms.
Soon after the Barcelona trial, the COST trial was reported from the United
States which evaluated noninferiority of LAC compared to OC [4]. The study
included 872 patients who underwent colectomy at 48 institutions by expert sur-
geons. Similar to the Barcelona study, hospital stay was shorter and operation time
was longer in LAC group. There were no significant differences between LAC
group and OC group in terms of postoperative complications, 5-year OS, and 5-year
DFS.
The Conventional versus Laparoscopic-Assisted Surgery in Patients with
Colorectal Cancer (CLASICC) trial was the first major trial including colectomy as
well as rectal resection in the United Kingdom [5]. They evaluated 794 patients with
colon and rectal cancer and compared short-term and long-term outcome of LAC
versus OC. Similar to previous studies, operation time, blood loss, hospital stay, and
complication rate were similar between the two groups. There were no significant
differences in long-term outcome including DFS and OS. However, in this study,
in-hospital mortality rate was higher compared with other RCTs (LAC: 4%, OC:
5%).
The European Colon Cancer Laparoscopic or Open Resection (COLOR) trial
included 1248 patients with colon cancer [6]. This large randomized trial demon-
strated noninferiority of LAC compared to OC in terms of 3-year disease-free sur-
vival (74.2% vs. 76.2%, p = 0.70). Operation time was longer in LAC group, but the
LAC group was superior in reduced blood loss, less use of narcotics after operation
and shorter length of hospital stay. Notably, the conversion rate in this study was
very high (17%).
The Australian Laparoscopic Colon Cancer Surgery (ALCCaS) group reported a
randomized trial that compared LAC with OC. A total of 601 patients were enrolled,
and short-term and long-term outcome including 5-year OS and 5-year RFS were
evaluated [7]. Regarding short-term outcome, there was no differences in postopera-
tive complications, reoperation rate, and perioperative mortality. In LAC group,
recovery of bowel movement was quicker and hospital stay was shorter. Patients
who were converted to open surgery had a higher rate of infectious complications,
but a reoperation rate and in-hospital mortality were similar. There were no differ-
ences between LAC group and OC group regarding 5-year OS (77.7% vs. 76.0%,
P = 0.64) and RFS (72.7% vs. 71.2%, P = 0.70).
All these RCTs for colon cancer consistently showed that LAC for the patients
with colon cancer was safe and feasible compared with OC. In spite of longer opera-
tion time, the LAC group demonstrated better short-term outcome such as less
blood loss, shorter hospital stay and better recovery of bowel function. Regarding
long-term outcome, all the studies failed to show statistical differences in OS or
RFS. Some limitations in these RCTs should be noted in terms of quality control
and perioperative therapy. First, the conversion rates were relatively high among
these study, reported by Barcelona (11%), COST (21%), CLASICC (29%), COLOR
42 T. Tominaga and T. Konishi
(17%), and ALCCaS (14%). Second, The number of harvested lymph nodes was
relatively small, reported by Barcelona (11), COST (12), CLASICC (12–14),
COLOR (10), and ALCCaS (13). In terms of postoperative chemotherapy, COST,
CLASICC, and COLOR trials did not regulate regimens or criteria on adjuvant
chemotherapy.
In Japan, the JCOG 0404 RCT which started in 2004 evaluated LAC with OS for
clinical stage II/III colon cancer [8]. A total of 1057 patients were randomized to
LAC (n = 533) and OC (n = 524). The primary endpoint was overall survival. In this
study, the patients with pathological stage III received adjuvant chemotherapy with
fluorouracil and l-leucovorin per protocol. Further, operations were performed by
expert surgeons, and quality of surgery was monitored by photographs taken during
the operations. The conversion rate was 5.4%, which was much lower than the rates
reported in the previous RCTs. The mortality rate was 0%. The operation time was
longer in LAC group than in OC group (211 vs. 159 min, p < 0.001). Laparoscopic
surgery had less blood loss (30 vs. 85 mL, p < 0.001), shorter to pass first flatus (1.8
vs. 2.4 day, p < 0.001), less use of analgesics after surgery (175 vs. 241 times per 5
postoperative days, p < 0.001), and a shorter hospital stay (12.0 vs. 13.7, p < 0.001).
The rate of wound complication was lower in laparoscopic surgery compared with
open surgery (2.1% vs. 7.4%). Regarding long-term outcome, the 5-year OS was
91.8% in LAC and 90.4% in OC. The study failed to show the noninferiority of
LAC, possibly due to better OS and fewer events than expected in the protocol.
However, the survival curves were almost identical between the two groups.
4.2 Laparoscopic Surgery for Rectal Cancer (Table 4.2)
In the CLASICC trial, 386 patients had rectal cancer and underwent anterior resec-
tion or abdominoperineal resection [5]. There were no significant differences in
postoperative complications between LAC and OC. The patients who received lapa-
roscopic anterior resection had a trend toward increased positive circumferential
resection margin (CRM) compared to open (12% vs. 6%, p = 0.18). The 5-year local
recurrence rate was similar between the groups.
In the COLOR II trial, 1103 rectal cancer patients were randomized to laparo-
scopic and open surgery groups [9]. Although laparoscopic surgery had longer oper-
ation time (240 min vs. 188 min), it had improved perioperative outcome in terms
of less blood loss (200 mL vs. 400 mL), earlier return of bowel (2 days vs. 3 days),
and short hospital stay (8 days vs. 9 days). Rate of positive CRM, number of har-
vested lymph nodes, and perioperative morbidities and mortalities were similar in
both groups. Regarding long-term outcome, 3-year DFS of laparoscopic surgery
group was 74.2%, and open surgery group was 76.2% (p = 0.70). Three-year OS of
laparoscopic surgery group was 81.8%, and open surgery group was 84.2%
(p = 0.45).
Kang et al. randomized 340 patients with locally advanced rectal cancer
(T3N0-2M0) who had undergone neoadjuvant chemoradiation therapy to
Table 4.2 Evidences on laparoscopic versus open surgery for rectal cancer
Disease-
CRM Overall free
Operation Blood loss Hospital positive survival survival
time (min) (mL) stay (day) Complication rate (%) (%) (%)
Cases LAC vs. LAC vs. LAC vs. (%) LAC vs. LAC vs. LAC vs.
(LAC, Primary Conversion OC, OC, OC, LAC vs. OC, OC, OC, OC,
Trial Country Year OS) endpoint Results rate (%) p-value p-value p-value p-value p-value p-value p-value
CLASICC England 1996– n = 386 3-year OS Met 34.0 180 vs. – 11 vs. 13, 18 vs. 14, NC 16 vs. 14, 68.4 vs. 66.3 vs.
2002 LAC 246 3-year DFS 165, NC NC p = 0.80 66.7, 67.6,
OC 140 3-year LR p = 0.12 p = 0.72
3 year 3 year
COLOR II Netherlands 2004– n = 1044 3-year LR Met 17.4 240 vs. 200 vs. 8 vs. 9, 40 vs. 37, 10 vs. 10, 74.8 vs. 86.7 vs.
2010 LAC 699 188, 400, p = 0.03 p = 0.42 p = 0.85 70.8, NC 83.6, NC
OC 345 p < 0.001 p < 0.001 3 years 3 years
4 Laparoscopic Surgery for Colorectal Cancer
COREAN Korea 2006– n = 340 3-year DFS Met 2.9 244 vs. 200 vs. 9 vs. 8, 40 vs. 37, 2.9 vs. 79.2 vs. 91.7 vs.
2009 LAC 170 197, 217.5, p = 0.05 p = 0.60 4.1, 72.5, NC 90.4, NC
OC 170 p < 0.001 p = 0.006 p = 0.77 3 years 3 years
ACOSOG USA, 2008– n = 462 Successful Failed 11.0 266 vs. 256 vs. 7 vs. 7.3, 22.5 vs. 22.1, 12.1 vs. – –
Z6051 Canada 2013 LAC 240 resection 220, 318, p = 0.10 p = 0.46 7.7,
OC 222 (CRM-, DM-, p < 0.001 p = 0.004 p = 0.11
good TME)
ALaCaRT Australia 2010– n = 473 Successful Failed 8.8 210 vs. 100 vs. 7 vs. 8, 19 vs. 23, 7 vs. 3, – –
2014 LAC 238 resection 190, 150, p = 0.21 p = 0.98 p = 0.06
OC 235 (CRM-, DM-, p = 0.007 p = 0002
good TME)
Hida Japan 2010– n = 964 Postoperative Met 5.2 330 vs. 90 vs. 603, 19 vs. 19, 30.3 vs. 39.2, 4.53 vs. 89.9 vs. 70.9 vs.
2011 LAC 482 complications 326, p < 0.001 p = 0.90 p = 0.005 4.47, 90.4, 71.8,
OC 482 p = 0.12 p = 1.00 p = 0.12 p = 0.85
NC not calculated, OS overall survival, DFS disease-free survival, LR local recurrence, CRM circumferential resection margin, DM distal margin, TME total mesen-
teric excision
43
laparoscopic (n = 170) versus open (n = 170) surgery groups [10]. Quality of lapa-
roscopic surgery was very well controlled in this study with the conversion rate of
2.9%. In this study, blood loss was less in laparoscopic surgery group (200 vs.
217 mL, p < 0.05). There were no significant differences in hospital stay, CRM posi-
tive rate, and postoperative complication. Three-year DFS was 79.2% for the lapa-
roscopic group and 72.5% for the open group (p < 0.001).
ACOSOG Z6051 was a randomized phase III trial from the United States that
compared laparoscopic versus open surgery for stage II/III rectal cancer [11]. This
study was designed to assess the noninferiority of laparoscopic surgery to open
surgery, setting the primary endpoint as the composite pathologic and histologic
findings of “successful resection” defined as complete/near complete TME, a clear
CRM (≥1 mm), and a clear distal resection margin (≥1 mm). A total of 462 patients
were randomized to laparoscopic (=240) and open (n = 222) groups. Conversion to
open surgery occurred in 11.3%. They showed longer operation time in the laparo-
scopic group (266 min vs. 220 min). There were no significant differences in hospi-
tal stay (7.3 days vs. 7.0 days), readmission within 30 days (3.3% vs. 4.1%), and
severe complications (22.5% vs. 22.1%). As for the primary endpoint, the study
failed to show noninferiority of laparoscopic surgery (81.7% in laparoscopic sur-
gery, 86.9% in open surgery). Complete or near complete TME was found in 92.1%
in laparoscopic surgery and 95.1% in open surgery. Positive CRM was observed in
12.1% of laparoscopic surgery and 7.7% of open surgery.
Australian Laparoscopic Cancer of the Rectum (ALaCaRT) trial was a random-
ized, noninferior, phase III trial which enrolled patients between 2010 and 2014
[12]. A total of 473 patients were randomized to laparoscopic group (n = 238) and
open surgery group (n = 237). Similar with the ACOSOG Z6051 trial, the primary
endpoint was the successful resection in the surgical specimen (CRM-, DM-, good
TME). The conversion rate to open surgery was 9%. In the laparoscopic group, 194
patients (82%) had successful resection compared to 208 patients (89%) in open
surgery (p = 0.38). The CRM positive rate was 7% in the laparoscopy group and 7%
in the open group (p = 0.06). The rate of clear distal margin was 99% in the both
groups (p = 0.67). Complete TME was found in 87% of the laparoscopic group and
92% of the open group (p = 0.06). Again, noninferiority was not proven, and the
authors concluded that there was not enough evidence to support routine use of
laparoscopic surgery in the management of rectal cancer.
In Japan, Yamamoto et al. reported short-term outcomes of laparoscopic surgery
for stage 0/I rectal cancer [13]. A total 490 patients were eligible from 43 institu-
tions in Japan. Eight patients (1.6%) needed conversion to open surgery. The median
operation time and blood loss were 270 min and 28 mL, respectively, and these data
were comparable to previous RCTs. The rate of CRM positivity was 0.4%. There
were no perioperative mortalities. One hundred seventeen patients (23.9%) of the
patients experienced postoperative complications (23.9%), and the anastomotic
leakage occurred in 8.3% of anterior resection and 9.1% of intersphincteric
resection.
In 2018, Hida et al. conducted a retrospective multicenter study that evaluated
outcomes of laparoscopic and open surgery for cStage II-III low rectal cancer [14].
After propensity score matching, a total 482 patients who had laparoscopic surgery
were compared to 482 patients who had open surgery. Conversion rate was 5.2%. In
laparoscopic surgery, estimated blood loss was lower (p < 0.001), postoperative
complication was lower (p = 0.005), and fasting period was shorter (p < 0.001) com-
pared with open surgery. The 3-year overall survival (89.9% in the laparoscopic
group, 90.4% in the open group, p = 0.128) and the 3-year relapse-free survival
(70.9% vs. 71.8%, p = 0.885) were similar between the groups.
4.3 Laparoscopic Lateral Pelvic Lymph Node Dissection
Multiple RCTs in the Western countries have demonstrated that neoadjuvant chemo-
radiotherapy/radiotherapy reduces local recurrence in rectal cancer [15, 16]. Based
on these findings, neoadjuvant chemoradiotherapy/radiotherapy followed by TME
is a standard treatment in patients with cStage II-III rectal cancer in the Western
countries [17]. In contrast, the Japanese guideline recommends lateral pelvic lymph
node dissection (LPLND) as the standard treatment for T3-4 rectal cancer that
extends below peritoneal extension, and chemoradiotherapy/radiotherapy is not
routinely performed [18, 19]. Recent studies have demonstrated safety and feasibil-
ity of laparoscopic LPLND (Table 4.3) [20–28]. Ogura et al. reported a series of 327
patients with cStage II-III low rectal cancer who underwent neoadjuvant chemora-
diotherapy followed by laparoscopic TME [23]. Laparoscopic LPLND was selec-
tively performed in patients with clinically suspicious lateral lymph node before
neoadjuvant therapy. Short-term and long-term outcomes were compared between
the patient with (n = 107) and without (n = 220) LPLND. As expected, the operation
time was longer and blood loss was grater in LPLND group (461 min vs. 298 min,
and 115 mL vs. 30 mL, p < 0.001, respectively). However, there was no conversion
to open surgery, and the major complication rate was not different between the
groups (9.3% vs. 5.5%, p = 0.188). In terms of long-term outcome, there was no
significant differences in 3-year recurrence-free survival (84.7% vs. 82.0%,
p = 0.536) and 3-year local recurrence (3.2% vs. 5.2%, p = 0.565).
In 2017, Yamagichi et al. conducted a multicenter retrospective study in Japan
that examined 676 patients who underwent LPLND. Laparosocopic LPLND was
conducted in 137 patients, and open LPLND in 539 patients [24]. After case-
matching, 118 patients were included in each group. Operation time was signifi-
cantly longer in laparoscopic surgery (474 min vs. 363 min, p < 0.001). However,
blood loss was less (213 mL vs. 775 mL, p < 0.001) and blood transfusion was less
common (6.8% vs. 22.2%, p = 0.001) in laparoscopic surgery. There were no sig-
nificant differences in postoperative complications (40.7% vs. 45.8%). In terms of
long-term outcome, there was no significant differences in 3-year RFS (80.3% and
72.6%, p = 0.07), 3-year local recurrence-free survival (93.9% vs. 91.8%, p = 0.30),
and 3-year overall survival (93.9% vs. 92.2%, p = 0.52) between the laparoscopic
and open groups.
46
Table 4.3 Evidences on laparoscopic lateral pelvic lymph node dissection for rectal cancer
Neoadjuvant Operation time, Blood loss, No. of harvested lateral Overall
Author year N chemoradiotherapy min mL pelvic lymph nodes Conversion morbidity
Liu T 2011 68 N/A 271 150 23d N/A 7%
Park JS 2011 16a 56% 310 188 9 0% 31%
Liang TJ 2011 34 100% 58c 44c 6 N/A 21%
Konishi T 2011 14 100% 413 25 23d 0% 36%
Bae SU 2014 21b 86% 396 200 7 0% 29%
Furuhata T 2014 18 0% 604 380 17 0% 17%
Ogura A 2016 107 100% 461 115 25d 0% 34%
Yamaguchi T 2017 118 24% 474 213 10 17% 41%
N/A not available
a
Including 2 robotic surgery
b
Including 11 robotic surgery
c
For unilateral lateral pelvic lymph node dissection
d
Total retrieved lymph nodes
T. Tominaga and T. Konishi
4.4 Conclusions
Major clinical trials in the world and large case series from Japan were reviewed on
laparoscopic colorectal surgery. Multiple studies demonstrated advantages of lapa-
roscopic surgery in short-term outcomes, including lower blood loss, faster recov-
ery, shorter length of hospital stay and lower postoperative complications. In colon
cancer, long-term outcome of laparoscopic surgery has been reported similar to
open surgery. However, in rectal cancer, recent two RCTs demonstrated potential
disadvantage of laparoscopic surgery in pathologic outcomes of the resected speci-
mens. Further evidences are needed to assess whether long-term outcomes are truly
similar between laparoscopic and open surgery in rectal cancer.
Conflict of Interest The authors have no conflicts of interest to declare.
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13. Yamamoto S, et al. Laparoscopic surgery for stage 0/I rectal carcinoma: short-term outcomes
of a single-arm phase II trial. Ann Surg. 2013;258(2):283–8.
14. Hida K, et al. Open versus laparoscopic surgery for advanced low rectal cancer: a large, mul-
ticenter, propensity score matched cohort study in Japan. Ann Surg. 2018;268(2):318–24.
15. Sauer R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl
J Med. 2004;351(17):1731–40.
16. Breugom AJ, et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative
(chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG)
randomized phase III trial. Ann Oncol. 2015;26(4):696–701.
17. Folkesson J, et al. Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on
survival and local recurrence rate. J Clin Oncol. 2005;23(24):5644–50.
18. Watanabe T, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines
2016 for the treatment of colorectal cancer. Int J Clin Oncol. 2018;23(1):1–34.
19. Sugihara K, et al. Indication and benefit of pelvic sidewall dissection for rectal cancer. Dis
Colon Rectum. 2006;49(11):1663–72.
20. Liang JT. Technical feasibility of laparoscopic lateral pelvic lymph node dissection for

patients with low rectal cancer after concurrent chemoradiation therapy. Ann Surg Oncol.
2011;18(1):153–9.
21. Furuhata T, et al. Clinical feasibility of laparoscopic lateral pelvic lymph node dissection fol-
lowing total mesorectal excision for advanced rectal cancer. Surg Today. 2015;45(3):310–4.
22. Nagayoshi K, et al. Laparoscopic lateral pelvic lymph node dissection is achievable and
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2016;30(5):1938–47.
23. Ogura A, et al. Feasibility of laparoscopic total mesorectal excision with extended lateral pel-
vic lymph node dissection for advanced lower rectal cancer after preoperative chemoradio-
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24. Yamaguchi T, et al. Laparoscopic versus open lateral lymph node dissection for locally
advanced low rectal cancer: a subgroup analysis of a large multicenter cohort study in Japan.
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2011;25(10):3322–9.
Chapter 5
Robotic-Assisted Laparoscopic Surgery
for Rectal Cancer
Tomohiro Yamaguchi and Yusuke Kinugasa
Abstract Conventional laparoscopic surgery (CLS) for rectal cancer involves

manipulation in the narrow and deep pelvic space and is thus technically demand-
ing. Therefore, robotic-assisted laparoscopic surgery (RALS) is a promising
advanced technology that is expected to overcome the inherent limitations of CLS
for rectal cancer. RALS equipment has several notable advantages, including free-
moving multi-joint forceps, a motion scaling function, high-quality three-
dimensional imaging, operator-mediated stable camera work, and greatly improved
ergonomics. In this chapter, we reviewed previous articles regarding RALS, in
which this technique was associated with shorter learning curves, better functional
outcomes, and similar or better oncological outcomes relative to CLS. Furthermore,
many reports described a lower conversion rate of RALS compared to that of
CLS. However, a randomized clinical trial comparing RALS versus CLS demon-
strated that former did not significantly reduce the risk of conversion to open sur-
gery. The high cost associated with RALS is also an important issue. As high-level
evidence for RLAS remains to be well established, surgeons should expand their
indications safely and cautiously. Further evaluations of the short- and long-term
outcomes of RALS, including the patient’s quality of life and cost-effectiveness, are
needed to support the use of this technique.
Keywords Conventional laparoscopic surgery · da Vinci surgical system

Lateral lymph node dissection · Open surgery · Rectal cancer
Robotic-assisted laparoscopic surgery
T. Yamaguchi
Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese
Foundation for Cancer Research, Tokyo, Japan
Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
e-mail: tomohiro.yamaguchi@jfcr.or.jp
Y. Kinugasa (*)
Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
e-mail: kinugasa.srg1@tmd.ac.jp

50 T. Yamaguchi and Y. Kinugasa
5.1 Introduction
The conventional laparoscopic approach to colorectal surgery has become increas-

ingly popular in many countries. Although the potential benefits of laparoscopic
surgery include a magnified view via the laparoscope and minimal invasiveness, the
efficacy of conventional laparoscopic surgery (CLS) for rectal cancer remain con-
troversial. To date, three large multicenter randomized controlled trials (RCTs) have
reported comparisons of CLS with open surgery (OS) for rectal cancer [1–3], and
all demonstrated similar or better short-term outcomes with CLS and similar onco-
logical outcomes between the two approaches, thus confirming the safety and feasi-
bility of CLS for rectal cancer. However, two recent RCTs did not establish the
noninferiority of CLS vs. OS in assessments of a composite of pathological factors
such as total mesorectal excision (TME) completeness, circumferential resection
margin (CRM), and distal margins [4, 5]. These findings are most likely attributable
to the technical difficulty of CLS, which uses straight and inflexible instruments, in
the narrow and deep pelvis. Accordingly, these problems should be addressed dur-
ing the process of standardizing CLS for rectal cancer.
Robotic-assisted laparoscopic surgery (RALS) is a promising advanced technol-
ogy that is expected to overcome the inherent limitations of CLS. Compared with
CLS, RALS equipment features advantages such as free-moving multi-joint for-
ceps, a motion scaling function, high-quality three-dimensional imaging, operator-
mediated stable camera work, and greatly improved ergonomics. In 2000, the
United States Food and Drug Administration approved the da Vinci surgical system
(Intuitive Surgical, Sunnyvale, CA, USA). Subsequently, Weber et al. performed the
first robotic-assisted colectomy for benign disease in 2001 [6], and Pigazzi et al.
first described robotic-assisted laparoscopic TME for rectal cancer in 2006 [7].
Despite numerous reports on RALS, there remains a paucity of high-level evidence
indicating the clinical superiority of this technique over CLS or OS. In this chapter,
we review the existing RALS-related literature and discuss the learning curve;
short-term, functional, and oncological outcomes; costs and future prospects of this
procedure.
5.2 Learning Curve
It is important to assess the effects of a newly adopted technique on the surgeon’s

learning curve. Through a systemic review of the literature, Jiménez-Rodríguez
et al. identified three phases of the learning curve of RALS for rectal cancer and
calculated that a mean of 29.7 cases were necessary for the initial phase [8]. By
contrast, the learning curve of CLS reportedly requires approximately 40–90
patients before a plateau is reached [8]. This difference is potentially advantageous
not only for experienced surgeons [9–13], but also for novice surgeons. For
5 Robotic-Assisted Laparoscopic Surgery for Rectal Cancer 51
example, Melich et al. reported the learning curves of a colorectal surgeon who had
been primarily trained in OS but was a novice in terms of minimally invasive sur-
gery and found that after an initial 41 cases, the surgeon’s total operative time curve
was faster for RALS than for CLS [14]. These findings indicate that RALS offers
technical advantages and a potentially shorter learning curve, compared with CLS.
5.3 Perioperative Outcomes
5.3.1 Operation Time and Blood Loss
To date, numerous studies have evaluated the short-term outcomes of RALS. For

example, a meta-analysis by Lee et al. reported longer operation times in the RALS
group, compared to the CLS group [15]. On the other hand, the majority of the pre-
vious meta-analyses found no significant differences in the operation times between
RALS and CLS [16–19]. Still, The ROLARR trial reported that RALS was associ-
ated with a mean operation time of 37.5 min longer than that of CLS [20]. These
variations in reported operation times are likely attributable to the differences in the
robotic system, the use of either a totally robotic or hybrid technique, use of single
or dual docking to the patient cart, and the early phase of the RALS learning curve.
Additionally, a meta-analysis by Yang et al. reported a lower estimated blood loss
volume in the RALS group, compared to the CLS group [18]. However, other meta-
analyses reported comparable blood losses between the two groups [15, 17, 21].
5.3.2 Conversion
Conversion from CLS has been reported to negatively influence postoperative com-
plications [22] and overall survival [23]. Therefore, a lower conversion rate is an
important predictor of the feasibility of CLS or RALS. To date, many previous
reports described a lower conversion rate with RALS, compared to CLS [24–27]. A
recent systematic review or meta-analysis also observed a lower conversion rate in
the RALS group, compared to the CLS group [28–31]. However, the ROLARR
trial, which assessed the conversion rate as the primary endpoint, demonstrated that
RALS did not significantly reduce the risk of conversion to open surgery (RALS
8.1% vs. CLS 12.2%, p = 0.158). That trial assumed a 25% conversion rate in the
CLS group, which would require a sample size of 400 patients to demonstrate a
50% relative reduction in the conversion rate with RALS. However, the actual con-
version rate in the CLS group was much lower, at 12.2%. Accordingly, the ROLARR
trial may have failed to detect a clinically relevant difference.
The authors of the ROLARR trial also discussed the surgeon’s level of experi-
ence, noting that the surgeons had performed a mean of 152.5 (±178.38) previous
laparoscopic operations and 67.9 (±48.75) operations robotic operations prior to

randomization of the first trial patient. Therefore, the surgeons in the CLS group
were considered experts, whereas those in the RALS group might still have been
participating in the learning phase. A subgroup analysis from the ROLARR study
revealed possible benefits in male patients, suggesting that RALS may be particu-
larly effective in technically demanding cases.
5.3.3 Postoperative complications
In a previous study, Baik et al. reported a significant difference in the serious com-
plication rates (excluding back pain and scrotal swelling) between the RALS and
CLS groups (5.4% vs. 19.3%, p = 0.025) [27]. Similarly, a meta-analysis by Sun
et al. reported a lower overall complication rate in the RALS group, compared to the
CLS group [31]. However, the majority of other meta-analyses reported comparable
results between the two groups [16–19, 21].
5.3.4 Functional Outcomes
Urinary and sexual dysfunction, which affect the patient’s postoperative quality of
life, are largely attributable to pelvic autonomic nerve injury. Kim et al. reported
that RALS with TME was associated with an earlier recovery of normal urinary and
sexual functions, compared to CLS [32], while Panteleimonitis et al. reported better
postoperative urological and sexual outcomes in male patients and better urological
outcomes in female patients with RALS, compared to CLS [33]. Similarly, a meta-
analysis by Broholm et al. demonstrated that the 3- and 12-month International
Prostate Symptom Scores favored RALS, as did the 3- and 6-month International
Index of Erectile Function follow-up scores [34]. However, the ROLARR trial
found no statistically significant difference between the RALS and CLS groups in
terms of bladder and sexual function scores at 6 months postoperatively [20].
However, the authors noted that the function scores had changed little between the
baseline and 6 months postoperatively, indicating the surgeons’ expertise with auto-
nomic nerve preservation and the infrequency of relevant bladder and sexual dys-
function. Moreover, the ROLARR trial did not publish data obtained at 3 and
12 months postoperatively.
A phase II randomized controlled trial by Kim et al. revealed no significant dif-
ferences in sexual function scores between the RALS and CLS groups at 3 weeks
and 3 months postoperatively; by contrast, the RALS group had a significantly bet-
ter score at 12 months [35]. These benefits in terms of urinary and sexual function
are likely related to the technological advantages of RALS, including the superior
free-moving multi-joint forceps, high-quality three-dimensional imaging, and
steady “traction and countertraction,” as these features allow easier recognition and
preservation of the pelvic autonomic nerves [24, 32–36].
5.4 Oncological Outcomes
The incompleteness of TME and positivity of the CRM are associated with the risk
of rectal cancer recurrence [37]. In a case-matched study, Kang et al. reported a
significantly lower rate of positive CRM in the RALS group, compared to the OS
group (4.2% vs. 10.3%, p = 0.034), but no significant difference between the RALS
and CLS groups (4.2% vs. 6.7%) [38]. By contrast, a meta-analysis by Xiong et al.
found that RALS was associated with a significantly lower positive rate of CRM,
compared with CLS (2.74% vs. 5.78%, p = 0.04) [17]. However, the ROLARR trial
reported that neither the rate of positive CRM (5.1% vs. 6.3%, p = 0.56) nor the
highest-standard plane of surgery (mesorectal plane) (76.4% vs. 77.6%, p = 0.14)
differed significantly between the RALS and CLS groups [20].
Regarding long-term oncological outcomes, most previous reports described
comparable results between the RALS and CLS groups [25, 26, 39, 40]. In a study
of matched patients with stage I–III rectal cancer, Kim et al. reported that 5-year
overall, cancer-specific, and disease-free survival rates of 90.5% and 78.0%
(p = 0.3231), 90.5% and 79.5% (p = 0.4465), and 72.6% and 68.0% (p = 0.6409) for
RALS and CLS with TME, respectively. However, a multivariate analysis identified
RALS as a significantly good prognostic factor for overall and cancer-specific sur-
vival, suggesting that this technique confers potential oncological benefits [41].
5.5 Costs
One of the main concerns regarding robotic systems involves the high costs of pur-
chasing and maintaining the equipment. Kim et al. reported that RALS yielded simi-
lar short-term outcomes as CLS at a higher cost; therefore, the cost-effectiveness of
RALS in terms of short-term perioperative outcomes could not be determined [42].
Interestingly, however, Byrn et al. reported decreases in operation times and direct
hospital costs as the surgeon’s experience increased [43]. The ROLARR trial, which
included a comparison of health care costs between the RALS and CLS groups,
found that the costs in the former (mean of £11,853 or $13,668) were significantly
higher than those in the latter (mean of £10,874 or $12,556; total mean differ-
ence = £980 or $1132, p = 0.02). Notably, the higher operative costs in the RALS
group were largely attributed to a longer mean use of the operating theater and
higher mean cost of instruments [20]. Therefore, the costs associated with robotic
systems must be reduced if robotic proctectomy is to be widely applied in the future.
5.6 Lateral Lymph Node Dissection
Mesorectal excision with lateral lymph node dissection (LLD) is indicated for
patients with clinical T3-4 low rectal cancer, in accordance with Japanese guide-
lines [44]. LLD is a technically difficult procedure because the lateral pelvic cavity
is narrow and anatomically complex. In a comparison of the short-term outcomes of

robotic-assisted laparoscopic LLD vs. open LLD [36], Yamaguchi et al. reported a
significantly longer operative time and significantly reduced blood loss in the RALS
group, compared to the OS group. Furthermore, the rates of wound infection, small
bowel obstruction, anastomotic leakage, and urinary retention were significantly
lower in the RALS group. Kim et al. reported better urinary function in the robotic-
assisted laparoscopic LLD group, compared to the conventional laparoscopic LLD
group [45], likely due to the superior magnification effect and steady traction and
countertraction of RALS, which reduce bleeding while facilitating recognition and
preservation of the pelvic splanchnic nerves and inferior hypogastric plexus.
Regarding oncological outcomes, Yamaguchi et al. observed a tendency toward a
lower positive resection margin rate in a robotic-assisted laparoscopic LLD group
vs. a matched open LLD group (p = 0.059), with respective 5-year local relapse-free
survival rates of 98.6 and 90.9% (p = 0.029) [46].
5.7 Future Prospects
Despite its advantages, the da Vinci surgical system could be improved in terms of
technology and cost. The introduction of other robotic technologies to the market
would reduce the cost of the da Vinci surgical system, which may improve the cost-
effectiveness of RALS over OS or CLS. The frequency of collision from each arms
or instruments will decrease after the introduction of smaller and thinner arms like
the da Vinci Xi system (Intuitive Surgical, Sunnyvale, CA, USA). Furthermore,
other technological advances, such as touch sensors, a remote operation support
system, artificial intelligence, single port system, or collaboration of various images,
are desired. These developments may subsequently shift the available evidence
regarding RALS.
5.8 Conclusions
RALS, a promising advanced technology, is expected to overcome the inherent

limitations of CLS for rectal cancer. Although previous studies of RALS have
reported similar or better short- and long-term outcomes when compared with CLS,
the high cost associated with RALS is an important issue. Furthermore, surgeons
should expand their indications for RALS safely and cautiously, given the relative
lack of high-level evidence. Accordingly, further evaluations of the short- and long-
term outcomes of RALS, including the patient’s quality of life and cost-effectiveness,
are needed to support the use of this technique.
Acknowledgement Disclosure: Tomohiro Yamaguchi and Yusuke Kinugasa have no conflicts of

interest or financial ties to disclose.
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Chapter 6
Intersphincteric Resection for Rectal
Adenocarcinoma Near the Anus
Yoshito Akagi and Fumihiko Fujita
Abstract Abdominoperineal resection (APR) is commonly performed as radical

surgical treatment for low rectal cancer near the anus. To improve the postoperative
quality of life (QOL), various sphincter-saving operations have been developed. In
particular, intersphincteric resection (ISR) was devised as a new concept of
sphincter-saving operation. Current protocols now focus on ISR, which differs from
conventional hand-sewn coloanal anastomosis (CAA) after ultimate low anterior
resection (LAR). However, the efficacy of ISR remains unclear. In this report, the
surgical, oncological, and functional outcomes after ISR are reviewed. This review
of the literature was conducted by searching the PubMed online database. Articles
focusing on conventional hand-sewn CAA were excluded from this study. The mean
mortality rate was <2%, and the mean morbidity rate ranged from 7.5 to 38.3%. The
mean local recurrence rate has varied widely from 0 to 22.7%. The mean disease-
free survival rate was 69–86 months, and the overall 5-year survival rate was 76–97
months. The functional outcomes have not been excellent but were generally accept-
able, although the resting pressure gradually recovered with time. An accurate eval-
uation of the outcomes is extremely difficult due to the difference among individuals
and the absence of any unified appraisal methods. ISR appears to be surgically,
oncologically, and functionally acceptable. However, more experience and knowl-
edge of the oncology, anal physiology, and pelvic anatomy are necessary to achieve
successful outcomes without complications, and to improve patient survival.
Keywords Intersphincteric resection (ISR) · Intersphincteric space (ISS)

Coloanal anastomosis (CAA) · Low rectal cancer
Y. Akagi (*) · F. Fujita

Department of Surgery, Kurume University School of Medicine, Kurume, Japan
e-mail: yoshisg@med.kurume-u.ac.jp; ffujita@med.kurume-u.ac.jp

60 Y. Akagi and F. Fujita
6.1 Introduction
The surgical treatment for rectal cancer is generally determined by the tumor loca-
tion and by the degree of tumor extension. Abdominoperineal resection (APR) has
been used for a long time as the standard procedure for very low rectal cancer.
Improvements in surgical devices and techniques have enabled anal preservation
after resection. Very low anterior resection followed by hand-sewn coloanal anasto-
mosis (CAA) was introduced as a procedure to preserve the anus for lower rectal
cancer in 1972 [1]. However, APR is commonly applied when preservation of the
anus is technically impossible. Careful resection is required for cancers located near
the anus, because it is important to secure safe distal and radial margins. Surgical
treatment for low rectal cancer must seek a balance between curability and func-
tional preservation. Recent studies have encouraged surgeons to adopt an anus-
preserving technique with sphincter muscle resection. In 1994, Schiessel introduced
the intersphincteric resection (ISR) followed by hand-sewn CAA as an anal preser-
vation procedure for rectal cancer near the anus [2]. The ISR is initiated to avoid
permanent colostomy for very low rectal cancers which might previously have
required APR. This procedure has now become widely applied around the world
since the beginning of this twenty-first century [3–5]. The present review set out to
investigate the surgical, oncological, and functional outcomes after ISR based on
findings published in the past two decades.
6.2 Definition of ISR
The “real” ISR partially or totally resects the internal sphincter (IS) at the anal canal
followed by dissecting the intersphincteric space (ISS) (Fig. 6.1). The term “inter-
sphincteric resection (ISR)” was adopted by Lyttle in 1977 to mean a resection of
the IS for inflammatory bowel disease [6]. In addition, ISR is a procedure involving
Fig. 6.1 Anatomy in ISR.

LAM levator ani muscle,
ES external sphincter,
IS internal sphincter,
ISS intersphincteric space, LAM
DL dentate line, ISG
intersphincteric groove
ES
IS DL
ISG
ISS
hand-sewn CAA accompanied by IS resection, and without use of mechanical anas-

tomosis. In brief the “real” ISR is to divide the IS transabdominally and transanally
from the external sphincter (ES) by dissecting the ISS. Some surgeons have inten-
tionally reported conventional hand-sewn CAA as a subtype of partial-ISR. This is
why “real” ISR must be discriminated from conventional hand-sewn CAA and LAR
with IS resection. Thus, the ISR is defined as the surgical procedure specifically for
the IS removal followed by hand-sewn CAA. Schiessel has subsequently classified
the ISR procedure into two types as subtotal-ISR or total-ISR [2]. In Japan, the
study group defined total-ISR as resecting the IS at the intersphincteric groove
(ISG), subtotal-ISR as resecting the IS between the dentate line (DL) and ISG, and
partial-ISR as resecting the IS at the DL [7].
6.3 Surgical Technique
The following briefly describes the procedure of ISR. The rectum is mobilized
according to the concept of total mesorectal excision (TME) [8] down to the attached
level of the levator ani muscle (LAM). Dissection in the ISS between the LAM and
puborectalis is performed as low as possible, after transecting the hiatal (anococ-
cygeal) ligament (Fig. 6.2a). Then dissection is advanced via the transanal approach.
Circular incision of the anal canal is started. IS is dissected from the ES, and then
dissection is connected to the transabdominal dissection (Fig. 6.2b). After the lesion
is taken out from the anus, then hand-sewn CAA is performed using straight colon
[9–11], J-pouch [12, 13], or coloplasty [14] (Fig. 6.2c).
6.4 Patients and Methods
Published articles were collected by searching the PubMed online database for origi-
nal articles reporting ISR. In some studies, the cases involving conventional hand-
sewn CAA (Parks’ method) [1] and ultralow anterior resection with stapled
a b c
LAM
IS ISS ES IS
Fig. 6.2 Procedure of ISR. (a) Division of the IS transabdominally and transanally by dissecting
the ISS. (b) Removal of the specimen with total or partial IS resection. (c) Transanal hand-sewn
CAA
anastomosis were included. These articles which do not focus on “real” ISR as defined
by Schiessel [2] were excluded. As a result, for this review, the data of surgical, onco-
logical, and functional outcomes were gathered from twenty-three articles [6–28],
because each article presented different patients. If a same series of patients or research
was identified, then only the study with the most comprehensive data was included.
6.5 Results
6.5.1 Patient and Tumor Characteristics
The available data were extracted and are summarized in Table 6.1. The mean dis-
tance of the tumor from the anal verge was 30~35 mm. The most common tumor for
which ISR was carried out was rectal adenocarcinoma located at 10~50 mm from
the anal verge and with depth of tumor invasion at T1-3. Poorly differentiated
Table 6.1 Patient and tumor characteristics

Sex Distance from AV
Author Ref # Year Patients Age/years (M/F) [DL]/mm T category
Köhler [9] 2000 31 60 17/14 13 ± 9 [DL] T1-T3
Vorobiev [16] 2004 27 55 (26–75) 16/11 10 (5–15) [DL] T2-T3
Schiessel [10] 2005 121 65/62 83/38 30 (10–50) T1-T3
(M/F)
Rullier [23] 2005 92 65 (25–86) 57/35 30 (15–45) T1-T3
Hohenberger [24] 2006 65 NR NR <20 [DL] T1-T2
Chin [12] 2006 18 61 (42–79) 7/11 10–30 [DL] T2-T3
(T4)
Saito [11] 2006 228 58 (27–77) 168/60 34 (20–50) T1-T3
(T4)
Chamlou [13] 2007 90 59 (27–82) 59/31 35 (22–52) T1-T3
(T4)
Portier [25] 2007 173 64 57/116 41 ± 1.4 T1-T3
(T4)
Krand [14] 2009 47 57 (27–72) 31/16 33 (15–50) T2-T3
Saito 2009 132 57 (27–80) 97/35 35 (15–50) T1-T3
(T4)
Han [15] 2009 40 62 (34–73) 24/16 20–50 [DL] T1-T-2
Weiser [55] 2009 44 54 (28–78) 25/19 50 (30–60) T3-T4
Akagi [27] 2013 83 65 (28–91) 48/35 30 (10–50) T1-T3
(T4)
Saito [17] 2014 199 59 (27–80) 144/55 35(10–55) T1-T4
Kanso [28] 2015 85 59 (32–82) 62/23 0–35 [DL] T0-T4
Ref # reference number (available data are summarized); M male, F female, AV anal verge,
DL dentate line, NR not reported
adenocarcinoma or a suspected T4 depth of tumor invasion was contraindication in

some articles. Moreover, ISR was not indicated for patients with distant metastasis,
poor anal function, or mental disease. Determinations of the tumor location and the
depth of invasion were commonly done using endoscopy, barium enema, computed
tomography (CT), and/or magnetic resonance imaging (MRI). The mobility of the
tumor was confirmed by digital examination via the transanal approach, although
this was subjective.
6.5.2 Surgical Procedures
The available data are extracted and shown in Table 6.2. Many reports showed that
preoperative chemoradiotherapy (CRT) was performed for the rectal cancer. Partial-
ISR and subtotal-ISR were commonly performed. Total-ISR was frequently per-
formed for selected patients in several reports. ISR combined with external sphincter
resection (ESR) was required for tumors with suspected invasion into the ISS and/
or the ES [4, 29]. Straight anastomosis was performed more often than transverse
coloplasty, J-pouch, and other methods. Finally, diverting ileostomy or colostomy
was added in most cases.
Table 6.2 Surgical procedures

Pre-op Method of ISR Pouch Diverting
Author Patients CRT (%) P-ST/T/ESR Anastomosis (%) Stoma (%)
Köhler 31 0 31/0/0 0 100
Vorobiev 27 7 0/27/0 100 (C-pouch) 100
Schiessel 121 0 Almost P-ST, T 0 100
Rullier 92 88 Almost P-ST, T 57 100
Hohenberger 65 65 Almost P-ST Sometimes 100
Chin 18 33 NR 100 100
Saito 228 25 159/69 (T & ESR) 22 NR
Chamlou 90 41 Almost P-ST 100 100
Portier 173 53 Almost P NR 100
Krand 47 100 47/0/0 40 (coloplasty) 100
Saito 132 36 105 (P-ST & T)/27 NR 100
Han 40 2.5 35/5/0 18 28
Weiser 44 100 44/0/0 48 NR
Kuo 26 88 26/0/0 0 100
Akagi 83 1.2 17/34/32 30 100
Laurent 175 90 119/56/0 NR 100
Kanso 85 84 64/21/0 0 100
Pre-op CRT preoperative chemoradiotherapy, ISR intersphincteric resection, P partial, ST subtotal,
T total, ESR external sphincter resection (ISR with combined resection of partial or extended exter-
nal sphincter), NR not reported
Table 6.3 Postoperative complications Complication Range (%)

Mortality 0–1.7
Leakage 3.8–48
Vaginal fistula 0–19.4
Vesical fistula 0–0.8
Colonic ischemia (necrosis) 0–14.3
Sepsis 0–8.7
Pelvic abscess 0–8.1
Pelvic hematoma 0–6.5
Ileus (bowel obstruction) 0–15.4
Stenosis 4.8–23.3
Unable to divert stoma closure 0–12.5
Additional surgerya 0–12.9
Overall 7.5 –38.3
Available data are summarized
a
Abdominoperineal resection, Hartmann’s proce-
dure, and/or re-creation of stoma were required
because of postoperative surgical and/or functional
complications
6.5.3 Postoperative Complications
The available data are summarized in Table 6.3. The rate of overall complications
varied widely from 7.5 to 38.3%. Morbidities included anastomotic leakage, pelvic
abscess, ischemic colitis, ileus, ano-vaginal fistula, and others. Anastomotic leakage
occurred with a wide range of frequencies, and subsequent stenosis was observed
within a range from 4.8 to 23.3%. Operative mortality was rare, in the range 0–1.7%.
6.5.4 Oncologic Outcomes
The oncologic outcomes are summarized in Table 6.4. The rate of pathologic radical
(R0) resection is over 90%. The distal resection margin (DRM) was maintained at a
minimum of 5 mm. The frequency of a circumferential resection margin (CRM)
≤1 mm ranged from 4 to 19.6%. The overall recurrence rate, distant metastasis, and
local recurrence (LR) ranged from 13.3 to 28.8%, 0 to 24%, and 0 to 22.7%, respec-
tively. The disease-free and overall 5-year survival rates were both fine, with ranges
of 69–86%, and 79–97%, respectively.
6.5.5 Functional Outcomes
There are many reports for the anal function with assessment at 1 year after stoma
closure. The available data are summarized and shown in Table 6.5 [6, 7, 9–15,
18–22]. Anorectal manometric examination was used for an objective assessment of
Table 6.4 Oncologic Oncologic item Range

outcomes (available data are
TNM stage: I/II/III/IV (%) 0–58/4–63/16–86/0–7
summarized)
R0 resection (%) 90–100
Distal resection margin (DRM)/mm 5–40
Circumferential resection margin 4.0–19.6
(CRM) ≤1 mm (%)
Median follow-up/months 12–110
Overall recurrence (%) 13.3–28.8
Distant metastasis (%) 0–24
Local recurrence (%) 0–22.7
Disease-free 5-year survival (%) 69–86
Overall 5-year survival (%) 76–97
Table 6.5 Functional outcomes (available data were summarized)

Assessment at 1 year after stoma closure
Mean maximum resting pressure/cmH2O 4–75
Mean maximum squeeze pressure/cmH2O 20–259
Median stool frequency/24 h 1.8–6
1–3 (%) 46–85
4–5 (%) 12–57.1
>5 (%) 0–36
Stool fragmentation (%) 15–81
Urgency (<15 min) (%) 2–83
Incontinence for flatus (%) 7.7–72.8
Nocturnal soiling (%) 16–92
Daytime soiling (%) 22–92
Pad wearing (%) 19–57
Feces and flatus discrimination (%) 4–88
Anti-diarrhea medication (%) 0–33.3
Mean Wexner score (range) 2.8–12
Kirwan grade (%)
Grade I (perfect) 13.9–84.6
Grade II (incontinence of flatus) 7.7–36.6
Grade III (occasional minor soiling) 3.8–38.6
Grade IV (frequent major soiling) 0–27
Grade V (requiring colostomy) 0–5.9
Patient satisfaction (%)
Very low 9–18
Medium 19
Perfect (almost) 72
anal function in some studies. The mean maximum resting pressure (MRP) which
represents the contraction of IS ranged from 4 to 75 cmH2O. The mean maximum
squeeze pressure (MSP) which represents the contraction of ES ranged from 20 to
259 cmH2O. The MRP was lower than the base line (70~130 cmH2O) in most
reports. In a subjective assessment, the rates of stool fragmentation, urgency,
nocturnal soiling, daytime soiling, and pad wearing were high. The Wexner score
(in which the maximum 20 points is worst) was <12, and the Grade IV or V in
Kirwan classification (in which the relatively better assessment is grade I or II) was
not so high rates.
6.6 Discussion
Reports of ISR for very low rectal cancer near the anus have increased during the
past two decades around the world. Investigation into the actual state of complica-
tions, functional disorders, and prognosis after ISR is required in order for ISR to be
accepted as the new standard surgical procedure. This article has reviewed the surgi-
cal, oncological, and functional outcomes from only “real” ISR which is consistent
and depends on the original idea and procedure by Schiessel.
6.7 Surgical and Oncological Outcomes
The overall morbidity varied widely and up to 38.3%, while operative mortality was
rare. Anastomotic leakage was the most common complication, and subsequent ste-
nosis was seen. However, critical conditions such as pelvic abscess and/or sepsis
were few. The most reported cause of leakage was likely colonic ischemia due to a
narrow anal canal and the tension of the reconstructed colon. Patient indication for
this operation should be carefully determined because of the expectable decrease in
quality of life (QOL) and the possibility for local recurrence (LR). A patient with
long anal canal or presenting obesity including much visceral fat may be contrain-
dicated. The LR rate varied from 0 to 22.7%. These results are lower than those in
previous reports that showed a higher rate in APR (10–57%) for mid or low rectal
cancer [5, 15, 30]. The disease-free and overall 5-year survival (OS) rates were fine,
with ranges from 69 to 97%. These results are mostly consistent with or not mark-
edly different from those after APR or conventional CAA [13, 25–27, 29, 31, 32]
(although Saito et al. showed significant differences in OS between ISR and APR)
[26]. These results suggested that ISR was acceptable oncologically. We should
deeply engrave in our mind that any development of anastomotic leakage was asso-
ciated with a poorer prognosis even when surgery was performed curatively [33].
6.8 Functional Outcomes
Stool frequency, fragmentation, urgency, soiling, and fecal incontinence are known
as “low anterior resection syndrome (LARS)” and were generally found after
sphincter-saving operations for rectal cancer [34, 35]. Complaints in bowel
movement after ISR were similarly quite general. The subjective assessment of anal
function is often done using the Kirwan grade [36] and the Wexner score [37]. The
Kirwan grade and Wexner score showed relatively good assessments. Anorectal
manometric examination is used as an objective assessment of anal function. The
MRP is mainly affected by the internal sphincter and in part by the external sphinc-
ter [38]. A degradation in MRP is reasonable after the IS was removed. MRP gradu-
ally recovered over time, but did not recover completely [2, 3, 5]. Dysfunction in
bowel movement recovered much later after several years [10, 11]. Besides the sur-
gical technique, the factors associated with anal dysfunction include age, sex, eating
habits, life style, and so on. Preoperative CRT is a standard therapy for low rectal
cancer in western countries, as preoperative CRT affects the down-sizing of the
tumor and avoids a positive CRM and LR. However, preoperative CRT induces
bowel function [21, 39–42]. Reconstruction type such as straight anastomosis and
pouch operation also relate to the bowel function [21, 39–43]. Anorectal manomet-
ric findings do not always accurately reflect the symptoms. Other studies are
required in the future, as there is no accurate examination.
6.9 Indication to ISR
Careful pre-selection of patients for ISR is required. The choice of surgical proce-
dure depends on a balance between radicality and functional disorder. The DRM
and CRM should be safely maintained without residual cancer cells to avoid LR
after ISR. The recurrent site most feared after ISR is the pelvic cavity including the
anastomotic site. Better understanding of high-risk DRM and CRM is useful for
successful surgery. In this review, the indication of the oncologic inclusion criteria
is as follows: (1) the distance between the anal side of the tumor wedge and the anal
verge is >30 mm, and (2) the depth of tumor invasion is T1-T3.
In DRM, the distal spread in rectal cancer rarely exceeded 10 mm by previous
histological examination [44–46]. When preoperative CRT was performed, DRM
decreased to 5~10 mm [32, 47, 48]. From these results, DRM ≥10 mm is thought to
be safe and reasonable when ISR is applied.
CRM is well known as an indicator for LR [49]. In ISR, CRM around the anal
canal is likely to represent a risk factor for LR, when the tumor is located on or
beyond the dentate line (DL), because of a higher rate of ISS invasion [27]. Therefore
correct evaluation of the extent of tumor invasion into the anal canal complex is
essential before surgery. Salerno et al. reported that MRI can predict the extent of
invasion into the ISS [50]. In contrast, Dent et al. have reported that MRI cannot
predict histological tumor involvement of CRM [51]. Digital examination is impor-
tant for evaluating tumor mobility and for making a final surgical decision [15, 23,
25], though it is subjective.
ISR absolutely is applicable for tumors located within 5 cm from the anal verge
with good mobility. However, there needs to be the option of pre-selecting ISR
cases. This procedure may sometimes be very difficult in obese patients and/or in
male patients with a narrow pelvis. Enough time to inform these results after ISR to
the patient is needed before surgery. Expert knowledge of anal anatomy and physi-
ology is required, so only surgeons with sufficient experience in pelvic surgery
should perform this procedure.
Recently, many colorectal surgeons perform laparoscopic low anterior resection
(LAR) for rectal cancer, and no difference in the safety and efficacy has been dem-
onstrated between laparoscopic LAR and open LAR [52]. Laparoscopic ISR will
therefore be increasingly performed as the view of the pelvic diaphragm is improved
by new technical advances in laparoscopic surgery [53, 54].
6.10 Conclusion
The ISR procedure has demonstrated acceptable surgical and oncological safety,
with low risk to mortality. However, future surgical techniques could further
improve the anal function, and better objective assessments of anal function could
be developed. Additional diagnostic techniques for safe CRM and assessment of
QOL may be necessary.
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Chapter 7
Chemoradiation for Rectal Cancer
Keiji Koda
Abstract Chemoradiation therapy (CRT) is a component of various rectal cancer

treatments. Preoperative CRT is administered in combination with local excision
when the depth of invasion is limited to the muscle layer (cT2). It is also adminis-
tered in combination with total mesorectal excision (TME) when the tumor is of
higher T stage or N-positive and curative resection is anticipated. In Japan, lateral
pelvic lymph node dissection (LLND) is often performed without preoperative CRT
when a rectal cancer of T3 stage or greater depth of invasion is located below the
peritoneal reflection. When there is a risk of a positive circumferential margin or the
tumor is T4, preoperative CRT is performed with the aim of making the resection
curative. Total pelvic exenteration is often performed in Japan when massive tumor
invasion of the genitourinary organs is suspected. The “watch-and-wait” strategy
when clinical CR has been achieved is to be evaluated further.
Keywords Chemoradiation therapy · Rectal cancer · Chemotherapy

Local excision · Total mesorectal excision · Lateral pelvic lymph node dissection
Watch-and-wait
7.1 Introduction
Preoperative chemoradiation therapy (CRT) is widely used to treat rectal cancer.

The chemotherapy recommended for CRT is either capecitabine, infusion of
5-fluorouracil (5-FU), or bolus 5-FU plus leucovorin [1]. When combined with che-
motherapy, the dosage of radiation therapy is commonly 45–50 Gy in 25–28 frac-
tions. If the cancer is resectable, a tumor bed boost with 5.4 Gy in three fractions to
a 2-cm margin is considered after 45 Gy has been administered. Short course radia-
tion therapy (25 Gy in five fractions) may also be administered.
K. Koda (*)
Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba, Japan
e-mail: k-koda@med.teikyo-u.ac.jp

72 K. Koda
The indications for preoperative CRT for rectal cancer include: (A) planned local
excision of a cT2 tumor [2]; (B) planned total mesorectal excision (TME) for T3
with any N status or T1–2 with N1–2 [1]; and (C) planned TME for a T3 tumor that
is suspected to be circumferential margin positive or a T4 tumor diagnosed preop-
eratively by magnetic resonance imaging (MRI). CRT is also indicated for locally
unresectable or medically inoperable cancers [1]. Resectable isolated pelvic recur-
rences may be candidates for preoperative CRT. Chemotherapy alone prior to
administering CRT is recommended for T3 or more deeply invasive and node-
positive cancers. In such cases, the recommended chemotherapy regimens are either
FOLFOX or CAPEOX, 5-FU/LV, or capecitabine [1]. When lateral sidewall lymph
nodes are involved, lateral lymph node dissection (LLND) is routinely performed in
Japan; however, this is the procedure rarely performed in Europe or the USA unless
lymph nodes have remained enlarged following CRT.
7.1.1 CRT with Local Excision
Although this is not supported by strong evidence, CRT with local excision is an
option for cT2 cancers less than 4 cm, located within 8 cm of the anal verge, and
involving less than 40% of the circumference of the rectum [3]. This treatment
option is not described in the NCCN guidelines [1]. Recently, several reports regard-
ing the oncological safety of this approach [3, 4] have indicated that functional
outcomes, including anorectal and sexual function, may not be as well preserved as
had been expected for radiotherapy plus local excision [5]. Transanal endoscopic
microsurgery (TEM) is the recommended technique for local excision [2]. When the
tumor has been curatively removed, the recurrence rate is reportedly approximately
10% [3]. When pathological complete response (pCR) or near pCR has been
achieved by CRT, the postoperative outcome is reportedly satisfactory [4]. A ran-
domized clinical trial comparing local excision using TEM with TME following
CRT in 100 patients found that the postoperative incidence of both local recurrence
and distant metastasis did not differ between these treatment groups [6]. Further
studies are needed regarding this treatment strategy.
7.1.2 CRT with TME
In patients with T2 cancer with adverse pathological features, such as poorly dif-
ferentiated histology or vessel invasion, or in those with shallow T3 invasion (T3a/
T3b, <5 mm) without clear involvement of the mesorectal fascia (MRF), surgery
alone is recommended in the ESMO guidelines. In contrast, the NCCN guidelines
recommend that all T3 cancers and T1–2 cancers with node involvement are treated
by CRT or chemotherapy followed by CRT, after which transabdominal surgery is
performed provided there are no contraindications to it. The treatment algorithms
for cT2 and cT3 rectal cancers are summarized in Figs. 7.1 and 7.2.
7 Chemoradiation for Rectal Cancer 73
Clinical CR
(optional)
cT2 rectal cancer CRT Watch-and-wait
Adverse pathological features* Local excision Recurrence
Pathological exam*
Recurrence
Transabdominal resection (TME)
Fig. 7.1 Treatment options for cT2 rectal cancer. *Adverse pathological features include histopa-
thology of the tumor (G3) and vessel invasion
cT3 rectal cancer CT ® CRT
or
CRT
*
Enlarged lateral nodes Enlarged lateral nodes
TME
TME + LLND**
Fig. 7.2 Treatment options for cT3 rectal cancer. *Recommended in ESMO guidelines when
cT3a/b without clear involvement of MRF. **Performed routinely in Japan
7.1.3 Borderline Resectable, Locally Advanced Rectal Cancer
When a T3 cancer has invaded deeply and is MRF-positive or tumor is T4, an ade-
quate resection margin can be hard to achieve. In such cases, preoperative CRT
with/without preceding chemotherapy is recommended by both the NCCN and
ESMO guidelines, the aim being to achieve sufficient tumor shrinkage to achieve an
adequate margin [1]. Adjuvant chemotherapy is recommended after tumor resection
unless preoperative chemotherapy has been administered [1].
Unresectable/borderline cancers that cannot be curatively resected without mul-
tivisceral resection are often diagnosed by MRI. In Japan, total pelvic exenteration
(TPE) with en bloc pelvic side wall dissection is often performed for cT4b rectal
74 K. Koda
cT4 rectal cancer CT ® CRT
or Chemotherapy
CRT
Massive invasion of
genitourinary organs Tumor shrinkage
TME Massive invasion of

genitourinary organs
Total pelvic exenteration*
Fig. 7.3 Treatment options for cT4 rectal cancer. *Performed in selected cases
cancer and can achieve favorable outcomes in selected patients [7]. According to the
NCCN and ESMO guidelines, CRT is the standard therapy for those cancers, the
aim being to shrink the tumor sufficiently to enable R0 resection. If resection is still
contraindicated on completion of CRT, additional systemic therapy is recommended
(Fig. 7.3).
7.1.4 Lateral Pelvic Lymph Node Dissection and CRT
In Japan, lateral pelvic lymph node dissection (LLND) is performed routinely for
lower rectal cancer with a depth of invasion of T3 or deeper [8]. The incidence of
lateral node metastasis from rectal cancers located below the peritoneal reflection is
reportedly 7.7% in T3, 18% in T4a, and 29% in T4b [9]. The survival rate of patients
who undergo LLND without CRT and have histologically positive lymph node
metastases is reportedly approximately 50% [10]. Recently, laparoscopic [11, 12] or
robotic [13] LLND has been performed with favorable outcomes.
Whether chemoradiotherapy (CRT) can be substituted for LLND in patients with
histologically proven lateral node metastases has not yet been determined. However,
recent studies have shown that, even after CRT, approximately half the patients who
had initially been diagnosed as having lateral node metastases still have pathologi-
cally proven metastasis-positive lymph nodes when they undergo LLND [14]. Thus,
curative LLND may be necessary when enlarged lateral pelvic lymph nodes sus-
pected of harboring metastases persist after CRT.
A randomized controlled study has recently evaluated prophylactic LLND in
patients with clinical stage II/III low rectal cancer without lateral node enlargement.
These researchers found that the local recurrence rate was significantly better in the
LLND group (7.4%) than the TME alone group (12.6%). However, neither relapse-
free nor overall survival was superior in the LLND group [15].
7.1.5 Local Recurrence and CRT
When there is an isolated local recurrence of rectal cancer in the pelvis, resection
may be considered. If CRT has not already been administered, preoperative CRT
may be considered. Transabdominal surgeries such as abdominoperineal resection
(APR) or total pelvic exenteration (TPE) [16] can be performed when feasible.
7.1.6 Management of Clinical Complete Response in CRT
The treatment strategy for rectal cancers that achieved clinical complete response
(cCR) by CRT is controversial. The “watch-and-wait” approach [17] has become an
attractive alternative that could avoid postoperative comorbidities associated with
transabdominal surgery such as defecatory malfunction, urinary or sexual dysfunc-
tion, and colostomy. Pathological complete response after CRT was reported to be
achieved in 15% of patients that received TME following CRT in a large-scale
review [18]. It is also reported that the rate of pathological CR increases up to 31%
as the interval from CRT to surgery lengthens [19]. Although it has not been deter-
mined by large-scale prospective studies, overall survival is suggested to be similar
in the “watch-and-wait” approach to immediate surgery [4], although disease-free
survival is reported to be better in the surgery group [20]. It is reported that approxi-
mately 50% of cCR cases sustain complete response after 56 months of the “watch-
and-wait” approach [21]. In addition, most of the cases that have regrowth had
successful salvage surgery [20, 22]. The rate of pCR among cCR differs signifi-
cantly between reports; therefore, improvement of diagnosis and close follow-up
after “watch-and-wait” for cCR patients are warranted.
7.1.7 P
reoperative CRT and Postoperative Defecatory,
Urinary, and Sexual Functions
It has been reported that postoperative anal function is damaged by preoperative

radiation therapy when sphincter preserving operation (SPO) is performed. Both
anal resting pressure and anorectal sensations are reported to be impaired by radia-
tion therapy [23]. When compared with SPO without radiation therapy, postopera-
tive bowel function is worse [24, 25], resulting in a higher low anterior resection
76 K. Koda
syndrome (LARS) score in SPO with preoperative radiation therapy [26]. Male
sexual function is reported to be impaired more when preoperative radiation therapy
is applied [24, 27].
7.2 Conclusions
Surgical treatment of rectal cancer is often completed in combination with

CRT. Because positive circumferential resection margin and lymph node metastasis
are closely associated with local recurrence and overall survival, preoperative CRT
is expected to achieve better postoperative outcomes. However, adverse events asso-
ciated with CRT, such as radiation-induced injury, and postoperative defecatory and
sexual dysfunction, should be taken into account when administering preoperative
CRT to individual patients. Intensive preoperative evaluation of the cancer stage
with several examination modalities (endoscopy, CT, MRI) is necessary, together
with informed consent from patients.
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analysis of individual patient data. Lancet Oncol. 2010;11(9):835–44.
19. Macchia G, Gambacorta MA, Masciocchi C, Chiloiro G, Mantello G, di Benedetto M, et al.
Time to surgery and pathologic complete response after neoadjuvant chemoradiation in rectal
cancer: a population study on 2094 patients. Clin Transl Radiat Oncol. 2017;4:8–14.
20. Dossa F, Chesney TR, Acuna SA, Baxter NN. A watch-and-wait approach for locally advanced
rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a sys-
tematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2017;2(7):501–13.
21. Habr-Gama A, Sabbaga J, Gama-Rodrigues J, Sao Juliao GP, Proscurshim I, Bailao Aguilar
P, et al. Watch and wait approach following extended neoadjuvant chemoradiation for dis-
tal rectal cancer: are we getting closer to anal cancer management? Dis Colon Rectum.
2013;56(10):1109–17.
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lowing “watch and wait” for rectal cancer after neoadjuvant therapy: a systematic review. Dis
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Part III
Chemotherapy
Chapter 8
Adjuvant Chemotherapy
Toshiaki Ishikawa and Hiroyuki Uetake
Abstract Recent remarkable advances in chemotherapy for colorectal cancer are

adding new knowledge to adjuvant chemotherapy, but it is not the case that recur-
rence can be prevented in all patients who undergo this treatment. Treatment should
be selected based on the evidence from clinical trials. Herein we present a review of
the development of systemic chemotherapy for colorectal cancer (CRC) in the adju-
vant treatment settings.
Adjuvant treatment with a fluoropyrimidine plus oxaliplatin has been the stan-
dard of care for resected stage III colon cancer. It has been suggested that stage III
CRC consists of subgroups of patients with various prognoses and the expected
benefits of L-OHP could vary according to subgroup stage. Oral fluoropyrimidine
alone treatment might be a considerable option for low-risk patients. Adjuvant treat-
ment for elderly patients who have formerly been excluded from clinical trials must
be considered. Although the usefulness of adjuvant chemotherapy for stage II colon
cancer remains controversial, guidelines recommend adjuvant chemotherapy for
patients with high-risk features.
In rectal cancer, the efficacy of adjuvant chemotherapy has not been established.
Although conclusive evidence of the benefits of adjuvant therapy in patients with
rectal cancer is unclear, adjuvant chemotherapy is recommended for patients with
stage II and stage III rectal cancer.
For resectable metastatic disease, there is no standard treatment and the effective
role of systemic adjuvant chemotherapy remains controversial. However, the cur-
rent international guidelines recommend an adjuvant treatment for patients with
initially resectable metastatic disease.
It is necessary to establish the optimal adjuvant chemotherapy corresponding to
the conditions of individual patients.
Keywords Adjuvant chemotherapy · Stage III · Stage II · Fluoropyrimidine

Oxaliplatin · Elderly patients · High risk · Biomarker · Biological targeted agents
T. Ishikawa (*) · H. Uetake

Department of Specialized Surgeries, Tokyo Medical and Dental University,
Graduate School of Medicine and Dentistry, Tokyo, Japan
e-mail: ishi.srg2@tmd.ac.jp

82 T. Ishikawa and H. Uetake
8.1 Introduction
The prognosis for resectable colorectal cancer is improved, and curative resection
appropriate to the stage of colorectal cancer offers a high cure rate. Once an unre-
sectable recurrence develops, however, cure is difficult to achieve even if several
different treatment modalities are used, including chemotherapy. The goal of post-
operative adjuvant chemotherapy is to prevent recurrence after curative surgery and
improve prognosis. Recent remarkable advances in chemotherapy for colorectal
cancer are adding new knowledge to postoperative adjuvant chemotherapy, but it is
not the case that recurrence can be prevented in all patients who undergo this treat-
ment, and many patients are cured without undergoing postoperative adjuvant che-
motherapy. Treatment should be selected based on the evidence from clinical trials.
Also, the search for molecular biological biomarkers capable of identifying patients
who will benefit from postoperative adjuvant chemotherapy should perhaps be a
focus of attention. The advent of an increasingly aging society also raises the ques-
tion of how to treat very elderly patients who have formerly been excluded from
clinical trials. In this chapter, we provide an overview of the advances in adjuvant
chemotherapy for colorectal cancer and its current status.
8.2 Adjuvant Chemotherapy for Colon Cancer
Although local failure rates are very low in colon cancer patients undergoing poten-
tially curative resection, systemic recurrence of the disease following surgery is
frequent and is very often the ultimate cause of death. Adjuvant therapy is a sys-
temic treatment administered after primary tumor resection with the aim of reduc-
ing the risk of relapse and death. Because not all the patients get the benefits of
adjuvant chemotherapy, decision on adjuvant treatment must be based on thorough
discussion with the patient. Each treatment option, including observation alone,
should be discussed with the patient, taking account of prognostic aspects of the
tumor disease, performance status, age, comorbidities, and the individual’s prefer-
ences. Generally, adjuvant treatment is recommended for stage III and “high-risk”
stage II patients in guidelines for the management of colorectal cancer [1–3].
8.2.1 Stage III Colon Cancer
Adjuvant chemotherapy is well established in stage III colon cancer. Adjuvant che-
motherapy is recommended to all eligible patients with stage III disease. Treatment
options for adjuvant chemotherapy are displayed in Table 8.1. Following surgery,
the standard treatment is a doublet schedule with oxaliplatin and a fluoropyrimidine.
In case of clinically relevant neurotoxicity, oxaliplatin should be stopped. When
8 Adjuvant Chemotherapy 83
Table 8.1 Recommended regimens

Regimen Drug, dose, and schedule
Single agent
5-FU/LV (RPMI Leucovorin 500 mg/m2 2 h infusion + 5-FU 500 mg/m2 bolus, weekly ×6,
regimen) every 8 weeks, 4 cycles
5-FU/LV Leucovorin 400 mg/m2 + 5-FU 400 mg/m2 followed by 5-FU 2400 mg/m2
(sLV5FU2 46 h-continuous infusion, every 2 weeks, 12 cycles
regimen)
capecitabine Capecitabine 1000~1250 mg/m2, twice daily, day 1~14, every 3 weeks,
8 cycles
UFT/LV Tegafur-uracil (UFT) 100 mg/m2 + leucovorin 25 mg/day, three times daily,
day1~28, every 5 weeks, 5 cycles
S-1 S-1 40 mg/m2, twice daily, day 1~28, every 6 weeks, 4 cycles
Combination
mFOLFOX6 Oxaliplatin 85 mg/m2 day 1 and leucovorin 400 mg/m2 + 5-FU 400 mg/m2
bolus followed by 5-FU 2400 mg/m2 46 h-continuous infusion, every
2 weeks, 12 cycles
FOLFOX4 Oxaliplatin 85 mg/m2 day 1 and leucovorin 200 mg/m2 + 5-FU 400 mg/m2
bolus followed by 5-FU 600 mg/m2 22 h-continuous infusion day1 + 2,
every 2 weeks, 12 cycles
CapeOX Oxaliplatin 130 mg/m2 day 1 and capecitabine 1000 mg/m2, twice daily,
day 1~14, every 3 weeks, 8 cycles
oxaliplatin is contraindicated, monotherapy with 5-FU/LV or oral fluoropyrimi-

dines is performed. Recommended regimes are listed in Table 8.1.
8.2.1.1 Transition of Standard Therapy
Table 8.2 shows results of major clinical trials of adjuvant chemotherapyin colon
cancer. In 1989, the North Central Cancer Treatment Group (NCCTG) reported that
treatment with levamisole with 5-FU led to a significant reduction in cancer recur-
rence and a significant increase in OS when compared with no adjuvant therapy [4].
In 1990, similar results were published by Charles Moertel and colleagues [5].
These findings led to the acceptance of 5-FU with levamisole as the standard adju-
vant therapy in the 1990s.
The IMPACT (International Multicenter Pooled Analysis of Colorectal Cancer
Trials) [6] pooled data from 3 randomized trials that investigated high-dose 5-FU/
leucovorin (LV) compared with no adjuvant therapy. 5-FU/leucovorin significantly
reduced mortality and cancer recurrence compared with no adjuvant therapy.
NSABP C-04 trial compared the efficacy of 5-FU/LV with that of FU/LEV or
with the combination of FU/LV/LEV [7]. 5-FU/LV group had significant prolonga-
tion in disease-free survival (DFS) and a borderline prolongation in overall survival
(OS) when compared with FU/LEV group. Similar results were reported from
adjCCA-01 trial [8]. And 5-FU/LV became established as the standard treatment.
Table 8.2 Results of major clinical trials
84
Number
of
Name of trial Test group vs. control group Stage patients DFS p value OS p value
Value of 5-FU, etc. NCCTG [4] 5-FU/LEV vs. surgery only II/III 158 74% (5 years) <0.01 74% (5 years) 0.02
151 58% 63%
Intergroup-0035 5-FU/LEV vs. surgery only III 304 63% (3.5 years) 0.0064 71% (3.5 years) 0.0064
[5] 315 47% 55%
IMPACT [6] 5-FU/LV vs. surgery only II/III 736 71% (3.5 years) <0.0001 83% (3 years) 0.029
757 62% 78%
NSABP C-04 [7] 5-FU/LV vs. 5-FU/LEV vs. II/III 691 65% (5 years) 74% (5 years)
5-FU/LV/LEV 696 60% 70%
691 64% 73%
adjCCA-01 [8] 5-FU/LV vs. 5-FU/LEV II/III 117 – – 70% (5 years) 0.01
144 – 61%
Comparison with NSABP C-06 [9] UFT/LV vs. 5-FU/LV II/III 805 67% (5 years) 0.96 78.5% (5 years) 0.45
oral 803 68.2% 78.7%
fluoropyrimidines X-ACT [10] Capecitabine vs. 5-FU/LV III 1004 60.8% (5 years) <0.0001 71.4% (5 years) <0.0001
983 56.7% 68.4%
Combination NSABP C-07 FLOX vs. 5-FU/LV II/III 1209 69.4% (5 years) 0.002 77.7% (6 years) 0.06
therapy with [13] 1200 64.2% 73.5%
oxaliplatin MOSAIC [14] FOLFOX4 vs. 5-FU/LV II/III 1123 73.3% (5 years) 0.003 78.5% (6 years) 0.046
1123 67.4% 76.0%
NO16968 XELOX vs. 5-FU/LV III 944 63% (7 years) 0.004 73% (7 years) 0.04
(XELOXA) [15] 942 56% 67%
Combination CALGB 89803 IFL vs. 5-FU/LV III 635 61.1% (5 years) 0.84 68% (5 years) 0.74
therapy with [16] 629 59% 71%
irinotecan PETACC-3 [17] FOLFIRI vs. 5-FU/LV II/III 1050 56.7% (5 years) 0.106 73.6% (5 years) 0.094
T. Ishikawa and H. Uetake
1044 54.3% 71.3%

Combination NSABP C-08 mFOLFOX6 + bevacizumab II/III 1334 77.9% (3 years) 0.35 82.5% (5 years) 0.56
therapy with [18] vs. mFOLFOX6 1338 75.1% 80.7%
molecular targeted AVANT [19] FOLFOX4 vs. high risk 955 76% (3 years) 85% (5 years)
drugs FOLFOX4 + bevacizumab II/III 960 73% 81%
vs. XELOX + bevacizumab 952 75% 82%
NCCTG mFOLFOX6 + cetuximab vs. III (data 954 71.5% (3 years) 0.08 85.6% (3 years) 0.15
intergroup mFOLFOX6 on the 909 74.6% 87.3%
8 Adjuvant Chemotherapy
N0147 [21] right are

wild-type
KRAS)
PETACC-8 [22] FOLFOX4 + cetuximab vs. III (data 791 75.1% (3 years) 0.66 88.3% (3 years) 0.56
FOLFOX on the 811 78.0% 90.5%
right are
wild-type
KRAS)
*
p = 0.07, **p = 0.44, +p = 0.02, ++p = 0.21
85
Further clinical trials of the form of administration of fluoropyrimidines led to

the currently recommended method of administration of 5-FU/LV, and the oral
agents tegafur-uracil (UFT)/LV and capecitabine were also shown to be effective in
the NSABP C06 study and the X-ACT trial, respectively [9, 10].
Turning to evidence from Japan, in the JCOG0205 trial, which compared bolus
5-F/LV and oral UFT/LV, the oral regimen was found to be noninferior in terms of
3-year disease-free survival (DFS), the primary endpoint [11]. The ACTS-CC trial
has been performed in Japan as comparative trials of oral anticancer agents for stage
III colon cancer [12]. The ACTS-CC trial demonstrated the noninferiority of S-1
compared with UFT/LV as adjuvant chemotherapy for stage III colon cancer (haz-
ard ratio (HR) 0.85, p = 0.1003). Therefore UFT/LV, capecitabine, and S-1 became
the standard oral fluoropyrimidines of adjuvant chemotherapy in Japan.
Moving into the 2000s, multiple-drug therapies were found to be effective, and
the efficacy of adjuvant chemotherapy with oxaliplatin was demonstrated in the
National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 and the
Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the
Adjuvant Treatment of Colon Cancer (MOSAIC) trials, both of which addressed
stage II and III colorectal cancer [13, 14]. NO16968 (XELOXA) trial also showed
that capecitabine plus oxaliplatin (CapeOX) is effective for stage III patients [15].
In the clinical trial, FU and oxaliplatin combinations (FLOX, FOLFOX, CapeOX)
are superior to single-agent 5-FU in terms of DFS and OS [13–15]. Therefore, adju-
vant chemotherapy with FU and oxaliplatin is recommended for stage III patients.
However, the spectrum of toxicity between NSABP-C07 and MOSAIC was differ-
ent: grade 3–4 diarrhea occurred more often with FLOX than with FOLFOX, while
grade 3 sensory neuropathy was observed in 12% with FOLFOX and 8% with
FLOX. FLOX should probably not be used in clinical practice, due to its toxicity.
8.2.1.2 Drugs Not Recommended in Adjuvant Chemotherapy
Irinotecan
The use of irinotecan in combination with 5-FU (bolus or infusional) is not recom-
mended. The Cancer and Leukemia Group B (CALGB) 89,803 and Pan-European
Trials in Adjuvant Colon Cancer (PETACC)-3 trials, which verified the additional
effect of irinotecan, did not show that adjuvant chemotherapy was valuable [16, 17].
The CALGB-89803 trial [16] compared 5-FU/LV + irinotecan (IFL) with the
Roswell Park scheme. The trial was prematurely closed because of an elevated rate
of mortality in the IFL group with respect to the FL regimen (2.2% vs. 0.8%). No
improvement in either OS or DFS was observed for patients receiving IFL com-
pared with those receiving FL. The PETACC-3 trial [17] compared FOLFIRI and
5-FU/LV. Results did not show any significant advantage for the regimen with irino-
tecan in terms of DFS.
Bevacizumab
Bevacizumab has no role in the adjuvant chemotherapy for colon cancer. All trials
evaluating bevacizumab, NSABP C-08 trial [18], AVANT trial [19], and QUASAR
2 trial [20] failed to show a benefit associated with bevacizumab. NSABP C-08 trial
[16] and AVANT trial [17] showed that bevacizumab had no benefit in the adjuvant
setting when added to FOLFOX6. QUASAR 2 trial showed the similar result when
added to capecitabine [20].
Anti-EGFR Antibody
The NCCTG NO147 [21] and PETACC-8 [22] assessed the addition of cetuximab
to FOLFOX in the adjuvant treatment of stage III colon cancer. In patients with
wild-type KRAS, both trials failed to show the benefit associated with cetuximab.
Moreover, adverse events were more common in the cetuximab group. Therefore,
cetuximab has no role in the adjuvant chemotherapy of colon cancer.
8.2.1.3 Choice of Standard Treatment
Bolus 5-FU, Infusional 5-FU, or Oral Fluoropyrimidine
Infusional 5-FU is preferred to bolus 5-FU because of better tolerability. The

GERCOR C96.1 study [23] compared the Mayo Clinic regimen with LV5FU2 (de
Gramont regimen) [24]. There were no statistically significant differences between
the 2 arms in terms of DFS or OS, but the de Gramont regimen was significantly less
toxic than the Mayo Clinic regimen. However, infusional regimen implies the use of
a (central) venous device, potentially associated with complications, such as throm-
bosis, pulmonary embolism, and infection. Oral fluoropyrimidine does not require
central venous access, this treatment modality might be preferred whenever appli-
cable. The X-ACT trial showed that capecitabine is an active agent with a favorable
toxicity profile and may reduce overall costs compared with i.v. treatments [10].
In Japan, UFT/LV, capecitabine, and S-1 are the standard oral fluoropyrimidines
of adjuvant chemotherapy.
The ACTS-CC trial [13] and JCOG0910 trial [25] have been performed in Japan
as comparative trials of oral anticancer agents for stage III colon cancer. The ACTS-CC
trial demonstrated the noninferiority of S-1 compared with UFT/LV as adjuvant che-
motherapy for stage III colon cancer. However, the JCOG0910 trial failed to demon-
strate the noninferiority of S-1 compared with capecitabine. For patients who are
reluctant to use capecitabine due to associated adverse events such as hand–foot skin
reactions, UFT/LV and S-1 might be useful option to complete chemotherapy because
of lower frequency of hand–foot syndrome compared with capecitabine.
Oxaliplatin Containing Regimens or Fluoropyrimidine Alone Remains
The benefit of combinations with oxaliplatin has been demonstrated in three land-
mark trials [13–15] and a pooled analysis of four clinical trials (NSABP C-05, C-06,
C-07, and C-08) [26].
Western guidelines recommend oxaliplatin containing regimens (FOLFOX or
CapeOX) as the first choice for adjuvant chemotherapy in stage III colon cancer [1,
2]. Monotherapy with capecitabine or 5-FU/LV can be an alternative approach in
special situations (such as contraindication for oxaliplatin).
In Japan, oxaliplatin-based combination chemotherapy is not considered as the
best or optimal standard for all stage III colon cancer patients considering the
expected benefits and the possible risks of adding oxaliplatin. It is well known that
prolonged peripheral neuropathy and high medical cost are clinically and socially
significant problems in oxaliplatin-based adjuvant chemotherapy.
de Gramont et al. indicated that stage III consists of subgroups of patients with
various prognoses, and the expected benefits of oxaliplatin could vary according to
stage subgroups [27].
As shown in Fig. 8.1, both JCOG0205 trial [11] and ACTS-CC trial [12] in which
oxaliplatin was not used showed similar or better DFS than that with oxaliplatin in
the Western pivotal studies [13–15]. The outcomes for colorectal cancer surgery in
59
5-FU+LV
MOSAIC
66
FOLFOX4
5-FU+LV 58
NSABP C-07
64
FLOX
5-FU+LV 60
XELOXA
CapeOX 66
5-FU+LV 57
X-ACT
capecitabine 60
5-FU+LV 74
JCOG0205
UFT+LV 74
UFT/LV 67
ACTS-CC
S-1 70
0 10 20 30 40 50 60 70 80 90 100
%
Fig. 8.1 Five y- disease-free survival rate of patients with stage III colon cancers. Comparing the
results of Japanese clinical trials with those of western clinical trials
Japan are generally good. The reasons include the different level of lymph node dis-
section from that performed in Europe and North America and the fact that detailed
pathological tests mean that there is little stage migration. In Japan, the expected
gain in disease-free survival and overall survival with oxaliplatin-based combina-
tion chemotherapy for stage III patients could be as little as 2–3% [12]. Thus, it is
considered that additional effects of L-OHP for stage III CRC may be small and
differ between Japan and the USA and Europe.
It will be necessary to identify patient groups for whom the benefits of the effect
of treatment outweigh the risk of adverse events such as cumulative peripheral neu-
ropathy. The prognosis of stage IIIA patients in ACTS-CC trial was favorable
(3-year DFS rate: 88%), oral fluoropyrimidine alone might be a considerable option
for these patients [12].
Recent subgroup analysis showed marginal survival benefit from oxaliplatin as
adjuvant treatment of patients aged ≥70, whereas oral fluoropyrimidines retained
their efficacy [28, 29]. Therefore, oral fluoropyrimidines may play an important role
in adjuvant chemotherapy for elderly patients.
8.2.1.4 Timing of Adjuvant Chemotherapy
Adjuvant chemotherapy is recommended to be started as early as possible, starting

from the third week up to a maximum of 8–12 weeks after surgery [1–3]. A system-
atic review and meta-analysis showed that a 4-week increase in time to adjuvant
chemotherapy was associated with a significant decrease in both overall survival
and disease-free survival [30]. Another meta-analysis was performed stratifying the
data according to a common cutoff delay of 8 weeks between surgery and adjuvant
chemotherapy because chemotherapy is usually prescribed within 2 months after
curative surgery. Delaying the initiation of adjuvant chemotherapy for more than
8 weeks after surgery showed significantly shorter overall survival. However,
relapse free survival was not significantly different between the two groups strati-
fied by the timing of adjuvant chemotherapy and this discrepancy was speculated to
be due to factors not directly related to cancer (such as postoperative complications,
comorbidities, social status) [31].
8.2.1.5 Appropriate Duration of Adjuvant Chemotherapy
The current standard duration of postoperative adjuvant chemotherapy is 6 months.

However, there is no definitive conclusion regarding the appropriate duration of
treatment.
In the randomized, 2 × 2 factorial study which compared a semimonthly (LVFU2)
regimen with a monthly (FULV) regimen and 24 versus 36 weeks of each regimen
as adjuvant treatment of patients with stage II and III colon cancer, no statistically
significant difference could be detected in disease-free or overall survival between
the treatment groups or treatment durations [32].
To reduce the burden of adjuvant chemotherapy by shortening the duration of

treatment, a pooled analysis of data for 12,834 stage III colon cancer patients, from
six randomized phase III trials of adjuvant therapy, the International Duration
Evaluation of Adjuvant chemotherapy (IDEA) study, was carried out [33]. This
pooled analysis evaluated the noninferiority of 3 versus 6 months of adjuvant
FOLFOX/CAPOX therapy but the noninferiority of 3 months of treatment versus
6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95%
confidence interval [CI], 1.00–1.15). Therefore appropriate duration of adjuvant
chemotherapy should be 6 months. In an exploratory analysis dividing the patients
to low-risk (T1-3, N1) and high-risk (T4, N1-2 or T any, N2), in patients treated
with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the
lower-risk subgroup. This study suggests that the choice of treatment regimen, dura-
tion of therapy, and characteristics of the patients may be balanced against the risk
of recurrence of disease and toxicity of longer oxaliplatin-based therapy. To imple-
ment these data in clinical practice, further discussion is needed.
8.2.1.6 Adjuvant Treatment in Elderly Patients
In advanced countries, the number of older patients diagnosed with cancer contin-
ues to increase. The low number of older patients enrolled on large clinical trials
results in a paucity of evidence to manage this population appropriately.
Although the percentage of older patients receiving chemotherapy in the adju-
vant setting for stage II/III colon cancer is lower compared with their younger coun-
terparts, the rate of adjuvant use among older patients has increased and elderly
patients had the same benefit as younger patients [34]. Population studies [35] dem-
onstrated the effectiveness of adjuvant chemotherapy for patients older than
75 years with stage III colon cancer. Pooled analysis of 3 large randomized trials
showed the benefit of 5-FU-based adjuvant chemotherapy for patients over the age
of 70 [36].
Subset analyses of major trails have failed to show benefit of addition of oxali-
platin in older patients. Subset analysis of the MOSAIC trial showed that the addi-
tion of oxaliplatin gave no survival benefit in patients aged 70–75 years with stage
II or III colon cancer [37]. Similar result was demonstrated in a subset analysis of
the NSABP C-07 trial [38]. The NO16968 study showed a non-statistically signifi-
cant trend towards benefit with the addition of oxaliplatin in patients over the age of
70 [15].
However, in stage III disease observational data from five US registries demon-
strated a maintained survival benefit for the addition of oxaliplatin to 5-FU-based
adjuvant treatment in patients up to 75 years of age [39]. And a pooled analysis of
individual data from patients in NSABP C-08, XELOXA, X-ACT, and AVANT tri-
als found that DFS and OS were improved with CapeOX or FOLFOX over 5-FU/
LV in patients aged >70 [40].
In summary, single-agent 5-FU appears to provide benefit for older patients with
stage III disease in the adjuvant setting, whereas the benefit from combination
c hemotherapy with 5-FU and oxaliplatin in the adjuvant setting remains controver-
sial. Therefore, single-agent FU is the treatment of choice. However, oxaliplatin
combination therapy might be applicable to patients with good general health status
and younger biological features.
8.2.2 Adjuvant Chemotherapy in Stage II Colon Cancer

8.2.2.1 Benefits and Indication
The usefulness of adjuvant chemotherapy for stage II colon cancer remains contro-
versial [41]. Although the results from some meta-analyses showed the survival
benefit of adjuvant chemotherapy using 5-FU alone [42, 43], recent meta-analysis
of 25 studies demonstrated no benefit of adjuvant chemotherapy in patients with
stage II colon cancer [44]. Population-based study using the National Cancer Data
Base found that adjuvant chemotherapy was associated with improved survival in
stage II colon cancer patients [45].
Recently results of SACURA trial was reported [46]. This trial was a phase III
study to evaluate the superiority of 1-year adjuvant treatment with oral tegafur-
uracil (UFT) to surgery alone in stage II colon cancer. This study failed to demon-
strate the superiority of the UFT adjuvant chemotherapy compared with surgery
alone but the recurrence rate was lower in the UFT group than in the control group
(10.4 vs. 13.4%).
Adjuvant therapy is not routinely recommended for unselected stage II colon
cancer patients in the clinical guidelines [1–3]. These guidelines list T4 lesions, less
than 12 examined lymph nodes (LNs), bowel perforation and obstruction, lympho-
vascular involvement, poorly differentiated histology, perineural invasion, and ele-
vated carcinoembryonic antigen (CEA) as poor prognostic factors in stage II colon
cancer and recommend adjuvant chemotherapy for patients with these “high-risk”
features [1–3]. However, the benefit of adjuvant chemotherapy for those patients has
not been confirmed [41]. Low-risk stage II patients should not generally receive
adjuvant treatment. Decision on adjuvant treatment must be based on thorough dis-
cussion with the patient on an individual basis.
8.2.2.2 Recommended Treatment
High-risk stage II patients may be treated with postoperative chemotherapy with FU

with or without oxaliplatin because of a small absolute benefit. The addition of
oxaliplatin in the MOSAIC trial in stage II patients showed no benefit in either DFS
or OS [47]. In patients with a simplified definition of high-risk stage II disease (T4,
tumor perforation, or fewer than 10 lymph nodes examined), the estimated 10-year
probability of OS was 75.4% for FOLFOX4 and was 71.7% for LV5FU2 (p = 0.058)
in this trial. Results of a population-based study, which showed the survival benefit
of adjuvant chemotherapy in patients with stage II colon cancer, also could not show
the benefit of addition of oxaliplatin to adjuvant regimens for these patients [45].
However, combination with oxaliplatin may be considered in the clinical practice,
particularly in case of multiple risk factors or younger age.
8.2.3 Biomarkers
There is no evidence for a predictive marker regarding the benefit of adjuvant che-
motherapy for early CRC, and therefore the use of any predictive marker informa-
tion for decision making is not indicated.
8.2.3.1 Microsatellite Instability (MSI)/Mismatch Repair (MMR)
Mutation or promotor methylation of MMR genes can result in MMR protein defi-
ciency and MSI. In patients with stage II colon cancer, MSI/MMR may be useful to
identify a subset of patients who are at a very low risk of recurrence and in whom
the benefits of chemotherapy are very unlikely. Although MSI/MMR is a prognostic
marker of a more favorable outcome, MSI/MMR status seems to be not predictive
of benefit or detrimental impact of adjuvant therapy [48–51]. In stage III, the prog-
nostic role of MSI/MMR status is not clear and conflicting data exist on the poten-
tial benefit of treatment with 5-FU alone [52]. For the role of oxaliplatin in adjuvant
chemotherapy for stage III, no conclusive data are available with respect to the role
of MSI/MMR status.
8.2.3.2 18q Loss of Heterozygosity (LOH)
Loss of heterozygosity (LOH) at chromosome 18q frequently occurs late during

colon cancer development. 18q LOH were reported to predict shorter survival in
patients with colorectal cancer in some studies [53, 54], but large prospective stud-
ies have shown that 18q LOH was not associated with patient survival [55, 56].
Currently, the prognostic value of 18q loss of heterozygosity (LOH) is unclear.
8.2.3.3 Gene Expression Profiling
Gene expression profiling has become a successful prognostic and predictive tool in
the management of breast cancer. In colon cancer, Oncotype DX Colon Cancer
Assay and ColoPrint have been developed to provide the information to determine
adjuvant chemotherapy in patients with stage II and stage III colon cancer. Although
prognostic values of these assays have been shown in some studies [57–59], there is
no evidence of predictive value of adjuvant chemotherapy. Therefore multigene

assays have not achieved the clinical utility in colon cancer.
8.3 Adjuvant Chemotherapy for Rectal Cancer
8.3.1 Postoperative Adjuvant Chemotherapy
The efficacy of adjuvant chemotherapy has not been established in regard to rectal
cancer. In contrast to colon cancer, the available data from randomized trials for
rectal cancer investigating the value of adjuvant chemotherapy are limited. Patients
with rectal cancer were specifically excluded from most phase III adjuvant studies
of colorectal cancer because of the potential toxicity and confounding impact of
radiotherapy (RT) or chemoradiotherapy (CRT). In the USA and Europe, total
mesorectal excision (TME) with preoperative RT or CRT is a standard strategy for
patients with stage II and stage III rectal cancer. Postoperative adjuvant chemo-
therapy is recommended for all patients with stage II and stage III rectal cancer
following the CRT and surgery [60, 61].
After surgery alone for rectal cancer, individual trials and meta-analyses showed
that there is a benefit for adjuvant 5-FU-based adjuvant chemotherapy in terms of
DFS and OS [61–64]. The addition of 5-FU adjuvant chemotherapy to preoperative
CRT provided no survival benefit in the EORTC Radiotherapy Group Trial [65].
Other individual randomized trials [66, 67] and meta-analyses [68] have shown no
benefit for 5-FU alone following CRT and surgery. The addition of oxaliplatin to
5-FU may improve DFS, but there is no effect on OS [69, 70]. Phase III trial using
CapeOX showed that the observed improvement for adjuvant CapeOX in DFS and
OS were not statistically significant [71].
Although conclusive evidence of the benefits of adjuvant therapy in patients with
rectal cancer is unclear, adjuvant chemotherapy is recommended for all patients
with stage II and stage III rectal cancer.
It also remains unclear whether the initial clinical (yc) or pathological (yp) stage
should be used to determine the risk/benefit of adjuvant treatment.
In the USA, adjuvant chemotherapy is recommended in patients with stage II
and stage III rectal cancer. Indication of treatment depends on initial clinical stag-
ing and predicted CRM status. FOLFOX or CapeOX is preferred and 5-FU/LV or
capecitabine is selected in low-risk case, such as responder to the preoperative
CRT [59].
In Europe, adjuvant chemotherapy is recommended in rectal cancer patients after
preoperative CRT/RT with yp stage III and “high-risk” yp stage II [60]. In general,
downgrading in T or N stage has been recognized as a prognostic factor of favorable
outcome.
In Japan, mesorectal excision (ME) with lateral lymph node dissection (LLND)
is the standard treatment for stage II and stage III lower rectal cancer. Postoperative
adjuvant chemotherapy is recommended in the patients with pathological stage III

and high-risk stage II according to the indication for colon cancer [3].
8.3.2 Preoperative (Neoadjuvant) Chemotherapy
Strategies using induction chemotherapy before/following CRT and surgery are

being investigated in several phase II trials [72–75]. Induction CT may be associ-
ated with better treatment compliance and may allow full systemic doses of CT to
be delivered and be able to improve the outcome. Some approach might be exam-
ined in phase III trials.
8.4 Adjuvant Chemotherapy for Metastatic Disease
For resectable metastatic, there is no standard treatment and the effective role of
systemic adjuvant chemotherapy remains controversial. For initially R0 resectable
metastatic disease, the current international guidelines recommend an adjuvant
strategy for 6 months: postoperative adjuvant chemotherapy or perioperative che-
motherapy (3 months before surgery and 3 months after surgery) [1, 3, 76].
The rationale for adjuvant chemotherapy post-metastasectomy is based on sev-
eral studies. An ideal study would compare the putative most effective adjuvant
therapy post-metastasectomy versus surgery alone, stratifying resected patients also
on the basis of the risk of recurrence. However, this study is currently unlikely due
to the high dropout rate. A pooled analysis of two trials showed a marginal statistical
significance in favor of adjuvant chemotherapy 5-FU/LV-based regime, indepen-
dently associated with both PFS and OS [77]. A phase III trial (UFT/LV trial) ran-
domized 180 patients after metastasectomy to receive adjuvant UFT/LV
chemotherapy or surgery alone. This study showed that the adjuvant UFT/LV che-
motherapy improved DFS, but not OS [78].
Cytotoxic doublets have also been studied in the perioperative adjuvant setting.
Three hundred and sixty-four patients with resectable liver metastases randomized
to compare the combination of surgery and perioperative FOLFOX-4 treatment
(6 cycles before and 6 cycles after surgery) with liver resection alone. This study
showed that the 3-year PFS was better in the chemotherapy group compared with
controls. However, the gain in PFS did not affect the long-term OS, the median
5-year OS was 51.2% in the perioperative chemotherapy group versus 47.8% in the
surgery only group, without a significant difference between the two [79]. A ran-
domized, controlled phase II/III trial comparing hepatectomy followed by
m-FOLFOX-6 adjuvant chemotherapy with surgery alone is ongoing in Japan [80].
A pooled analysis of 3 trials showed the benefit of adjuvant chemotherapy in PFS
and DFS, but not in OS [81]. A meta-analysis of 10 studies with total of 1896
patients showed that the perioperative chemotherapy improved DFS, but not
OS. And chemotherapy significantly increased the postoperative complications

[82]. Other 2 meta-analysis also failed to show significant improvement in OS in
resectable colorectal cancer with liver metastases patients who received adjuvant
chemotherapy compared with surgery alone [83, 84].
The use of irinotecan-based regimen was studied in a phase III study [85]. This
study treated 306 patients with two different adjuvant chemotherapy regimens:
FOLFIRI versus 5-FU/LV. Although the median DFS was 24.7 months in the
FOLFIRI group (vs. 21.6 months), this difference was not statistically significant
(p = 0.44). Their study showed that the use of FOLFIRI after R0 resection added no
benefit compared with only 5-FU/LV.
There is no evidence supporting the use of biological targeted agents in the adju-
vant setting after metastasectomy. A randomized phase III trial compared the com-
bination of bevacizumab plus CapeOX versus CapeOX alone as adjuvant treatment
post-radical resection of liver metastases [86]. But the trial was prematurely closed
due to slow accrual. Regarding anti-EGFR antibody, a phase III clinical trial ran-
domized 236 patients (KRAS wild type) to receive chemotherapy with or without
cetuximab before and after liver resection. PFS was 14.1 months in the chemother-
apy plus cetuximab group and 20.5 months in the chemotherapy alone group (HR
1.50; 95% CI, 1.00–2.25; p < 0.048). Addition of cetuximab to adjuvant chemo-
therapy resulted in shorter progression-free survival [87]. Therefore the use of bio-
logical target agents is not recommended in the adjuvant chemotherapy.
8.5 Conclusion
We have provided a general overview of the adjuvant chemotherapy for colorectal

cancer and its current status, while mentioning the results of clinical trials and
resulting advances. It is necessary to establish the optimal adjuvant chemotherapy
corresponding to the conditions of individual patients, taking into account the fact
that oral anticancer agents are also an option. The results of biomarker studies using
samples from clinical trials should be a focus of attention in order to establish even
more appropriate adjuvant chemotherapy.
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Chapter 9
Chemotherapy for Metastatic
Colorectal Cancer
Takeshi Yamada, Michihiro Koizumi, Seiichi Shinji, Akihisa Matsuda,

Yasuyuki Yokoyama, Goro Takahashi, Takuma Iwai, Keisuke Hara,
Masahiro Hotta, Kohki Takeda, Kohji Ueda, and Hiroshi Yoshida
Abstract The overall survival of patients with unresectable metastatic colorectal

cancer (mCRC) has increased from approximately 1 year during the era of fluoro-
pyrimidine monotherapy to >30 months with the combination of cytotoxic agents
and molecular-targeted agents. Here, we review the current landscape of chemo-
therapy for mCRC. The recent establishment of late-line chemotherapy, including
regorafenib and TAS-102, and development of biomarker analysis have attracted
much attention. Maintenance and rechallenge are relatively new concepts. The for-
mer has been developed for less-invasive treatment and the latter because perfor-
mance status of patients with mCRC is good beyond standard second-line
chemotherapy.
Keywords Colorectal cancer · Chemotherapy · EGFR · VEGF · Rechallenge
9.1 Introduction
The overall survival (OS) of patients with unresectable metastatic colorectal cancer
(mCRC) has increased from approximately 1 year during the era of fluoropyrimidine
monotherapy to >30 months with the combination of cytotoxic agents and molecular-
targeted agents. Here, we review the current landscape of chemotherapy for
mCRC. Standard treatment for these patients involves chemotherapy based on fluoro-
pyrimidines, oxaliplatin, and irinotecan, and monoclonal antibodies targeting vascular
endothelial growth factor (VEGF). In patients with RAS wild-type tumors, monoclo-
nal antibodies targeting epidermal growth factor receptor (EGFR) are also used.
T. Yamada (*) · M. Koizumi · S. Shinji · A. Matsuda · Y. Yokoyama · G. Takahashi · T. Iwai

K. Hara · M. Hotta · K. Takeda · K. Ueda · H. Yoshida
Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical
School, Tokyo, Japan
e-mail: y-tak@nms.ac.jp; k-michi@nms.ac.jp; s-shinji@nms.ac.jp; a-matsu@nms.ac.jp;
s9057@nms.ac.jp; takumaiwai@nms.ac.jp; keisuke-hara@nms.ac.jp; s9083@nms.ac.jp;
take-yokohama@nms.ac.jp; ueda0721@nms.ac.jp; hiroshiy@nms.ac.jp

102 T. Yamada et al.
Table 9.1 Cytotoxic agents used for Regimen Line Reference

colorectal cancer
Oxaliplatin base
FOLFOX First or second
XELOX First or second NO 16966
SOX First or second SOFT
FOLFOXIRI First TRIBE
Irinotecan base
FOLFIRI First or second
XELIRI First or second AXEPT
IRIS or SIR First or second FIRIS
Others
TAS-102 Late line RECOURSE
9.2 Cytotoxic Agents
Cytotoxic agents used for colorectal cancer are shown in Table 9.1. Fluorouracil-
based combination therapy with oxaliplatin or irinotecan is the mainstay of first-
line treatment for mCRC. First-line treatment includes the doublet cytotoxic
combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI), infusional
fluorouracil, leucovorin, and oxaliplatin (FOLFOX), and capecitabine (CapeOX,
NO 16966 study) [1] or S-1 plus oxaliplatin (SOX, SOFT study) [2], as well as
the triplet combination fluorouracil, leucovorin, oxaliplatin, and irinotecan
(FOLFOXIRI).
FOLFOXIRI has greater activity compared with FOLFIRI or FOLFOX. The
TRIBE study showed that OS was 29.8 (95% confidence interval [CI] 26.0–34.3)
months in the FOLFOXIRI plus bevacizumab group compared with 25.8 (22.5–
29.1) months in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0.80, 95%
CI 0.65–0.98; P = 0.03). OS was 37.1 (95% CI 29.7–42.7) months in the RAS and
BRAF wild-type subgroup compared with 25.6 (22.4–28.6) months in the RAS-
mutation-positive subgroup (HR 1.49, 95% CI 1.11–1.99), and 13.4 (8.2–24.1)
months in the BRAF-mutation-positive subgroup (HR 2.79, 95% CI 1.75–4.46;
P < 0.0001) [3]. The OLIVIA trial compared FOLFOXIRI plus bevacizumab with
mFOLFOX-6 plus bevacizumab in patients with initially unresectable liver metas-
tases [4]. FOLFOXIRI plus bevacizumab was associated with higher response rate
(RR) (81% [95% CI 65–91%] vs. 62% [45–77%]) and resection rate (61% [45–
76%] vs. 49% [32–65%]), and prolonged progression-free survival (PFS) (18.6
[12.9–22.3] months vs. 11.5 [9.6–13.6] months).
9.3 Molecular Target Agents
Cytotoxic agents used for colorectal cancer are shown in Table 9.2. Molecular target
agents are most frequently used for colorectal cancer among various digestive neo-
plasms. Anti-EGFRs, anti-VEGFRs and multikinase are included in this criteria.
9 Chemotherapy for Metastatic Colorectal Cancer 103
Table 9.2 Molecular target agents Agents Line Reference

used for colorectal cancer
Anti EGFRs
Cetuximab First, second, or late CRYSTAL
Panitumumab First, second, or late PRIME
Anti VEGFRs
Bevacizumab First, second, or late AVF2107g
Ramucirumab Second RAISE
Aflibercept Second VELOUR
Multikinase
Regorafenib Late CORRECT
9.4 Anti-EGFRs
Activity of first-line therapy with FOLFOX4 plus cetuximab was shown in a phase
II study (RR 72%, PFS 12.3 months, and OS 30.0 months) [5]. This was confirmed
in the randomized phase II OPUS trial that compared FOLFOX4 plus cetuximab
and FOLFOX4 alone. In patients with KRAS wild-type tumors, addition of cetux-
imab to FOLFOX4 was associated with a clinically significant increase in RR of
61% versus 37% (odds ratio [OR] 2.54; P = 0.011) [6]. The CRYSTAL trial showed
that activity of first-line FOLFIRI plus cetuximab was better than that of FOLFIRI
alone in patients with KRAS wild-type tumors: PFS 9.9 (95% CI 8.7–14.6) months
versus 8.7 (7.4–9.9) months (HR 0.68 [0.50–0.94]; P = 0.02) [7].
Cetuximab and irinotecan combination therapy showed better prognosis com-
pared to cetuximab monotherapy: RR 22.9% (95% CI 17.5–29.1%) versus 10.8%
(5.7–18.1%) (P = 0.007); PFS 4.1 versus 1.5 months (P < 0.001 by log-rank test);
and OS 8.6 versus 6.9 months (P = 0.48) [8]. In this study, all the patients had
received irinotecan and 62.6% had received oxaliplatin. This indicates the effective-
ness of third-line cetuximab and irinotecan combination therapy. This was con-
firmed by another phase II study including only patients under third-line therapy,
who had PFS 4.7 (95% CI 2.5–7.1) months and OS 9.8 (3.9–10.1) months [9].
The PRIME trial showed that the addition of panitumumab to FOLFOX signifi-
cantly improved PFS compared with FOLFOX alone (10.1 vs. 7.9 months, HR 0.72,
95% CI 0.58–0.90; P = 0.004) and OS (26.0 vs. 20.2 months, HR 0.78 [0.62–0.99];
P = 0.04) [10]. In patients with wild-type KRAS and liver-limited disease, RR of
first-line panitumumab–FOLFOX4 and that of panitumumab–FOLFIRI were
comparable (PLANET-TTD trial) [11]. The ASPECCT trial showed that efficacy of
panitumumab is comparable with that of cetuximab in third line [12].
9.5 Anti-VEGFs
Angiogenesis is regulated principally by interactions between VEGF and VEGF

receptors (VEGFRs) and plays a key role in cancer growth and metastasis [13].
VEGF-A is the central regulator of tumor angiogenesis, endothelial proliferation,
permeability, and survival [14]. VEGF-A binds with high affinity to two structurally
similar tyrosine kinase receptors, VEGFR-1 and VEGFR-2, that are both expressed
on tumor vasculature.
9.6 Bevacizumab
Bevacizumab is the most frequently used anti-VEGF. Addition of bevacizumab to

irinotecan and fluorouracil significantly improved survival [15], as did addition of
bevacizumab to oxaliplatin, fluorouracil, and leucovorin [16]. In patients treated
with first-line bevacizumab and chemotherapy, continuance of bevacizumab to stan-
dard second-line chemotherapy (bevacizumab beyond first progression: BBP)
improved OS compared with chemotherapy alone: 11.2 (95% CI 10.4–12.2) months
versus 9.8 (8.9–10.7) months (HR 0.81 (0.69–0.94); P = 0.0062) [17]. BBP
improved PFS in patients with KRAS wild-type and mutant tumors. However, OS
benefit was not observed in patients with KRAS mutation [18].
9.7 Maintenance Treatment with Bevacizumab
In elderly patients, S-1 (BASIC trial) or capecitabine (AVEX trial) plus bevaci-
zumab had therapeutic activity [19, 20]. Thus, development of less-invasive treat-
ment for non-elderly patients was expected. Standard treatments that are continued
until disease progression or unacceptable toxicity may induce cumulative toxicity.
Intermittent treatment and treatment-free intervals (maintenance) can promote bet-
ter patient compliance and reduce adverse effects. A maintenance strategy that com-
prises aggressive initial cytotoxic treatment of short duration (3–6 months), followed
by maintenance with a less toxic treatment, could be a further therapeutic strategy.
This approach could maintain the best response to initial treatment with an appro-
priate and less toxic long-term treatment to optimize the duration of disease control.
Several randomized trials, including AIO 0207 and CAIRO3, have addressed the
potential role of bevacizumab maintenance treatment [21, 22].
9.8 Ramucirumab
VEGFR2 is the critical receptor involved in malignant angiogenesis, and its activa-
tion induces several other cellular modifications resulting in tumor growth and
metastases. Ramucirumab is a fully human IgG1 monoclonal antibody that binds
with high affinity to the extracellular VEGF-binding domain of VEGFR2 [23].
Ramucirumab plus FOLFIRI significantly improved OS compared with placebo

plus FOLFIRI as second-line treatment in the RAISE trial. Median OS was 13.3
(95% CI 12.4–14.5) months for the ramucirumab group versus 11.7 (10.8–12.7)
months for the placebo group (HR 0.844 [0.730–0.976]; P = 0.0219). PFS was also
significantly longer in the ramucirumab group than in the placebo group [24]. In the
second-line setting, adding ramucirumab to FOLFOX did not improve OS and PFS
of patients who were pretreated with an irinotecan-based regimen [25].
Subgroup analysis showed that KRAS wild-type patients had greater benefit
compared with KRAS mutant patients [26]. Biomarker analysis of the RAISE trial
showed that the median OS in the ramucirumab plus FOLFIRI arm compared with
placebo plus FOLFIRI showed an improvement of 2.4 months in the high VEGF-D
subgroup (13.9 [95% CI 12.5–15.6] months vs. 11.5 [10.1–12.4 months), and a
decrease of 0.5 months in the low VEGF-D subgroup (12.6 [10.7–14.0] months vs.
13.1 [11.8–17.0] months) [27]. The OS benefit of ramucirumab over placebo was
greater for patients with carcinoembryonic antigen ≤10 ng/mL compared with
>10 ng/mL (median OS: 3.6 vs. 0.8 months) [28].
9.9 Aflibercept
Aflibercept is a recombinant fusion protein of the VEGFR1 and VEGFR2 extracel-

lular domains that binds to VEGF-A, VEGF-B, and placental growth factor 1 and 2.
Aflibercept showed limited single-agent activity in pretreated patients [29]. Addition
of aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated
with higher toxicity [30].
The VELOUR trial showed that addition of aflibercept to FOLFIRI significantly
improved OS relative to that with placebo plus FOLFIRI, with median survival
times of 13.50 versus 12.06 months (HR 0.817, 95% CI 0.713–0.937, P = 0.0032)
after failure of the oxaliplatin regimen. Aflibercept also significantly improved PFS,
with median times of 6.90 versus 4.67 months (HR 0.758, 95% CI 0.661–0.869,
P = 0.00007). RR was 19.8% with aflibercept plus FOLFIRI compared with 11.1%
with placebo plus FOLFIRI (P < 0001) [31]. The benefits of aflibercept in combina-
tion with FOLFIRI in patients pretreated with bevacizumab are comparable to those
in patients pretreated without bevacizumab [32].
9.10 Anti-EGFRs or Anti-VEGFs: Which Are Favorable?
The PEAK trial showed that OS of patients treated with panitumumab and
mFOLFOX6 was better than that of patients with wild-type KRAS exon 2 treated
with first-line bevacizumab. However, PFS was similar [33]. The FIRE-3 trial
showed that OS of patients treated with FOLFIRI plus cetuximab was better than
that of patients treated with FOLFIRI plus bevacizumab: 33.1 (95% CI 24.5–39.4)
months versus 25.0 (23.0–28.1) months (HR 0.70 [0.54–0.90]; P = 0.0059).
However, RR and PFS were comparable [34]. The SPIRITT trial showed that pani-
tumumab or bevacizumab with FOLFIRI as second-line treatment had similar effi-
cacy in patients whose disease progressed during oxaliplatin-based chemotherapy
with bevacizumab [35].
9.11 Late-Line Therapies
Many patients beyond cytotoxic doublet (after the second line) maintain good per-
formance status and might be candidates for further therapy. A phase III trial showed
evidence of efficacy of late-line therapy with regorafenib and TAS-102. Conversely,
there is limited evidence for rechallenge.
9.12 Regorafenib
Regorafenib is an oral multikinase inhibitor that blocks the activity of several pro-
tein kinases, including those involved in the regulation of tumor angiogenesis
(VEGFR1, VEGFR2, VEGFR3, and TIE2), oncogenesis (KIT, RET, RAF1, and
BRAF), and tumor microenvironment (PDGFR and FGFR) [36]. In two interna-
tional phase III, double-blind, placebo-controlled trials (CORRECT [37] and
CONCUR [38]), regorafenib demonstrated a survival benefit and improvement in
disease control in patients with late-line therapy.
The benefit from regorafenib was reported to have no association with KRAS or
PIK3CA mutational status [39]. Regorafenib inhibits epithelial-to-mesenchymal
transition [40]. In vitro, combined treatment with cetuximab and regorafenib
induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant
cell lines by blocking mitogen-activated protein kinase and AKT pathways [41].
Lung-limited metastatic disease was significantly associated with better OS and
PFS from treatment with regorafenib [42]. Also, lung metastasis cavitation was a
good predictor for better PFS [43]. HER2 gene alterations were found in poor
responders. Conversely, GAS6 amplification and SMAD4 mutation were detected in
long-term responders [42].
In a recommended schedule, regorafenib is administered at a dose of 160 mg
once daily for the first 3 weeks of each 4-week cycle. However, patients with this
treatment experience severe adverse effects such as skin reaction and fatigue.
Grothey reported dose escalation therapy with regorafenib: starting at 80 mg daily
for the first week, escalation to 120 mg daily for the second week, and then to
160 mg daily, if possible, for the third week [44].
9.13 TAS-102
In two international phase III, double-blind, placebo-controlled trials (RECOURSE

[45] and TERRA [46]), TAS-102 demonstrated a survival benefit and improvement
in disease control in patients receiving late-line therapy. TAS-102 was effective in
all subgroups, regardless of age, geographical origin, or KRAS status [47]. The
C-TASK FORCE trial showed that addition of bevacizumab to TAS-102 improved
PFS, OS, and disease control, with acceptable toxicity [48].
In indirect comparison of patients in the CORRECT, CONCUR, and RECOURSE
trials, no significant differences were observed between regorafenib and TAS-102
for OS or PFS [49]. Retrospective propensity score analysis (the REGOTAS trial)
showed no significant difference in OS between regorafenib and TAS-102 [50].
9.14 Rechallenge
Rechallenge is defined as the use of the same drug or regimen to which the tumor
has been proved to be initially sensitive and then resistant, after the patient has
received other therapies, or a relevant period of time has elapsed. Evidence for
rechallenge with anti-EGFR [51] or oxaliplatin is limited [52], whereas no evidence
for rechallenge with irinotecan is available, unless in combination with an anti-
EGFR agent [8]. Anti-EGFR agents induce RAS mutation in tumors without RAS
mutations before administration of anti-EGFR agents [53, 54]. Therefore, the effi-
cacy of rechallenge with anti-EGFR agents may be limited. Rechallenge with
oxaliplatin-based regimens has the potential of causing serious toxicity, such as
oxaliplatin immune-induced syndrome. This is triggered by cumulative administra-
tion of oxaliplatin, which characteristically occurs three times earlier when the drug
is administered as a rechallenge [55].
Re-introduction is defined as a strategy that re-introduces the same agent or regi-
men after a period in which it was interrupted to avoid cumulative toxicity and/or to
manage adverse events. In this case, the interruption of therapy takes place in the
absence of disease progression. Oxaliplatin re-introduction has a benefit with 22%
of response rate and 5.5 months of PFS [56].
9.15 Molecular Biomarker
Biomarker analysis has supported the development of chemotherapy for mCRC. The

term liquid biopsy refers to the analysis of biomarkers in any body fluid, including
blood and urine. Liquid biopsy testing allows the analysis of tumor-derived DNA,
RNA, miRNA and proteins derived from circulating tumor DNA (ctDNA), circulat-
ing tumor cells, and extracellular vesicles. The tumor genotyping approach based on
ctDNA analysis is promising because tumors have spatial and temporal heterogene-
ity that can be detected using liquid biopsy [57, 58] and more mutations can be
detected by ctDNA analysis compared with tumor-tissue analysis [59]. Moreover,
liquid biopsy allows real-time monitoring of intratumor molecular dynamics [60].
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2014;32:579–86.
Part IV
Hereditary Colorectal Cancer
Chapter 10
Next-Generation Sequencing for Genetic
Diagnosis of Hereditary Colorectal Cancer
and Polyposis Syndrome
Hidetaka Eguchi and Yasushi Okazaki
Abstract Approximately 5% of the total colorectal cancers are thought to be the

hereditary ones. Phenotypes of the hereditary colorectal cancer and polyposis syn-
dromes (HCCPS) as represented mainly by the Lynch syndrome and familial adeno-
matous polyposis overlap each other to some extent, making it difficult to provide a
definite diagnosis, solely by the clinicopathological features. In order to cope with
this issue, the genetic testing based on the next-generation sequencing techniques
gathers much attention to the field of the HCCPS in recent years. In this chapter, the
utility of the next-generation sequencing techniques and some tasks to be solved are
discussed.
Keywords Next-generation sequencing · Hereditary gastrointestinal cancer

syndromes · Pathogenicity · Causative genes · Incidental/secondary findings
10.1 Genetic Testing
HCCPS consists of an array of syndromes such as Lynch syndrome (LS), familial

adenomatous polyposis (FAP), MUTYH-associated polyposis, hamartomatous pol-
yposis (Peutz–Jeghers syndrome, Juvenile polyposis syndrome, Cowden syn-
drome), and serrated polyposis syndrome [1] (Table 10.1). Clinical features of the
HCCPS overlap each other to some extent, and thus it is sometimes difficult to
provide a definite diagnosis solely based on the clinicopathological factors, e.g., age
at diagnosis, numbers of polyps in the gastrointestinal tracts, morphological fea-
tures of the polyps, and family cancer history. Identification of the causative genes
for the HCCPS has provided the alternate and solid ways of diagnosis, i.e., the
genetic testing. Traditionally, Sanger sequencing followed by the multiplex ligation-
dependent probe amplification (MLPA) analysis for detection of large deletion or
amplification of the causative genes have been the golden standards for the genetic
H. Eguchi (*) · Y. Okazaki

Diagnosis and Therapeutics of Intractable Diseases, Juntendo University Graduate School
of Medicine, Bunkyo-ku, Tokyo, Japan
e-mail: h-eguchi@juntendo.ac.jp; ya-okazaki@juntendo.ac.jp

116 H. Eguchi and Y. Okazaki
Table 10.1 Established and novel causative genes for the HCCPS
Syndrome Causative gene Inheritance
Established FAP APC Dominant
MUTYH-associated MUTYH Recessive
polyposis
PPAP POLE, POLD1 Dominant
Juvenile polyposis SMAD4, BMPR1A Dominant
Peutz–Jeghers syndrome STK11 Dominant
Cowden syndrome PTEN Dominant
Mixed polyposis GREM1, BMPR1A Dominant
LS MLH1, MSH2, MSH6, PMS2, Dominant
EPCAM
Novel Oligo polyposis NTHL1, MSH3 Recessive
Serrated polyposis RNF43 Dominant
HCCPS hereditary colorectal cancer and polyposis syndromes, FAP familial adenomatous polypo-
sis, LS lynch syndrome
testing of the HCCPS. Since the Sanger sequencing technique is somehow labor-

some for processing numbers of samples or target genes, the genetic testing was
little bit too time-consuming and expensive and thus made it difficult to introduce to
the general clinics. In order to narrow down the candidate genes involved in LS to
be subjected to the genetic testing, additional tests like immunohistochemical stain-
ing of the protein of the causative genes, e.g., MLH1, MSH2, MSH6, and PMS2,
were required, in addition to the clinical features of the HCCPS patients.
Unfortunately, until recently, availability of good antibodies raised for some of
these proteins was very limited, and thus the screening of the candidate genes has
not always been effective.
In addition to the classical HCCPS, other syndromes such as Li-Fraumeni and
hereditary breast and ovarian cancer syndromes (HBOC) have also now become
widely accepted as the cause of the HCCPS [2], this makes the genetic testing for
the HCCPS to be more complicated one. This innovation of the genetic test has long
been desired.
10.2 N
ext-Generation Sequencing for the Genetic
Test of HCCPS
Next-generation sequence (NGS) technique is based on the short read sequence of

fragments of the length of dozens to hundreds of bases and it processes in a manner
of massively parallel sequencing [3]. The principles of the various types of the NGS
technologies provided by the Illumina, Ion Torrent, and others have already been
reviewed in many papers [3, 4]. The NGS provides inexpensive production of large
volumes of sequence data as compared to the over conventional methods like the
Sanger sequencing, specifically in analyzing large numbers of samples. The utility
of the next-generation sequencing (also called massively parallel sequencing) for
10 Next-Generation Sequencing for Genetic Diagnosis of Hereditary Colorectal 117
the LS and polyposis syndromes has first been reported in 2012 by the researchers
at the Washington University [5]. They provided seven genes panel including
MLH1, MSH2, EPCAM, MSH6, PMS2, APC, and MUTYH using the Agilent
SureSelectXT target enrichment system technology and sequenced with the high-
speed sequencer HiSeq2000 (Illumina). They demonstrated high sensitivity (99.4%)
and specificity (99.4%) in the molecular diagnosis system called “ColoSeq.” Not
only the small nucleotide variants such as insertions, deletions, and substitutions,
but also copy numbers variants such as large deletions and duplications were suc-
cessfully detected [5]. As compared to the classical molecular genetic testing tech-
niques using Sanger sequencing and MLPA, the developed ColoSeq system
apparently showed some advantages, i.e., cost-effectiveness, and avoidance of the
stepwise testing of various candidate genes. In the same year, one of the leading
private companies for the genetic testing, Ambry Genetics Corporation, also started
their multiple-gene panel sequencing service called “ColoNext” [6]. The ColoNext
in 2012 covered 14 genes: MLH1, MSH2, MSH6, PMS2, and EPCAM for LS;
BMPR1 and SMAD4 for juvenile polyposis syndrome; STK11 for Peutz–Jeghers
syndrome; APC for the FAP; MUYH for MUTYH-associated polyposis; CHEK2 for
colorectal cancer in general; TP53 for Li-Fraumeni syndrome; PTEN for Cowden
syndrome; CDH1 for Hereditary diffuse gastric cancer. We have also established
our own panel sequencing (SGHGCS) for the HCCPS using Agilent Haloplex gene
capture technology with a middle-range sequencer MiSeq (Illumina), aiming to
enabling introduction of such techniques to the more concise laboratories [7].
Although most of the genetic tests for the HCCPS have utilized Illumina’s sequenc-
ing technology, some researchers have also validated the usefulness of the genetic
test based on the Ion Torrent technology [8]. In the paper, they compared the costs
for the genetic tests for FAP and hereditary non-polyposis colorectal cancer between
Sanger sequencing only and the NGS combined with Sanger sequencing for confir-
mation; they clearly showed the reduced costs and required days for testing, show-
ing the advantage of the NGS test over the Sanger sequencing [8]. In response to the
identification of novel causative genes for the HCCPS in the decade as shown below,
we and others have been upgrading the gene panels for the HCCPS. Currently, we
and various other institutions and private clinical laboratories offer own multiple-
gene panel sequencing for the HCCPS and is summarized in Table 10.2. The num-
bers of the genes in the panels differ extensively among the tests, and thus, the costs
and the covered genes together with the limitation of the covered regions and depths
should be extensively considered for selection of the tests. Specifically when no
pathogenic mutation in the germline has been reported in a certain test, a careful
consideration of the reason of the result test is required for the explanation to the
patient. The advantage of the multiple-gene panel sequencing was highlighted in the
evaluation of the involvement of various gene mutations predisposed to the cancer
in the suspected Lynch syndrome patient [9]. By using the 25 cancer-susceptibility
gene panel sequencing, they identified 37% of cases of the suspected Lynch syn-
drome possessed non-Lynch mutation, such as BRCA1, BRCA2, APC, BMPR1A,
CDH1, CDKN2A, CDK4, biallelic/monoallelic MUTYH, SMAD4, STK11, and
TP53. Without the NGS technology, it would have never been unwrapped the
genetic background for such cases.
Table 10.2 Comparison of the multiple gene panels for the HCCPS
118
Washington U Mayo Clin Myriad Invitae Ambry Color GeneDx SGHGCS

Gene Coloseq HCRC COLARIS Colorectal cancer ColoNext Hereditary cancer test Colorectal cancer panel 2017 panel
MLH1 ○ ○ ○ ○ ○ ○ ○ ○
MSH2 ○a ○ ○ ○ ○ ○ ○ ○
MSH6 ○ ○ ○ ○ ○ ○ ○ ○
PMS2 ○ ○ ○ ○ ○ ○b ○ ○
EPCAM ○ ○ ○ ○ ○ ○c ○ ○
APC ○ ○ ○ ○ ○ ○ ○
MUTYH ○ ○ ○ ○ ○ ○ ○ ○
NTHL1 ○ ○
MSH3 ○ ○
PMS1 ○
MLH3 ○
CDH1 ○ ○ ○ ○ ○ ○
CTNNA1 ○
PTEN ○ ○ ○ ○ ○ ○ ○
AKT1 ○ ○
PIK3CA ○ ○
STK11 ○ ○ ○ ○ ○ ○ ○
TP53 ○ ○ ○ ○ ○ ○ ○
CHEK2 ○ ○ ○ ○ ○ ○
SMAD4 ○ ○ ○ ○ ○ ○ ○
BMPR1A ○ ○ ○ ○ ○ ○ ○
POLE ○ ○ ○d ○ ○
POLD1 ○ ○ ○e ○ ○
GALNT12 ○ ○ ○ ○
SCG5/GREM1
H. Eguchi and Y. Okazaki
○ ○f ○ ○
AXIN2 ○ ○ ○ ○
RPS20 ○ ○
PDGFRA ○
BRCA1 ○ ○ ○
BRCA2 ○ ○
MITF ○g
BAP1 ○
CDKN2A ○
CDK4 ○h
CDKN1B ○
PALB2 ○
ATM ○ ○ ○
NBN ○
BARD1 ○
BRIP1 ○ ○
BARD1 ○
BUB1 ○
BUB3 ○
BUB1B ○
RAD51C ○
RAD51D ○
RAD52 ○
MBD4
10 Next-Generation Sequencing for Genetic Diagnosis of Hereditary Colorectal
○
TGFBR2 ○
FAN1 ○
(continued)
119
Table 10.2 (continued)
120
Washington U Mayo Clin Myriad Invitae Ambry Color GeneDx SGHGCS

Gene Coloseq HCRC COLARIS Colorectal cancer ColoNext Hereditary cancer test Colorectal cancer panel 2017 panel
FANCC ○
FANCE ○
REV3L ○
SMARCA4 ○
XRCC4 ○
NFKBIZ ○
EPHX1 ○
XAF1 ○
RBL1 ○
RNF43 ○
CNTN6 ○
MCM9 ○
SMAD9 ○
SDHB ○
SDHD ○
ENG ○
a
MSH2, includes exon 1–7 inversion
b
PMS2: Exons 12–15 not analyzed
c
EPCAM: only large deletions and duplications including 3′ end of the gene analyzed
d
POLE: only chr12:g.133250250 (including c.1270C > G) analyzed
e
POLD1: only chr19:g.50909713 (including c.1433G > A) analyzed
f
GREM1: only duplications in the upstream regulatory region analyzed
g
MITF: only chr3:g.70014091 (including c.952G > A) analyzed
h
CDK4: only chr12:g.58145429-58145431 (codon 24) analyzed
H. Eguchi and Y. Okazaki
10.3 N
GS Sequencing for Identification of the Novel
Causative Genes for the HCCPS
Not only the panel sequencing of the established causative genes for the HCCPS,
the NGS technology demonstrated its utility in the identification of novel causative
genes. This is well exemplified by the identification of the POLE and POLD1 genes
as causative genes for individuals with multiple or large colorectal adenomas or
early-onset colorectal cancer without having detectable germline mutations in the
known cancer predisposition genes by means of the whole exome sequencing in
2013 [10]. Germline mutations in the exonuclease (proofreading) domains of the
two DNA polymerases encoded by the POLE and POLD1 genes have been associ-
ated with a dominantly inherited, highly penetrant syndrome of oligo adenomatous
polyposis and early-age-of-diagnosis colorectal cancer and then a new class of the
HCCPS called “polymerase proofreading-associated polyposis” (PPAP) has been
established [11]. The cancer developed among the PPAP patients was unique in
terms of their hyper-mutation features [11]. The mutation burden of the cancer
developed among the PPAP together with the LS has shown to be strongly associ-
ated with the responsiveness to the immune-checkpoint inhibitors [12]; the genetic
test of the HCCPS now becomes not only for the definite diagnosis but also a com-
panion for the molecular targeting therapy. Whole exome sequencing of individuals
with multiple colonic adenomas has also enabled identification of a homozygous
germline nonsense mutation in the base-excision repair (BER) gene NTHL1 [13],
that showed a novel autosomal recessive inheritance of oligo polyposis other than
the MUTYH-associated polyposis. The biallelic pathogenic mutations in the
mismatch-repair gene MSH3 have also been found to be causative for the recessive
subtype of colorectal adenomatous polyposis [14]. For the serrated polyposis syn-
drome, the discovery of the RNF43 gene as the causative gene for the polyposis
should be noteworthy [15]. Other than these, several novel causative candidate
genes for the HCCPS have also been identified by the whole exome sequencing,
such as FAN1, CDKN1B, XRCC4, EPHX1, NFKBIZ, SMARCA4, BARD1, BRCA2,
BRIP1, FANCC, FANCE, REV3L, BUB1, BUB3, BUB1B, and RPS20 in those
patients with accumulated colorectal cancer family history [16–21].
10.4 A
High-Power Resolution of the NGS Enables
the Identification of the Low-Level Mosaic Mutation
The low-level mosaicism of the causative genes in the HCCPS, specifically in the
FAP, has long been claimed for its importance [22, 23]. Though, since the detection
limit of the Sanger sequencing is limited to around 20%, the much less frequency of
the mutations has not been called efficiently, making it difficult to find the FAP
cases with mosaic mutations. The NGS technology of the massively reading over
the thousands of depths has offered the remarkable improvement of the detection
limit. Two studies using the NGS technology in identification of the low-level
mosaic mutation have recently published [24, 25], showing the advantage of the
NGS in the genetic test even for the mosaic mutation cases.
10.5 Interpretation of the Pathogenicity

of the Identified Mutations
Because of the introduction of the NGS technology in the genetic testing of the
HCCPS, we have now faced the problems in the interpretation of the pathogenicity
of the identified mutations. As a golden standard, we should generally follow the
standards and guidelines provided by the American College of Medical Genetics
and Genomics (ACMG) in 2015 [26]. In addition to this, the International Society
for Gastrointestinal Hereditary Tumours (InSiGHT) has reported the 5-tiered
scheme for standardized classification of 2360 unique mismatch-repair gene vari-
ants [27] with some refinements based on the assessment of the criteria by analyzing
population frequency, segregation, tumor molecular characteristics, RNA effects,
protein expression levels, and in vitro mismatch-repair activity in 2017 [28]. The
recent criteria for the pathogenicity of the four mismatch-repair genes, MLH1,
MSH2, MSH6 and PMS2, provided by the InSiGHT is available online (https://
www.insight-database.org/classifications/).
Searching for the shared databases for the variants such as ClinVar (https://www.
ncbi.nlm.nih.gov/clinvar/) is also a useful tool for interpretation of the pathogenic-
ity. Though, we have to keep it in our mind that the ClinVar database is based on the
deposited data from various submitters. The submitters have their own criteria for
the classification of the pathogenicity and you may encounter the conflicting clas-
sification of the pathogenicity of some variants among the submitters. A careful
evaluation of the submitters’ criteria may be needed for deciphering the reason of
the conflict. Other shared databases useful for the interpretation of the variants’
pathogenicity are the Universal Mutation Database (UMD) (http://www.umd.be),
InSiGHT (https://www.insight-database.org/genes/), the human gene variant-
disease database at the University of Utah (http://www.arup.utah.edu/database/
index.php), etc.
10.6 Concluding Remarks
The introduction of the NGS technology for the genetic testing of the HCCPS has
reduced the cost and consuming-time, making it possible to offer the service to the
public. On the other hand, when returning the test result, a careful examination of
each test should be required for the clinicians.
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Chapter 11
Clinical Management of Hereditary
Colorectal Cancer
Kensuke Kumamoto and Hideyuki Ishida
Abstract Lynch syndrome (LS) is an autosomal dominant inherited syndrome

characterized by the development of early-onset colorectal cancer (CRC), endome-
trial cancer, and other cancers. Universal tumor screening for detection of LS in all
CRC and endometrial cancer patients tends to be popular instead of use of conven-
tional clinical guidelines. Immunohistochemistry of mismatch repair proteins
appears to be favorable compared to microsatellite instability (MSI) testing in terms
of identification of the causative gene. The surveillance for individuals with LS is
established in CRC and gynecological cancer depending on the causative genes,
while there are still no evidences in other LS-associated cancers. Among adenoma-
tous polyposis syndrome, more than 100 polyps clinically come up with the diagno-
sis of familial adenomatous polyposis (FAP). If the number of polyps is less than
100, germline genetic testing of the APC, MUTYH, POLE, and POLD1 genes
should be needed to make an accurate diagnosis. Early diagnosis and management
is required due to complete penetrance and an almost 100% lifetime risk of CRC
without intervention in FAP patients. In addition to CRC, the screening of duodenal
cancer and desmoid tumors should be routinely performed to prevent the
mortality.
Keywords Hereditary colorectal cancer · Lynch syndrome · Lynch-like syndrome

Familial adenomatous polyposis (FAP) · Microsatellite instability (MSI)
K. Kumamoto (*)
Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University,
Miki-cho, Kagawa, Japan
e-mail: kumamotk@med.kagawa-u.ac.jp
H. Ishida
Department of Digestive Tract and General Surgery, Saitama Medical Center,
Saitama Medical University, Kawagoe, Saitama, Japan
e-mail: 05hishi@saitama-med.ac.jp

128 K. Kumamoto and H. Ishida
11.1 Introduction
Recent progress of genetic analysis, including next generation DNA sequencing,

has greatly improved the detection of DNA variations and contributes to a personal-
ized management of hereditary colorectal cancer (CRC). As much as 35% of CRC
have a hereditary component to their disease, and 5% linked to inherited mutations
in cancer-predisposing genes [1]. Lynch syndrome (LS) is most frequent disease
among hereditary CRC and comprises 2–4% of all CRCs. The following hereditary
CRC is the familial adenomatous polyposis (FAP) at less than 1% among all CRCs.
In this chapter, the clinical management of hereditary CRC focusing on LS and FAP
is outlined.
11.2 Classification
The classification of hereditary CRC can be macroscopically divided by polyp types

and the number of polyps though histological confirmation by biopsy of a represen-
tative polyp should be required for definitive diagnosis (Fig. 11.1). Adenomatous
polyps of more than ten polyps at colon and rectum indicate FAP, attenuated FAP
(AFAP), and MUTYH-associated polyposis (MAP). Grover et al. [2] reported that
80% (95/119), 56% (756/1338), 10% (326/3253), and 5% (50/570) had a patho-
genic germline APC mutation in individuals with ≥1000, 100–999, 20–99, and
10–19 adenomas, respectively. Since the number of polyps is mostly less than
100 in AFAP and MAP, genetic testing will be needed to accurate diagnosis of these
The number of polyp 0 10 100 1000
Familial adenomatous polyposis

(FAP)
Attenuated FAP
MUTYH-associated
Adenomatous polyposis (MAP)
polyps Polymerase proofreading-
associated polyposis (PPAP)
Lynch
syndrome
Li-Fraumeni
syndrome
Peutz-Jeghers
syndrome
Hamartomatous Juvenile polyposis
polyps syndrome
Cowden’s syndrome
Fig. 11.1 Classification of common syndromes by histological type and the number of polyps
11 Clinical Management of Hereditary Colorectal Cancer 129
diseases. Recently, polymerase proofreading-associated polyposis (PPAP) is also

included in these polyposis with mostly 10–99 adenomas. Individuals with LS or
Li-Fraumeni syndrome have usually a few adenomatous polyps.
When the histological type of polyps is a hamartomatous polyp and the number
of polyps is around 2–100, Peutz–Jeghers syndrome, Juvenile polyposis syndrome,
and Cowden/Hamartomatous syndrome are suspected with extraintestinal features
of each syndrome.
11.3 Lynch Syndrome
11.3.1 Clinical and Molecular Diagnosis
LS is an autosomal dominant inherited condition characterized by the development

of early-onset CRC, endometrial, and other cancers. The flowchart of diagnosis for
LS suspected patients is shown in Fig. 11.2. Routine use of the Amsterdam criteria
II (AC-II) [3] and revised Bethesda guidelines (rBG) [4] is recommended in clinical
practice to diagnose and identification of at-risk patients for LS (Table 11.1),
whereas diagnosis of LS requires presence of a genetically confirmed
Conventional screening Universal tumor screening
Clinical information from individuals

CRC<70 years, or CRC>70 years +
with suspected Lynch syndrome
Revised Bethesda guidelines
Family history Age of onset
Related tumors Pathological findings
Fulfillment of Fulfillment of revised

Amsterdam criteria II Bethesda guidelines
Immunohistochemistry (IHC) of MMR proteins ± MSI testing
Loss of expression by IHC ± MSI-H Normal staining by IHC and MSS/MSI-L
Loss of MLH1 Loss of MSH2, MSH6 or PMS2 Fulfillment of

Amsterdam criteria I
Somatic BRAF mutation ±
MLH1 hypermethylation analysis
Familial colorectal
cancer type X
Positive Negative
Germline genetic analysis of the corresponding gene

Sporadic MSI-H CRC
Positive Negative
Lynch syndrome Lynch-like syndrome
Fig. 11.2 Algorithm for molecular diagnosis of Lynch syndrome, Lynch-like syndrome, familial
colorectal cancer type X, and sporadic MSI-high colorectal cancer (MSI-H CRC)
Table 11.1 Primary screening for Lynch syndrome

Amsterdam II At least three relatives with Lynch syndrome (LS)-associated cancersa
criteria (a) One of which is a first-degree relative to the other two
(b) At least two successive generations should be affected
(c) At least one should be diagnosed before age 50
(d) Familial adenomatous polyposis should be excluded
(e) Tumors should be verified by pathological examination
Revised Bethesda Tumors from individuals should be tested for microsatellite instability
guidelines (MSI) in the following situations:
(a) Colorectal cancer (CRC) diagnosed in a patient who is younger than
50 years of age
(b) Presence of synchronous, or metachronous, colorectal or other
LS-associated tumorsb; regardless of age
(c) CRC with MSI-high histology diagnosed in a patient who is younger
than 60 years of age
(d) CRC diagnosed in a patient with one or more first-degree relatives with
a LS-associated cancer, with one of the cancers being diagnosed under
age 50 years
(e) CRC diagnosed in a patient with two or more first- or second-degree
relatives with LS-associated cancer regardless of age
a
Colorectal cancer (CRC), endometrial cancer, renal pelvic/ureteral cancer and small-intestinal
cancer
b
Endometrial cancer, gastric cancer, small-intestinal cancer, ovarian cancer, pancreatic cancer,
renal pelvic/ureteral cancer, biliary tract cancer, brain tumors, sebaceous gland adenomas, and
keratoacanthomas
disease-predisposing mismatch repair (MMR) gene’s mutation. The AC requires at

least three affected family members in two or more generations, with one being a
first-degree relative of the other two and at least one individual diagnosed before
50 years of age. AC-I applies to families with three or more cases of CRC and AC-II
also includes extracolonic tumors, such as endometrial cancer, renal pelvic/ureteral
cancer, and small-intestinal cancer. The rBG included the tumor marker of micro-
satellite instability (MSI) for patients with CRC and other LS-associated tumors,
including endometrial cancer, gastric cancer, small-intestinal cancer, ovarian can-
cer, pancreatic cancer, renal pelvic/ureteral cancer, biliary tract cancer, brain tumors,
sebaceous gland adenomas, and keratoacanthomas. It has been reported that 27–41%
[5, 6] of LS families meet the AC-II and that 68–89% meet the rBG, suggesting that
more patients with LS can be identified using the rBG [6]. But then, approximately
10–30% LS patients would be still missed with rBG. Therefore, the universal tumor
testing (UTS) is becoming popular in the Western countries for screening of all the
CRC patients under 70 years of age or CRC patients over 70 years with fulfillment
of rBG using MSI testing or immunohistochemistry (IHC) testing [6, 7], although
these testing have been conventionally performed to the individuals who fulfilled
AC-II or rBG (Fig. 11.2). IHC testing of tumor tissue can detect loss of MMR pro-
teins with sensitivity of 83% and specificity of 89%. The sensitivity for MSI is
estimated at 85% and specificity at 90%. Since the result of IHC testing can provide
the candidate MMR genes mutated, IHC is a reasonable method for UTS of
LS. Once one or two loss of MMR proteins are lost in tumor tissue using IHC test-
ing, germline genetic testing can be targeted to the gene associated with the absent
protein. However, 10–15% of sporadic CRC show MSI and loss of MLH1 expres-
sion due to somatic events such as the MLH1 promotor hypermethylation or a
BRAF-V600E mutation. When the loss of MLH1 expression is observed in cancer
cells, BRAF testing or analysis for the MLH1 promoter hypermethylation should be
performed first prior to the genetic testing. If the result is positive, germline analysis
is no longer required in most cases.
Lynch-like syndrome (LLS) has been suggested that tumor shows the presence
of MSI without the MLH1 promoter hypermethylation or a BRAF V600E mutation,
and shows deficient MMR proteins by IHC staining though no pathogenic germline
mutations or deletions of MMR genes or EPCAM are detected in patients with CRC
or other LS-associated cancers [8, 9]. Recently, somatic mutations in the MMR
genes in the absence of germline mutations have been revealed to be a novel mecha-
nism responsible for the occurrence of deficient MMR tumors in a subset of patients
initially suspected as having LS [10–12]. Patients defined as LLS are estimated to
account for as much as 70% of suspected LS patients [12, 13].
Families meeting AC-I for LS, but not carrying deleterious alterations in MMR
genes, nor MSI, are defined as having familial colorectal cancer type X (FCCTX)
[14, 15].
Recently, direct genetic testing is also becoming a more viable option with reduc-
tion in cost using next generation sequencer [16]. It would be a promising method
for direct diagnosis of LS and non-LS.
11.3.2 Clinical Feature
Approximately 70% of CRC in LS are predominantly found in the right colon [17,
18]. The median age of onset of CRC in patients with LS is earlier than the general
population (45 years compared to 63 years) [19]. CRC in LS is characterized by
accelerated carcinogenesis that an adenoma-carcinoma progression ratio is 1:1 and
an estimated adenoma-carcinoma transformation time is 1–3 years, while sporadic
CRC has a ratio of 30:1 and estimated adenoma-cancer transformation time of
8–17 years [20].
The lifetime risk (until 70 years) of CRC development in male patients with LS
is 54–74%, and that in female patients with LS is 30–52% [21]. The risk of develop-
ment of LS-associated tumors varies depending on the causative gene, the type of
mutation, environmental factors, etc. [21]. Together with MLH1, MSH2 is one of the
most frequently mutated MMR genes. Individuals with a pathogenic mutation of
these genes have an increased risk of the whole spectrum of LS-associated tumors.
On the other hand, individuals with mutations in MSH6 have a lower risk of CRC
since the estimated cumulative risks to ages 70 years are 10% in female patients and
22% in male patients. Moreover, their age at the onset of CRC is about 10 years later
than that in individuals with mutations in MLH1 or MSH2 [22]. Individuals with a
PMS2 mutation also have a lower risk of CRC (15% in female patients and 20% in
male patients) [23] similar with those with an MSH6 mutation.
Patients with LS can develop the extracolonic cancers called LS-associated can-
cers, including endometrial cancer (the estimated cumulative risks to ages 70 years;
28–60%), gastric cancer (5.8–13%), ovarian cancer (6.1–13.5%), small-intestinal
cancer (2.5–4.3%), biliary tract cancer (1.4–2.0%), pancreatic cancer (0.4–3.7%),
renal pelvic/ureteral cancer (3.2–8.4%), brain tumors (2.1–3.7%), and sebaceous
gland adenomas/keratoacanthomas (unknown) [21]. Muir–Torre syndrome refers to
patients with the addition of cutaneous gland tumors (sebaceous gland neoplasms or
keratoacanthomas). MSH2 mutations are predominantly involved with the develop-
ment of this syndrome [24]. The type 1 of Turcot’s syndrome is characterized by an
association of malignant tumors of central nervous system (glioblastoma) and CRC
or LS-associated cancers in patients with LS.
11.3.3 Clinical Management
A retrospective cohort study of 332 CRC patients with LS reported that the 10-, 20-
and 30-year cumulative incidences of development of metachronous CRC after par-
tial colectomy (segmental resection) were 16%, 41%, and 62%, respectively, and
that the risk of development of metachronous CRC was lower when a longer seg-
ment of the intestine was resected [25]. In addition, according to another retrospec-
tive cohort study from Korea, the cumulative risk of metachronous CRC was 20.4%
at 10 years after segmental colectomy, while none of the patients who underwent
extensive colectomy were diagnosed with metachronous CRC [26]. Although a total
colectomy may be considered to prevent the appearance of a second primary after
the primary CRC, no difference in overall survival was observed between segmental
colectomy and extensive colectomy [26]. Therefore, the decision to undertake a
total colectomy appears to be relatively aggressive when several problems may hap-
pen due to decreased anorectal function. Also, no consensus has been reached on
whether prophylactic colectomy should be performed in mutation carriers who have
not developed CRC since a substantial number of mutation carriers do not develop
CRC throughout their lifetimes. Women with LS should contemplate prophylactic
hysterectomy and oophorectomy after childbearing because these methods are only
proven intervention which significantly reduces the risk of both endometrial and
ovarian cancer [27].
There are currently no reliable evidences on the chemotherapeutic treatment of
CRC in LS, and adjuvant chemotherapy with 5-fluorouracil (5-FU). Previous stud-
ies [28, 29] have shown that stage II and III CRC patients with MSI-high (MSI-H)
have a better prognosis than those with MSI-low and microsatellite stable (MSS)
without adjuvant chemotherapy of 5-FU. In addition, adjuvant chemotherapy with
5-FU did not improve 5-year survival rates in patients who had MSI-H tumors [28].
However, another study has shown that stage III CRC patients with MSI-H receiving
adjuvant chemotherapy with 5-FU had significantly lower rates of distant recur-
rence compared to those who underwent surgery only (11% vs. 29%, p = 0.011)
[30]. Moreover, the subset of patients who had benefit from adjuvant chemotherapy
with 5-FU were those with suspected germline mutations in MMR genes, indicating
that adjuvant 5-FU-based treatment may be beneficial to reduce the distant recur-
rence risk in the stage III CRC patients with LS [30].
In May 2017, the US Food and Drug Administration granted accelerated approval
to pembrolizumab for refractory, defective MMR (dMMR)/MSI-H tumors includ-
ing dMMR/MSI-H metastatic CRC, where data from multi-cohort studies [31–34]
showed an overall objective response of 36% and a duration of response ranging
from 1.6 to 22.7 months. A subset of cancer patients with MSI-H or dMMR, includ-
ing LS patients, will have benefit for the improvement of overall survival by the
treatment of anti-PD-1 antibody [31, 35].
Regarding chemoprevention for CRC treated with intake of aspirin, recent data
from the Colorectal Adenoma/Carcinoma Prevention Program (CAPP2) in a ran-
domized, placebo-controlled trial showed a significant 60% reduction in the inci-
dence of CRC and other LS-associated cancers using 600 mg of aspirin per day for
at least 2 years [36, 37]. There is also some evidence for low-dose aspirin (100 mg),
but this is currently the subject of a randomized controlled trial (CAPP3).
11.3.4 Surveillance
There are substantial evidences that surveillance contributes the reduction in CRC
incidence and mortality in LS patients [38–42]. The recent screening recommenda-
tions for LS patients, including NCCN (National Comprehensive Cancer Network)
guidelines [43], ACG (American College of Gastroenterology) guidelines [44],
ESMO (European Society for Medical Oncology) guidelines [36], and JSCCR
(Japanese Society for Cancer of the Colon and Rectum) guidelines [21], are sum-
marized in Table 11.2. In general, CRC surveillance by colonoscopy is recom-
mended for all individuals with LS at age 20–25 years or 5 years younger than the
youngest case in the family (if diagnosed before age 25). It has been reported that a
lower risk of CRC development was observed when a colonoscopy interval of
1–2 years was followed as compared to screening in 2–3 years intervals [41]. NCCN
guidelines recommend the surveillance colonoscopy every 1–2 years in confirmed
mutation carriers. Since LS patients with MSH6 mutations are known to have a
lower cancer risk, colonoscopy is recommended every 2–3 years starting at age of
30–35 years (or 10 years before the age of the youngest case in the family). From
age 40 this changes to annual screening. In carriers of PMS2 mutations, screening
starts at 35–40 years of age at the same frequency (2–3 years) unless an early-onset
cancer exits in a given family. In women with LS for the screening of gynecological
cancers, transvaginal ultrasonography with endometrial aspiration and optional
CA-125 tumor marker detection are recommended starting at 30–35 years of age
and performed every year. In families with aggregation of gastric cancer, an upper
Table 11.2 Surveillance recommendations for Lynch syndrome families
134
NCCN guidelines ACG guidelines ESMO guidelines JSCCR guidelines

Cancer Recommendations Age Recommendations Age Recommendations Age Recommendations Age
Colon Colonoscopy every 20–25 years Colonoscopy at 20–25 years Colonoscopy every 20–25 years Colonoscopy every 20–25 years
1–2 years or 2–5 years least every 2 years 1–2 years or 5 years 1–2 years
prior to the Annual colonoscopy before the
earliest colon should be youngest
cancer if it is considered in case in the
diagnosed confirmed mutation family
before age carriers
25 years
Endometrium Endometrial biopsy Endometrial biopsy 30–35 years Gynecological 30–35 years Endometrial 30–35 years
and ovary every 1–2 years, and transvaginal examination, pelvic biopsy and
transvaginal ultrasound annually ultrasound, CA-125 transvaginal
ultrasound and analysis, and ultrasound,
serum CA-125 aspiration biopsy CA-125 every
every year 6 months to 1 year
Consider After Consider After Consider After Consider
prophylactic childbearing prophylactic childbearing prophylactic childbearing prophylactic
hysterectomy and complete hysterectomy and complete, hysterectomy and complete
bilateral bilateral optimally at bilateral
salpingo- salpingo- age salpingo-
oophorectomy oophorectomy 40–45 years oophorectomy
Upper Selected 30–35 years Urinalysis every 30–35 years
urinary tract individuals with a 1–2 years
family history of
urothelial cancer or
individuals with
MSH2 mutations
(especially males).
Annual urinalysis
K. Kumamoto and H. Ishida
Upper GI Selected 30–35 years If there is a family 30–35 years The search for the EGD every 30–35 years
tract individuals with a history of gastric or presence of 1–2 years
family history of duodenal cancer, Helicobacter Pylori
upper GI cancer or consider EGD every and subsequent
Asian descent. 3–5 years eradication is
Consider EGD recommended. In
every 3–5 years case of a high
incidence of gastric
cancer in some
populations, some
experts recommend
upper
gastrointestinal
endoscopy every
1–3 years
Central Consider annual 25–30 years
nervous physical/neurologic
system examination
(CNS)
Comments Other than colon and endometrial Screening beyond population- Other LS-associated cancers;
11 Clinical Management of Hereditary Colorectal Cancer
cancer, recommendations are based recommendations for Surveillance is not recommended

expert opinion rather than cancers of the urinary tract, due to the low sensitivity and
evidence-based. pancreas, prostate, and breast is specificity.
not recommended unless there is a
family history of the specific
cancers
135
gastrointestinal endoscopy with careful inspection of the duodenum is recom-

mended every 3–5 years starting at 30–35 years of age. For urothelial cancers, cyto-
logical analysis of urine and renal ultrasonography should be performed every
1–2 years starting at 30–35 years of age. It has been suggested that families with LS
have an increased risk of breast cancer but there is insufficient evidence to give
specific screening recommendations. There is no sufficient evidence for screening
of other tumors associated with LS (brain, pancreas, biliary tract, small bowel, etc.).
11.4 Familial Adenomatous Polyposis (FAP)
11.4.1 Clinical and Molecular Diagnosis
FAP is an autosomal dominant hereditary cancer caused by germline mutations in

the APC gene, which is a tumor suppressor gene associated with the WNT signaling
pathway. Flowchart for the diagnosis of FAP has shown in Fig. 11.3. A clinical
diagnosis of FAP can be made when at least 100 colonic adenomas are observed on
a colonoscopy. Although most patients have a family history of FAP, approximately
30% of FAP and AFAP have no family history, leading to suggest that most of these
represent de novo APC mutations [45]. Among these cases, mutations in MUTYH
have been identified in some patients. MAP is an autosomal-recessive pattern of
inheritance and shows an attenuated phenotype with fewer polyps [46]. Genetic
testing is recommended when more than 10 cumulative adenomatous polyps are
observed on a colonoscopy [2]. In 10–30% of patients clinically diagnosed with
Adenomatous polyps
More than 100 Less than 100
FAP family history

>1,000 or 2,000 100–1,000 or 2,000
A large number of Multiple adenomas Positive Negative or unknown

adenomas such that on a background of
the normal mucosa normal mucosa
cannot be visualized Germline APC mutation
(+) (-)
Frequent germline mutation site: Frequent germline mutation site: Germline MUTYH mutation
Codons 1250 to 1464 The alternative splicing region
or the 5’ or 3’ region (+) (-)
Profuse FAP Sparse FAP Attenuated FAP MUTYH- Multiple

associated adenomas
polyposis (possibility of
PPAP)
Fig. 11.3 Algorithm for clinical and genetic diagnosis in polyposis syndromes
FAP, no identifiable mutations are detected in the APC gene [2]. If the APC muta-
tion is not detected, the patient should be tested for a MUTYH mutation. Some cases
without APC and MUTYH mutations can be explained by mutations of other genes,
such as POLE and POLD1, which are causative genes of PPAP. There have also
been cases of mosaic APC mutations which cause polyposis in only one segment or
more of the colon. Somatic mutations found only in the tissue do not confer a repro-
ductive risk though mutations in the APC gene, if present in some germ cells (sex
mosaicism), may be passed on to the next generation. A genotype–phenotype cor-
relation has been described [47]. Mutations between codons 1250 and 1464, espe-
cially those in codon 1309, are associated with a more severe manifestation of the
disease [36]. On the other hand, mutations located at either end of the APC gene or
in exon 9 are associated with a mild polyposis phenotype known as AFAP.
11.4.2 Clinical Feature
FAP is the second most common hereditary CRC syndrome following LS. FAP is
an autosomal dominant syndrome that clinically presents with generally hundreds
to thousands of adenomatous polyps distributed throughout the colon and rectum.
The mean age of polyp occurrence is 15.9 years (range, 8–34 years) [48]. If patients
are not treated in a timely manner, polyps will develop CRC at an average age of
39 years [44]. By 45 years of age, 87% had developed cancer, and by 50 years, it
increased to 93% [44].
FAP is associated with upper gastrointestinal adenoma (95%), gastric fundic
gland polyps (80–90%), desmoid tumors (15–30%), osteomas (80%), congenital
hypertrophy of the retinal pigmented epithelium (CHRPE) (75%), supernumerary
teeth (17%), epidermoid cysts (50%), thyroid tumors, and brain tumors [49]. Fundic
gland polyps and adenomas in the duodenum are commonly found in 80% of
patients with FAP, but the risk of developing duodenal cancer is less than 15% in
untreated FAP patients [50]. Patients with FAP also typically develop desmoid
tumors in the mesentery and retroperitoneal tissues or in the abdominal wall after
surgery [51]. Among the main extracolonic manifestations, duodenal cancer and
desmoid tumor are the second or third causes of death following CRC in FAP
patients [52].
Gardner syndrome represents a variation on the FAP phenotype with the addition
of subcutaneous soft tissue tumors, osteomas, dental abnormalities, and desmoid
tumors. At present, the term Gardner syndrome is usually not used. Colorectal pol-
yposis associated with brain tumor (glioblastoma and medulloblastoma), and with a
germline mutation in the APC gene is called Turcot syndrome, type 2 (see Lynch
syndrome for Turcot syndrome, type 1).
AFAP patients often develop CRC at a later age than typical FAP patients. The
mean age at onset of CRC was 58 (29–81) years, and 75% of the patients had cancer
of the proximal colon [53]. The cumulative incidence of CRC up to 80 years of age
(69%) was lower than that in typical FAP patients (almost 100%).
11.4.3 Clinical Management
Early diagnosis and management is required due to complete penetrance and an

almost 100% lifetime risk of CRC without intervention in FAP patients. Surgery is
usually undertaken in the late teens or twenties if the disease is diagnosed at a young
age, depending on the number and size of adenomas and individual decision [54].
The surgical treatment for colorectal polyposis is total colectomy with ileorectal
anastomosis (IRA), or proctocolectomy with ileal-pouch-anal anastomosis (IPAA)
if patients have multiple adenomas in the rectum and/or if the patient has a genotype
that is associated with severe disease [47]. IPAA is the standard surgical procedure
for typical FAP [55]. IPAA is largely divided into hand-sewn IPAA, in which the
rectal mucosa is dissected from the dentate line and an ileal pouch is then anasto-
mosed manually to the dentate line, and stapled IPAA, in which stapling anastomo-
sis of the surgical anal canal and an ileal pouch is performed. IRA is recommended
for sparse-type FAP patients who have less than 20 rectal adenomas with a maxi-
mum diameter of less than 10 mm, young females who wish to become pregnant,
and children/adolescents before school age/employment [55, 56]. A recent report
has been described that IPAA was associated with improved long-term survival
without an increase in postoperative complications because the risk of death after
colectomy and IRA seemed to be predominantly related to the remaining risk of
rectal cancer [57]. It has been reported from Japan that laparoscopic surgery has
been performed in more than 70% of cases and that hand-sewn IPAA has been
selected in an increasing proportion of cases with similar outcome compared to
open approach [58, 59].
In AFAP patients without rectal cancer, IRA and endoscopic polypectomy with
long-term follow-up are valid options.
The preferred treatment for duodenal polyps is endoscopic removal of adenomas
by an experienced gastroenterologist. The duodenal adenoma burden is scored using
the Spigelman staging system [60], which is a scoring system ranging from stage 0
to IV and points are calculated based on the number of polyps, polyp size, histology,
and dysplasia (Table 11.3). Endoscopic surveillance intervals are determined using
the points obtained, and range between 6 months to 4 years [44]. Approximately
50% of FAP patients develop ampullary tumors [61, 62]. Surgical options include
pancreas-sparing duodenectomy (PSD) [63] that may be selected if there is a peri-
ampullary lesion that is difficult to treat endoscopically, and pancreaticoduodenec-
tomy and pylorus-preserving pancreaticoduodenectomy (PPPD) that should be
selected in more advanced cases.
Desmoid tumors are histologically benign tumors, but they can have an unpre-
dictable and sometimes aggressive growth pattern, leading to serious morbidity or
even mortality by local invasion into surrounding vital structures [64]. The first-line
treatment of large or growing intra-abdominal and abdominal wall tumors consists
of medical treatment with sulindac (300 mg), usually in combination with either
tamoxifen (40–120 mg) or toremifene (180 mg) [36, 65]. When desmoid tumors
rapidly grow without response to this treatment, chemotherapy will be adminis-
Table 11.3 Duodenal adenomatosis Spigelman staging systema

Score 1 2 3
Number of polyps <5 5–20 >20
Size 0–4 mm 5–10 mm >10 mm
Histology Tubular Tubulovillous Villous
Dysplasia Mild Moderate Severe
Spigelman stage Total points Management/surveillance frequencyb
0 0 Every 4 years
I <5 Every 2–3 years
II 5–6 Every 1–3 years
III 7–8 Every 6–12 months
IV 9–12 Expert surveillance every 3–6 months and surgical
evaluation
a
Adapted from [61]
b
Adapted from NCCN Guidelines [43]
Table 11.4 Staging system and treatment for intra-abdominal desmoid tumors according to
Church’s classification
I II III IV
Maximal size <10 cm 10–20 cm >20 cm
Growth speed No growth within 6 months Growth within More than 50%
6 months increase in
maximal diameter
within 3 months
Uretic obstruction No Yes
Bowel obstruction No Yes
Sensation of tumor No Yes
Pain No Yes
Restriction of daily No Yes
life
Hospitalization Unnecessary Necessary
Treatment Observation or NSAIDs ± TAM Chemotherapy ± Chemotherapy,
NSAIDs NSAIDs ± TAM surgical operation
TAM tamoxifen, NSAIDs nonsteroidal anti-inflammatory drugs
tered. Regarding cytotoxic chemotherapy, high response rates were reported with a
combination regimen of doxorubicin plus dacarbazine [54, 64]. Surgery is recom-
mended in patients with extra-abdominal desmoid tumors, while the role of surgery
in intra-abdominal desmoid tumors is controversial [64]. A staging system for intra-
abdominal desmoid tumors has been developed by reference to the classification of
Church et al. [66] (Table 11.4).
Cyclooxygenase-2 (COX-2) has been shown to be overexpressed in colorectal
adenomatous polyps and cancers. Secondary chemoprevention (after surgery) with
the use of sulindac, a nonsteroidal anti-inflammatory drug, and celecoxib, a selec-
tive COX-2 inhibitor, has been shown to reduce the number and extent of colorectal
adenomas and, less reliably, duodenal adenomas, while there is no evidence for
reduction in the incidence of CRC [54]. As cardiovascular side-effects have been
reported in patients receiving selective COX-2 inhibitors, caution is warranted.
11.4.4 Surveillance
Endoscopic screening for FAP patients and their family members has reduced the
rate of CRC at the time of FAP diagnosis by 55% [67]. According to the NCCN
guidelines [43], colonoscopy or sigmoidoscopy is performed every 12 months
beginning at age 10–15 years in the APC mutation carriers. The ESMO guidelines
recommend that sigmoidoscopy is performed every 2 years, starting at age
12–14 years and continued lifelong in individuals with an APC mutation [36]. Once
adenomas are detected, annual colonoscopy should be carried out until prophylactic
colectomy is planned.
The risk of rectal adenoma and cancer remains after colectomy with IRA and
even in the pouch after IPAA. Long-term follow-up after IRA has revealed that
24–43% of patients develop cancer in the remaining rectum [68, 69]. During a
20-year period after IRA, the rectum had to be resected in 10% of patients with
AFAP, 39% of patients with sparse FAP, and 61% of patients with profuse FAP [47].
Accordingly, regular endoscopic surveillance every 12 months after surgery is
needed to detect adenoma recurrence early.
For gastroduodenal adenomas, gastroduodenal endoscopy using both front- and
side-view scopes should be started when colorectal polyposis is diagnosed or at age
25–30 years, whichever comes first [36]. Surveillance of duodenal adenomatosis
will depend on its extension based on the Spigelman classification (Table 11.3),
since the risk of cancer appears to be related to stage. Duodenal cancer risk is 5%,
increasing to 36% in patients with Spigelman stage III/IV [54]. When it corresponds
to Spigelman stage I or II, upper endoscopy can be carried out every 1–3 years,
respectively, whereas in more advanced forms, intervals between examinations
should be shortened to every 6 months to 1 years (Spigelman stage III) or to
3–6 months (Spigelman IV). If there are risk factors related to desmoid tumors,
including positive family history for desmoids and site of the mutation in APC,
computed tomography (CT) scan or magnetic resonance imaging (MRI) should be
considered. ESMO also recommends annual cervical ultrasonography for thyroid
cancer, starting at age 25–30 years [36].
The risk for hepatoblastoma in FAP is 176–420 times higher than in the general
population [70, 71], although the absolute risk is estimated at less than 0.42–0.75%
[72]. The majority of hepatoblastoma occur prior to the age of 3 years. Screening
for hepatoblastoma in FAP using abdominal ultrasound examination (every
2–3 months) may be considered from infancy to the age of 5 years.
11.5 Conclusions
Clinical management and surveillance of hereditary CRCs are based on evidences

from Western countries in which families have been formally registered. With the
development of the next generation sequencer, it is coming time to easily diagnose
LS, FAP, and other inherited CRCs in the world. There is also the possibility that
novel genes will be discovered for hereditary CRCs, including FCCTX and unknown
polyposis, in near future. In recent years, it has been reported that anti-PD-1 anti-
body is effective for many cancers with MSI-H, and then potential individuals with
LS will be discovered when MSI testing is performed as companion diagnosis.
Since the confirmation of hereditary CRC by a genetic testing leads to a decrease in
mortality rate with proper surveillance, it is desirable to further enlightenment.
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Recent Advances

Recent Advances in the

ISBN 978-981-13-3049-0 ISBN 978-981-13-3050-6 (eBook)

Library of Congress Control Number: 2018965168

© Springer Nature Singapore Pte Ltd. 2019

Saitama, Japan Hideyuki Ishida

Part I Endoscopic Treatment

Part II Surgical Treatment

9 Chemotherapy for Metastatic Colorectal Cancer���������������������������������� 101

Part IV Hereditary Colorectal Cancer

Masayoshi Yamada, Yutaka Saito, Stefano Sansone, Hiroyuki Takamaru,

Abstract Endoscopic diagnosis and treatments have made considerable progress

Keywords Endoscopic resection · Endoscopic submucosal dissection

M. Yamada · Y. Saito (*) · H. Takamaru · T. Sakamoto

© Springer Nature Singapore Pte Ltd. 2019 3

1.2 Treatment Selection

Endoscopic diagnosis plays a crucial role in determining treatment strategy

Table 1.1 Strategy of endoscopic treatment in colorectum

Detailed inspection of colorectal lesions is required in order to pursue an accu-

1.3 Endoscopic Treatment Strategy

Cold polypectomy is the removal of small non-pedunculated polyps without

Image b Image c Image d

Image b, c Image b, c, d Image e

in detail as a full-thickness en-bloc specimen is obtained. The main limitation is

Table 1.2 LST-G with no risk of submucosal invasion

Fig. 1.4 Representative images of LST-G with no risk of submucosal invasion

1.6 Supportive Devices in Endoscopic Treatment

Selection of the appropriate endoscopic treatment is based on oncological indica-

Abstract Colonic stent (SEMS: self-expandable metallic stent) treatment for

Keywords Colonic stent · Colorectal obstruction · Palliative treatment · Bridge to

© Springer Nature Singapore Pte Ltd. 2019 17

2.3 Evaluation of Colonic Obstruction/Stenosis

The evaluation of colonic obstruction/stenosis lacks any formally established

Table 2.1 The ColoRectal Obstruction Scoring System: CROSS

2.4 Bridge to Surgery (BTS)

When an obstructive colorectal cancer is surgically curable, consideration must be

Right side obstruction Left side obstruction

Nasogastric or Long ileus tube Oral intake

Poor or failure Pre Op Exam

Fig. 2.1 Strategy for Curative Obstructive Colorectal Cancers

2.5 Indications and Contraindications for Colonic Stents

2012.1- WallFlex™ 2013.7- Niti-S Stent™

2017.10- Naturfit 2018.1- JentllyStent

Fig. 2.2 Colonic stent in Japan

Expanded colonic stent

Clip for marking

Fig. 2.3 Colonic stent for right side/proximal colon

2.6 Outcomes with Colonic Stents

Among endoscopic and interventional radiology treatments, colonic stenting to

4. Cheynel N, Cortet M, Lepage C, et al. Trends in frequency and management of obstructing

Abstract Regardless of Western countries or Japan, surgical resection is the most

Keywords Colorectal cancer · D3 lymph node dissection · Lateral lymph node

© Springer Nature Singapore Pte Ltd. 2019 27

3.2 D3 Lymph Nodes Dissection for Colon Cancer

3.2.1 J apanese Categorization of the Regional

Since the first publication of the Japanese Classification of Colorectal Carcinoma in

D1 dissection is defined as lymphadenectomy around the paracolic nodes, D2 as

Fig. 3.2 A schema of

Fig. 3.3 A schema of the

3.2.4 Longitudinal Resection Margin for Colon Cancer

3.3 D3 Lymph Nodes Dissection for Rectal Cancer

3.3.1 J apanese Categorization of Regional Lymph Nodes

According to the Japanese Classification of Colorectal Carcinoma, regional lymph

Saitama, Japan Hideyuki Ishida

Part I Endoscopic Treatment

Part II Surgical Treatment

9 Chemotherapy for Metastatic Colorectal Cancer�� 101

Part IV Hereditary Colorectal Cancer

1.2 Treatment Selection

1.3 Endoscopic Treatment Strategy

1.6 Supportive Devices in Endoscopic Treatment

2.3 Evaluation of Colonic Obstruction/Stenosis

2.4 Bridge to Surgery (BTS)

2.5 Indications and Contraindications for Colonic Stents

2.6 Outcomes with Colonic Stents

3.2 D3 Lymph Nodes Dissection for Colon Cancer

3.2.1 J apanese Categorization of the Regional

3.2.4 Longitudinal Resection Margin for Colon Cancer

3.3 D3 Lymph Nodes Dissection for Rectal Cancer

3.3.1 J apanese Categorization of Regional Lymph Nodes

3.3.3 I ndications for Lateral Lymph Node Dissection

4.1 Laparoscopic Surgery for Colon Cancer (Table 4.1)

4.2 Laparoscopic Surgery for Rectal Cancer (Table 4.2)

4.3 Laparoscopic Lateral Pelvic Lymph Node Dissection

5.2 Learning Curve

5.3 Perioperative Outcomes

5.3.1 Operation Time and Blood Loss

5.3.3 Postoperative complications

5.3.4 Functional Outcomes

5.4 Oncological Outcomes

5.6 Lateral Lymph Node Dissection

5.7 Future Prospects

6.2 Definition of ISR

6.3 Surgical Technique

6.4 Patients and Methods

6.5.1 Patient and Tumor Characteristics

6.5.2 Surgical Procedures

6.5.3 Postoperative Complications

6.5.4 Oncologic Outcomes

6.5.5 Functional Outcomes

6.7 Surgical and Oncological Outcomes

6.8 Functional Outcomes

6.9 Indication to ISR

7.1.1 CRT with Local Excision

7.1.2 CRT with TME

7.1.3 Borderline Resectable, Locally Advanced Rectal Cancer

7.1.4 Lateral Pelvic Lymph Node Dissection and CRT

7.1.5 Local Recurrence and CRT

7.1.6 Management of Clinical Complete Response in CRT