Int J Clin Oncol (2012) 17:129

DOI 10.1007/s10147-011-0315-2

SPECIAL ARTICLE

Japanese Society for Cancer of the Colon and Rectum (JSCCR)

guidelines 2010 for the treatment of colorectal cancer
Toshiaki Watanabe Michio Itabashi Yasuhiro Shimada Shinji Tanaka Yoshinori Ito Yoichi Ajioka
Tetsuya Hamaguchi Ichinosuke Hyodo Masahiro Igarashi Hideyuki Ishida Megumi Ishiguro
Yukihide Kanemitsu Norihiro Kokudo Kei Muro Atsushi Ochiai Masahiko Oguchi Yasuo Ohkura
Yutaka Saito Yoshiharu Sakai Hideki Ueno Takayuki Yoshino Takahiro Fujimori Nobuo Koinuma
Takayuki Morita Genichi Nishimura Yuh Sakata Keiichi Takahashi Hiroya Takiuchi
Osamu Tsuruta Toshiharu Yamaguchi Masahiro Yoshida Naohiko Yamaguchi Kenjiro Kotake
Kenichi Sugihara Japanese Society for Cancer of the Colon and Rectum

Received: 18 August 2011 / Accepted: 25 August 2011 / Published online: 15 October 2011
 Japan Society of Clinical Oncology 2011

Abstract Colorectal cancer is a major cause of death in
Japan, where it accounts for the largest number of deaths
from malignant neoplasms in women and the third largest
number in men. Many new treatment methods have been
developed over the last few decades. The Japanese Society
for Cancer of the Colon and Rectum (JSCCR) guidelines
2010 for the treatment of colorectal cancer (JSCCR
Guidelines 2010) have been prepared to show standard
This article was originally appeared in Japanese as Daicho gan chiryo
gaidorain  Ishiyo 2010 nen ban (JSCCR Guidelines 2010 for the
Treatment of Colorectal Cancer), published by Kanehara, Tokyo,
2010.
treatment strategies for colorectal cancer, to eliminate
disparities among institutions in terms of treatment, to
eliminate unnecessary treatment and insufficient treatment,
and to deepen mutual understanding between health-care
professionals and patients by making these Guidelines
available to the general public. These Guidelines have been
prepared by consensuses reached by the JSCCR Guideline
Committee, based on a careful review of the evidence
retrieved by literature searches and in view of the medical
health insurance system and actual clinical practice settings
in Japan. Therefore, these Guidelines can be used as a tool
for treating colorectal cancer in actual clinical practice
settings. More specifically, they can be used as a guide to

T. Watanabe (&) I. Hyodo

Department of Surgery, Teikyo University School of Medicine, Division of Gastroenterology, Graduate School of
2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan Comprehensive Human Sciences, University of Tsukuba,
e-mail: toshwatanabe@yahoo.co.jp Ibaraki, Japan

M. Itabashi M. Igarashi
Department of Surgery 2, Tokyo Womens Medical University, Department of Endoscopy, Cancer Institute Ariake Hospital,
Tokyo, Japan Tokyo, Japan

Y. Shimada  T. Hamaguchi H. Ishida

Division of Gastrointestinal Medical Oncology, National Cancer Department of Digestive Tract and General Surgery, Saitama
Center Hospital, Tokyo, Japan Medical Center, Saitama Medical University, Saitama, Japan

S. Tanaka M. Ishiguro  K. Sugihara

Department of Endoscopy, Hiroshima University Hospital, Department of Surgical Oncology, Graduate School, Tokyo
Hiroshima, Japan Medical and Dental University, Tokyo, Japan

Y. Ito Y. Kanemitsu
Department of Radiation Oncology, National Cancer Center Department of Gastroenterological Surgery, Aichi Cancer
Hospital, Tokyo, Japan Center, Nagoya, Japan

Y. Ajioka N. Kokudo
Division of Molecular and Diagnostic Pathology, Graduate Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ
School of Medical and Dental Sciences, Niigata University, and Transplantation Division, Department of Surgery, Graduate
Niigata, Japan School of Medicine, University of Tokyo, Tokyo, Japan

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2 Int J Clin Oncol (2012) 17:129
obtaining informed consent from patients and choosing the
method of treatment for each patient. As a result of the
discussions held by the Guideline Committee, controversial
issues were selected as Clinical Questions, and recom-
mendations were made. Each recommendation is accom-
panied by a classification of the evidence and a
classification of recommendation categories based on the
consensus reached by the Guideline Committee members.
Here we present the English version of the JSCCR
Guidelines 2010.
Keywords Colorectal cancer  Guideline  Treatment 
Surgery  Chemotherapy  Endoscopy  Radiotherapy 
Palliative care  Surveillance
Introduction
1. Guideline objectives
Mortality and morbidity from colorectal cancer have sub-
stantially increased in Japan recently. According to the
vital statistics for Japan in 2008, colorectal cancer
accounted for the largest number of deaths from malignant
K. Muro
Department of Clinical Oncology, Aichi Cancer Center Hospital,
Nagoya, Japan
A. Ochiai
Pathology Division, Research Center for Innovative Oncology,
National Cancer Centre Hospital East, Chiba, Japan
M. Oguchi
Radiation Oncology Department, The Cancer Institute Hospital,
Japanese Foundation for Cancer Research, Tokyo, Japan
Y. Ohkura
Department of Pathology, Kyorin University School of
Medicine, Tokyo, Japan
Y. Saito
Endoscopy Division, National Cancer Center Hospital, Tokyo,
Japan
Y. Sakai
Department of Surgery, Kyoto University, Kyoto, Japan
H. Ueno
Department of Surgery, National Defense Medical College,
Saitama, Japan
T. Yoshino
Department of Gastroenterology and Gastrointestinal Oncology,
National Cancer Center Hospital East, Chiba, Japan
T. Fujimori
Department of Surgical and Molecular Pathology, Dokkyo
Medical University School of Medicine, Tochigi, Japan
123
neoplasms in women and the third largest number in men,
after lung cancer and gastric cancer. Nevertheless, the
number of deaths from colorectal cancer per unit popula-
tion has increased approximately tenfold during the past
50 years. Many new treatment methods have been devel-
oped during that time, and their use in combination with
advances in diagnostic methods has led to a steady
improvement in the results of treatment. However, there
are differences in treatment among medical institutions in
Japan that provide medical care for patients with colorectal
cancer, and these differences may lead to differences in the
results of treatment.
Under such circumstances, the JSCCR guidelines 2010
for the treatment of colorectal cancer (JSCCR Guidelines
2010), which are intended for doctors (general practitioners
and specialists) who provide medical care for patients with
colorectal cancer at various disease stages and conditions,
have been prepared for the following purposes: (1) to show
standard treatment strategies for colorectal cancer; (2) to
eliminate disparities among institutions in terms of treat-
ment; (3) to eliminate unnecessary treatment and insuffi-
cient treatment; and (4) to deepen mutual understanding
between health-care professionals and patients by making
these Guidelines available to the general public [1].
N. Koinuma
Department of Health Administration and Policy, Tohoku
University Graduate School of Medicine, Sendai, Japan
T. Morita
Department of Surgery, Cancer Center, Aomori Prefectural
Central Hospital, Aomori, Japan
G. Nishimura
Department of Surgery, Japanese Red Cross Kanazawa Hospital,
Ishikawa, Japan
Y. Sakata
Department of Internal Medicine and Medical Oncology,
Misawa City Hospital, Misawa, Japan
K. Takahashi
Department of Surgery, Tokyo Metropolitan Cancer and
Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
H. Takiuchi
Cancer Chemotherapy Center, Osaka Medical College, Osaka,
Japan
O. Tsuruta
Division of Gastrointestinal Endoscopy, Kurume University
School of Medicine, Fukuoka, Japan
T. Yamaguchi
Department of Gastroenterological Surgery, Cancer Institute
Hospital, Tokyo, Japan
Int J Clin Oncol (2012) 17:129 3

The following are expected to be achieved with these randomized controlled trials,
Guidelines: (1) improved treatment of colorectal cancer in nonrandomized controlled trials,
Japan; (2) improved results of such treatment; (3) reduced cohort studies, casecontrol studies, and cross-sectional
human and financial burdens; and (4) increased benefits for studies.
patients.
[Low-level evidence]
2. How to use these Guidelines Case series studies, case studies, expert opinions, and
clinical experience.
These Guidelines have been prepared by consensuses
reached by the JSCCR Guideline Committee, based on a
(2) Clinical Questions and classification
careful review of the evidence retrieved by literature
of recommendation categories
searches and in view of the medical health insurance sys-
tem and actual clinical practice settings in Japan, so these
As a result of the discussions held by the Guideline
Guidelines can be used as a tool for treating colorectal
Committee, controversial issues were selected as Clinical
cancer in actual clinical practice settings. More specifi-
Questions (CQ), and recommendations were made.
cally, they can be used as a guide to obtaining informed
Each recommendation in response to a CQ is accom-
consent from patients and choosing the method of treat-
panied by a classification of the evidence and a classifi-
ment for each patient. However, these Guidelines provide
cation of recommendation categories based on the
only general recommendations for choosing treatment
consensus reached by the Guideline Committee members.
strategies for colorectal cancer, and they do not control or
In determining the recommendation categories, in addition
limit treatment strategies or treatment methods that are not
to an evaluation of the internal validity of the source of
described herein. These Guidelines can also be used as a
evidence for each recommendation, a comprehensive
document to explain the rationale for selecting treatment
investigation of the internal validity, external validity, and
strategies and treatment methods that differ from those
clinical applicability of each recommendation was per-
described in these Guidelines.
formed, considering the following points: (1) the treatment
JSCCR is responsible for the statements in these
method has a clear scientific rationale and is the best
Guidelines. However, the personnel directly in charge of
treatment method conceivable; (2) the treatment method is
treatment, not the JSCCR or the Guideline Committee, are
as safe as possible, causes little invasion, and maintains
responsible for the outcome of treatment.
physical function; (3) the treatment method is cost-effec-
tive and imposes the smallest financial burden on the
3. Method used to prepare these Guidelines
patient; and (4) the treatment method is in line with the
treatment methods used in actual clinical practice settings
(1) Classification of evidence
in Japan.
Recommendations with which all members of the
Levels of evidence were classified as high-level evi-
Guideline Committee agreed were classified as category A
dence or low-level evidence as follows:
or category B recommendations. Recommendations with
[High-level evidence]
which three or more members of the Committee disagreed
Meta-analyses of systematic reviews/randomized con- were classified as category D recommendations, and all
trolled trials (RCTs), other recommendations were classified as category C rec-
ommendations. The category D recommendations are not
included in these Guidelines.
Classification of recommendation categories:

M. Yoshida Category A: unanimous recommendations by the

Department of Hemodialysis and Surgery, Chemotherapy Guideline Committee based on high-level evidence
Research Institute, International University of Health and Category B: unanimous recommendations by the
Welfare, Ichikawa, Japan
Guideline Committee based on low-level evidence
N. Yamaguchi Category C: recommendations that were not agreed to
Library, Toho University Medical Center Sakura Hospital, completely by the members of the Guideline Commit-
Chiba, Japan tee, irrespective of the level of evidence
Category D: recommendations that were not agreed
K. Kotake
Department of Surgery, Tochigi Cancer Center, Utsunomiya, to by three or more members of the Guideline
Japan Committee

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4 Int J Clin Oncol (2012) 17:129

Table 1 Number of scientific articles retrieved and selected

Number of articles retrieved Number of articles selected Number of articles
retrieved manually
PubMed Ichushi PubMed Ichushi

(1) Endoscopic treatment of colorectal cancer 283 214 10 8 8

(2) Treatment of stage 0 to stage III colorectal cancer 347 268 49 11 2
(3) Treatment of stage IV colorectal cancer 189 98 79 14 9
(4) Treatment of liver metastases of colorectal cancer 645 281 255 42 14
(5) Treatment of lung metastases of colorectal cancer 54 134 28 22 2
(6) Treatment of recurrent colorectal cancer 488 125 111 18 7
(7) Adjuvant chemotherapy for colorectal cancer 340 189 154 27 31
(8) Chemotherapy for unresectable colorectal cancer 472 66 234 41 121
(9) Adjuvant radiotherapy for colorectal cancer 398 61 86 6 15
(10) Palliative radiotherapy for colorectal cancer 704 31 107 6 17
(11) Palliative care for colorectal cancer 182 58 19 5 8
(12) Surveillance after surgery for colorectal cancer 1,203 1,213 249 37 13
Total 5,305 2,738 1,381 237 247

4. Literature search a result of the searches (5,305 in the PubMed database and
2,738 in the Ichushi-Web database), 1,618 references were
Initially, the literature search was performed for the fol- retrieved and examined critically (Table 1).
lowing 12 broad categories. Then, a further search was
done as needed with additional search techniques. 5. Funding
(1) Endoscopic treatment of colorectal cancer
Preparation of these Guidelines was funded by the JSCCR
(2) Treatment of stage 0 to stage III colorectal cancer
(3) Treatment of stage IV colorectal cancer and the Health and Labour Sciences Research Fund (3rd
(4) Treatment of liver metastases of colorectal cancer Term Comprehensive 10-Year Strategy for Cancer Control
(5) Treatment of lung metastases of colorectal cancer Research Project).
(6) Treatment of recurrent colorectal cancer
(7) Adjuvant chemotherapy for colorectal cancer
6. Conflicts of interest
(8) Chemotherapy for unresectable colorectal cancer
(9) Adjuvant radiotherapy for colorectal cancer
None of the members of the committee in charge of the
(10) Palliative radiotherapy for colorectal cancer
preparation of these Guidelines has any conflict of interest
(11) Palliative care for colorectal cancer
with entities such as any specific profit or nonprofit orga-
(12) Surveillance after surgery for colorectal cancer
nizations or any entities related to pharmaceutical or
The PubMed and Ichushi-Web databases were selected medical products, and the board of the JSCCR confirmed
for the search, and the English and Japanese literature was the self-reported absence of any conflicts of interest by the
searched in both databases for the period from January Guideline Committee members.
1983 to December 2007. The task of searching was shared
by four members of the medical library; the four members
created a search formula by discussion with the Committee Treatment guidelines for colorectal cancer
members in charge of each item and collected literature
during the search period (January 2008 to July 2008). For Chapter 1: Treatment strategies for stage 0 to stage III
categories (7) and (8), however, April 2010 was set as the colorectal cancer
end of the search period. In addition, secondary documents
such as UpToDate and literature collected by manual 1. Endoscopic treatment
searching were added and critically examined as needed,
and other documents such as minutes and guidelines were General principles underlying the indications for
included as necessary. Of the 8,043 references identified as endoscopic resection (Fig. 1)

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Int J Clin Oncol (2012) 17:129 5

Fig. 1 Treatment strategies for

cM cancer and cSM cancer cM cancer, cSM
cancer

cM cancer or slightly Deep invasive

invasive cSM cancer cSM cancer

Maximum diameter Maximum diameter

< 2cm > 2cm

Endoscopic resection Endoscopic resection

is possible is impossible

Endoscopic resection

Pathological
diagnosis

Surveillance Surgical resection

There is little possibility of lymph node metastasis, and tumor is essential, and the histological type of the
the size and location of the tumor make en bloc tumor should also be taken into consideration.
resection possible.
Comments
Indication criteria for endoscopic resection:
Endoscopic resection is intended for both diagnosis and
(1) Intramucosal carcinoma or carcinoma with slight treatment. It consists of total excisional biopsy in which
submucosal invasion curability and the need for additional intestinal resec-
(2) Maximum diameter \2 cm tion are assessed by histopathological examination of
(3) Any macroscopic type the resected specimens (CQ-1).
En bloc resection is desirable for accurate diagnosis of
Endoscopic treatment is a method of endoscopically
the status of carcinoma invasion in the resection margin
resecting lesions in the large bowel and of collecting
and the deepest area.
the resected specimens.
2 cm is the largest size of a tumor that can be easily
Endoscopic treatment methods consist of polypec-
resected en bloc by polypectomy or snare EMR [3]
tomy,1 endoscopic mucosal resection (EMR),2 and
(CQ-2).
endoscopic submucosal dissection (ESD).3
Colorectal ESD has not become a common treatment
In determining the indication for endoscopic treatment
method, because the technique is difficult and there is a
and the treatment method, information on the size,
high risk of complications (perforation) [3].
predicted depth of invasion, and morphology of the
EMRC (EMR using a cap) involves a high risk of
perforation when used for colon lesions.
1
In polypectomy, a snare is placed on the stalk of the lesion, and the If the preoperative diagnosis is intramucosal carcinoma,
lesion is electrocauterized using a high-frequency current. This
method is mainly used for protruding lesions.
piecemeal resection can be performed. It should be
2
In EMR, the lesion is elevated through the local injection of a liquid
noted, however, that piecemeal resection is associated
such as physiological saline into the submucosa, and the lesion is with a high incomplete resection rate and a high local
electrocauterized just as in polypectomy. This method comprises the recurrence rate [3].
snare method [2] and EMR using a cap (EMRC). It is mainly used for
superficial tumors and large sessile lesions.
3
In ESD, the lesion is elevated through the local injection of a liquid 2. Surgical treatment (Fig. 2)
such as sodium hyaluronate solution into the submucosa of the
perilesional area; then, circumferential incision of the mucosa
The extent of lymph node dissection to be performed
surrounding the lesion and dissection of the submucosa are performed
with a special knife [3]. ESD is mainly indicated for large tumors that during colorectal cancer surgery is determined based on
cannot be resected by EMR. the preoperative clinical findings (c) or on the extent of

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6 Int J Clin Oncol (2012) 17:129

Fig. 2 Surgical treatment

strategies for stage 0 to stage III
colorectal cancer cN (-) cN (+)

cM cSM cMP cSS, cSE, cSI

cA, cAI

D0*, D1 D2 D3

*Includes local resection for rectal cancer.

lymph node metastasis and depth of wall invasion by peritoneal reflection and has invaded beyond the
the tumor observed intraoperatively (s). muscularis propria [9].
If lymph node metastasis is suspected based on the
[Local rectal resection]
preoperative/intraoperative diagnostic findings, D3 dis-
section is performed. Local resection is indicated for cM cancer and cSM
If no lymph node metastases are observed based on the cancer (slight invasion) located distal to the second
preoperative/intraoperative diagnostic findings, lymph Houston valve (peritoneal reflection). Approaches for
node dissection is performed based on the depth of wall local resection are classified into transanal resection,
invasion by the tumor [4]. transsphincter resection, and parasacral resection [10].
Transanal resection includes the conventional method
(1) Lymph node dissection is unnecessary for M cancer
in which the tumor is resected under direct vision and
(D0), because M cancer is not accompanied by lymph
transanal endoscopic microsurgery (TEM) [11]. More
node metastasis; however, D1 dissection can be per-
proximal lesions can be resected by TEM than by the
formed because the accuracy of the preoperative
conventional method.
diagnosis of invasion depth may be insufficient.
(2) D2 dissection is necessary for SM cancer, because the [Autonomic nerve-preserving surgery]
incidence of lymph node metastasis is approximately
The autonomic nervous system relating to surgery of
10% and because SM cancer is often accompanied by
rectal cancer consists of the lumbar splanchnic nerves,
intermediate lymph node metastasis.
superior hypogastric plexus, hypogastric nerves, pelvic
(3) Although there is insufficient evidence describing the
splanchnic nerves, and the pelvic plexus. Considering
area of dissection for MP cancer, at the very least D2
factors such as the degree of cancer progression and the
dissection is necessary. However, D3 dissection can
presence or absence of macroscopic nerve invasion,
be performed, because MP cancer is often accompa-
preservation of autonomic nerves is attempted in order
nied by main lymph node metastases and because
to preserve urinary and sexual functions as much as
preoperative diagnosis of depth of invasion is not very
possible, provided that curability is unaffected.
accurate.
Laparoscopic surgery:
Surgical treatment of rectal cancer:
Transabdominal surgery consists of open abdominal
The principle for proctectomy is TME (total mesorectal
surgery and laparoscopic surgery. The indications for
excision) or TSME (tumor-specific mesorectal exci-
laparoscopic surgery are determined by considering the
sion) [58].
surgeons experience and skills as well as tumor
[Indications criteria for lateral lymph node dissection] factors, such as the location and degree of progression
of the cancer, and patient factors, such as obesity and
Lateral lymph node dissection is indicated when the
history of open abdominal surgery (CQ-3).
lower border of the tumor is located distal to the

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Int J Clin Oncol (2012) 17:129 7

Table 2 Lateral lymph node dissection and lateral lymph node metastasis of rectal cancer
No. of No. of patients who Lateral lymph node No. of patients Lateral lymph node Lateral lymph node metastasis
patients underwent lateral dissection rate (%) with lateral lymph metastasis rate rate (% of patients who underwent
lymph node dissection node metastasis (% of all patients) lateral lymph node dissection)

RS
sm 124 0 0 0 0.0 0.0
mp 127 6 4.7 0 0.0 0.0
ss/a1 316 24 7.5 0 0.0 0.0
se/a2 177 8 4.5 0 0.0 0.0
si/ai 32 14 43.8 1 3.1 7.1
Total 776 52 6.7 1 0.1 1.9
Ra
sm 138 5 3.6 0 0.0 0.0
mp 149 18 12.1 0 0.0 0.0
ss/a1 230 58 25.2 4 1.7 6.9
se/a2 181 59 32.6 7 3.9 11.9
si/ai 15 8 53.3 0 0.0 0.0
Total 713 148 20.8 11 1.5 7.4
RaRb?Rb
sm 234 37 15.8 2 0.9 5.4
mp 372 218 58.6 20 5.4 9.2
ss/a1 350 230 65.7 28 7.7 12.2
se/a2 412 319 77.4 75 18.0 23.5
si/ai 59 48 81.4 17 28.8 35.4
Total 1,427 852 59.7 142 9.8 16.7
Project study by the JSCCR: patients in years 19911998

Comments The 5-year survival rates after curative resection of

[Lateral lymph node dissection]
An analysis of 2916 cases of rectal cancer in the project
study by the JSCCR showed that the lateral lymph node
metastasis rate in patients whose lower tumor border was
located distal to the peritoneal reflection and whose
cancer had penetrated through the rectal wall was 20.1%
(only patients who underwent lateral lymph node
dissection) (Table 2). After performing lateral lymph
node dissection for the indication mentioned above, the
risk of intrapelvic recurrence decreased by 50%, and the
5-year survival rate improved by 89% [9].
The lateral lymph node metastasis rate of patients
whose lower tumor border was located distal to the
peritoneal reflection and who had lymph node metas-
tasis in the mesorectum was 27%.
Urinary function and male sexual function may
be impaired after lateral lymph node dissection, even
if the autonomic nervous system is completely preserved.
[Aggregate data from the Colorectal Cancer Registry]
The incidence of lymph node metastasis according to
site and depth of invasion, curative resection rate, and
5-year survival rate is shown in Tables 3, 4, and 5 [4].
stage 0 to stage III colorectal cancer according to site
were: all sites 81.3%; colon 83.7%, rectosigmoid
81.2%; RaRb rectum 77.1%.
Chapter 2: Treatment strategies for stage IV colorectal
cancer (Fig. 3)
Stage IV colorectal cancer is associated with synchro-
nous distant metastasis to any of the following organs:
liver, lung, peritoneum, brain, distant lymph nodes, or
other organs (e.g., bone, adrenal gland, spleen).
If both the distant metastases and the primary tumor are
resectable, curative resection of the primary tumor is
performed, and resection of the distant metastases is
considered.
If the distant metastases are resectable but the primary
tumor is unresectable, in principle, resection of the
primary tumor and distant metastases is not performed,
and another treatment method is selected.
If the distant metastases are unresectable but the
primary tumor is resectable, the indication for the
resection of the primary tumor is determined, based on
the clinical symptoms of the primary tumor and the
impact on the prognosis (CQ-4).

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8 Int J Clin Oncol (2012) 17:129

Table 3 Incidence of lymph

No. of patients Extent of lymph node metastasis detected histologically
node metastasis according to
primary site and depth of n0 (%) n1 (%) n2 (%) n3 (%) n4 (%)
invasion
All sites (CP)
sm 2,846 90.1 7.5 2.1 0.1 0.2
mp 3,402 77.0 17.2 4.8 0.7 0.3
ss/a1 9,862 56.1 27.4 12.2 2.7 1.6
se/a2 6,175 37.0 32.4 20.2 5.8 4.5
si/ai 1,294 44.0 25.2 15.7 7.6 7.6
Total 23,579 57.6 24.7 12.2 3.2 2.3
Colon (CS)
sm 1,757 90.9 6.9 1.9 0.1 0.2
mp 1,598 79.0 16.1 4.4 0.2 0.3
ss/a1 6,428 57.7 25.8 1.2 2.8 1.4
se/a2 3,547 38.0 31.7 20.1 5.8 4.4
si/ai 814 46.3 24.8 15.2 5.4 8.2
Total 14,144 58.6 23.8 12.2 3.1 2.3
Rectosigmoid (RS)
sm 276 90.9 8.0 1.1 0 0
mp 388 78.9 16.2 4.4 0.3 0.3
ss/a1 1,227 54.9 30.6 10.2 1.6 2.6
se/a2 793 37.6 36.4 17.9 4.2 3.9
si/ai 134 44.8 28.4 14.2 4.5 8.2
Total 2,818 56.4 28.0 10.9 2.1 2.7
Rectum (RaRb)
sm 800 88.1 8.6 2.8 0.3 0.3
mp 1,377 74.3 19.0 5.1 1.5 0.2
ss/a1 2,169 51.7 30.5 13.4 2.8 1.7
se/a2 1,774 34.7 32.9 21.0 6.3 5.1
si/ai 322 37.6 26.1 17.7 13.7 5.0
National Registry of Patients Total 6,442 55.7 25.8 12.6 3.7 2.3
with Cancer of the Colon and
Rectum of the JSCCR: patients Anal canal (P)
in fiscal years 19951998. sm 13 84.6 7.7 7.7 0 0
Depth of invasion and the mp 39 69.2 12.8 12.8 2.6 2.6
degree of lymph node
ss/a1 38 65.8 18.4 13.2 2.6 0.0
metastasis were determined
according to the rules set forth se/a2 61 42.6 8.2 32.8 14.8 1.6
in the Japanese Classification of si/ai 24 45.8 8.3 12.5 16.7 16.7
Colorectal Carcinoma (6th Total 175 57.1 11.4 19.4 8.6 3.4
edition)

Comments Chapter 3: Treatment strategies for recurrent colorectal

cancer (Fig. 4)
The incidence of synchronous distant metastasis is
shown in Table 6. The goal of treatment for recurrent colorectal cancer is
Distant metastasis associated with peritoneal dissemi- to improve the prognosis and the patients QOL.
nation (CQ-5). Treatment methods include surgery, systemic chemo-
(1) Complete resection is desirable for P1. therapy, arterial infusion chemotherapy, thermal coag-
(2) Complete resection is considered for P2 when ulation therapy, and radiotherapy.
easily resectable. An appropriate treatment method is selected with the
(3) The efficacy of resection of P3 has not been informed consent of the patient in view of a variety of
demonstrated. factors, such as the prognosis, complications, and QOL
expected after treatment.

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Int J Clin Oncol (2012) 17:129 9

Table 4 Curative resection rate according to stage (lower rows: nos. of patients)
Stage I II IIIa IIIb IV All stages

All patients (CP) 99.5% 97.0% 91.1% 79.7% 78.4%

5,125 7,168 5,098 2,518 3,953 23,862
Colon (CS) 99.7% 97.9% 92.2% 82.7% 78.1%
2,838 4,609 2,924 1,436 2,567 14,374
Rectosigmoid (RS) 99.8% 96.2% 91.3% 82.2% 77.0%
548 870 647 258 519 2,842
Rectum (RaRb) 98.9% 95.5% 89.0% 74.7% 79.8%
1,699 1,644 1,497 775 852 6,467
Anal canal (P) 100.0% 80.0% 80.0% 59.2% 72.1%
40 45 30 49 15 179
National Registry of Patients with Cancer of the Colon and Rectum of the JSCCR: patients in fiscal years 19951998
Curative resection rate = number of patients with histological curability A cancer/total number of patients who underwent surgery
Staging was performed according to the rules set forth in the Japanese Classification of Colorectal Carcinoma (6th edition)

Table 5 Cumulative 5-year survival rate according to site (lower rows: nos. of patients)
Stage 0 I II IIIa IIIb IV All stages

Cecum 90.2% 86.7% 81.4% 69.3% 59.5% 9.8% 63.7%

(C) 110 149 252 209 137 225 1,082
Ascending colon 96.3% 90.9% 83.7% 73.9% 57.3% 14.2% 68.3%
(A) 209 257 698 398 254 409 2,225
Transverse colon 94.5% 89.1% 82.6% 70.1% 60.1% 9.6% 67.8%
(T) 176 199 447 270 143 261 1,496
Descending colon 94.7% 90.3% 82.8% 70.9% 57.8% 18.5% 73.4%
(D) 129 151 267 152 67 115 881
Sigmoid colon 95.2% 91.4% 84.5% 81.4% 67.4% 16.6% 75.0%
(S) 559 1,149 1,373 879 394 781 5,135
Rectosigmoid 95.4% 94.6% 79.2% 71.2% 58.1% 11.6% 69.3%
(RS) 184 390 534 448 149 340 2,045
Upper rectum 94.2% 93.1% 77.7% 69.5% 53.7% 9.8% 68.8%
(Ra) 211 471 579 523 238 329 2,351
Lower rectum 92.2% 87.3% 75.2% 60.6% 43.7% 12.3% 66.9%
(Rb) 370 876 653 623 431 336 3,289
Anal canal 91.3% 92.2% 78.9% 43.7% 47.0% 10.2% 59.7%
(P) 12 31 36 32 33 24 168
Colon 94.8% 90.6% 83.6% 76.1% 62.1% 14.3% 71.4%
(CS) 1,183 1,905 3,037 1,908 995 1,791 10,819
Rectum 92.9% 89.3% 76.4% 64.7% 47.1% 11.1% 67.7%
(RaRb) 581 1,347 1,232 1,146 669 665 5,640
All sites 94.3% 90.6% 81.2% 71.4% 56.0% 13.2% 69.9%
(CP) 1,960 3,673 4,839 3,534 1,846 2,820 18,672
National Registry of Patients with Cancer of the Colon and Rectum of the JSCCR: patients in fiscal years 19911994
Only adenocarcinomas (including mucinous carcinomas and signet-ring cell carcinomas) were counted
Survival rates were calculated by the life table method with death from any cause as an event
Lost to follow-up rate 2%; 5-year censoring rate 19%
Staging was performed according to the rules set forth in the Japanese Classification of Colorectal Carcinoma (6th edition)

123
10 Int J Clin Oncol (2012) 17:129

Fig. 3 Treatment strategies for

stage IV colorectal cancer Resection of synchronous Resectable Unresectable
distant metastases

Resection of the Resectable Unresectable Resectable

primary tumor
Symptoms caused by the primary tumor*

Absent Present

Resection of the Treatment other than Resection of the primary tumor +

primary tumor + resection for both the primary treatment other than resection for the
metastatic tumor tumor and the metastatic tumor** metastatic tumor

* Symptoms caused the primary tumor: Symptoms caused by events such as massive bleeding, severe
anemia, penetration / perforation, and stenosis.
** Treatment other than resection: Palliative surgery for the primary tumor, chemotherapy, radiotherapy;
see treatment strategies for hematogenous metastasis.

Table 6 Incidence of synchronous distant metastasis of colorectal cancer

Liver Lung Peritoneum Other sites
Bone Brain Virchow Other Total

Colon cancer 11.4% 1.6% 6.4% 0.3% 0.1% 0.1% 0.4% 0.9%
No. of patients 15,528 1,777 242 993 44 9 19 64 136
Rectal cancer 9.5% 1.7% 3.0% 0.3% 0.1% 0.01% 0.5% 1.0%
No. of patients 10,563 1,002 180 314 36 8 1 57 102
Total no. of patients 10.7% 1.6% 5.0% 0.3% 0.1% 0.1% 0.5% 0.9%
26,091 2,779 422 1,307 80 17 20 121 238
National Registry of Patients with Cancer of the Colon and Rectum of the JSCCR: patients in fiscal years 19951998

If recurrence is observed in a single organ and complete Local recurrences of rectal cancer take the form of
surgical resection of the recurrent tumor(s) is possible, anastomotic recurrences and intrapelvic recurrences.
resection is strongly considered.
(1) Resection is considered for resectable recurrences,
If recurrence is observed in more than a single organ,
(2) radiotherapy and systemic chemotherapy, either
resection can be considered if the recurrent tumors in
alone or in combination, are considered for
all of the organs are resectable [12, 13]; however, there
unresectable recurrences.
is no consensus on the effects of treatment.
Some authors believe that resection of liver or lung Comments
metastases should be performed only after a certain [Local recurrence of rectal cancer]
observation period to rule out occult metastases
The extent of spread of the recurrent tumor is evaluated
[14].
by diagnostic imaging, and resection is considered only
Treatment methods for hematogenous metastases (see
for patients in whom complete resection can be expected,
Chapter 4: Treatment strategies for hematogenous
after taking into consideration such factors as the pattern
metastases).
of recurrence, symptoms, and physical findings (CQ-6).

123
Int J Clin Oncol (2012) 17:129 11

Fig. 4 Treatment strategies for

recurrent colorectal cancer Recurrence

Resectable Unresectable

Performance status 0~2 Performance status 3~4

Surgical resection Systemic chemotherapy Symptomatic

Local treatment* treatment**

In principle, surgical treatment is indicated for recurrence limited to 1 organ, but it

is considered for recurrence in 2 or more organs, if the lesions are resectable.
* Local treatment includes hepatic arterial infusion therapy, thermal coagulation
therapy, and radiotherapy.
** Best supportive care (BSC).

Fig. 5 Treatment strategies for

hematogenous metastases Hematogenous
metastasis

Resectable Unresectable

Performance status 0~2 Performance status 3~4

Surgical resection Systemic chemotherapy Symptomatic

Local treatment* treatment**

* Local treatment includes hepatic arterial infusion therapy, thermal coagulation

therapy, and radiotherapy.
** Best supportive care (BSC).

Chapter 4: Treatment strategies for hematogenous
metastases (Fig. 5)
1. Treatment strategies for liver metastases
Treatment of liver metastases is broadly divided into
hepatectomy, systemic chemotherapy, hepatic arterial
infusion therapy, and thermal coagulation therapy.
Hepatectomy is recommended for liver metastases
when curative resection is possible.
Hepatectomy consists of systematic resection and
partial (nonsystematic) resection.
Indication criteria for hepatectomy
(1) the patient is capable of tolerating surgery,
(2) the primary tumor has been controlled or can be
controlled,

123
12
(3) the metastatic liver tumor can be completely
resected,
(4) there are no extrahepatic metastases or they can be
controlled,
(5) the function of the remaining liver will be adequate.
Systemic chemotherapy and hepatic arterial infusion
therapy, either alone or in combination, are considered
for patients with unresectable liver metastases whose
general condition can be maintained at a certain level or
higher (PS 0 to PS 2).
Thermal coagulation therapy consists of microwave
coagulation therapy (MCT) and radiofrequency abla-
tion (RFA).
If the patients general condition is poor (PS C 3), best
supportive care (BSC) is provided.
Comments
[Hepatectomy]
There are reports showing the efficacy of hepatectomy
in patients who have controllable extrahepatic metas-
tases (mainly lung metastases) in addition to liver
metastases [12, 13, 15, 16] (CQ-7).
The efficacy of systemic chemotherapy and hepatic
arterial infusion therapy after hepatectomy has not been
established (CQ-8).
The safety of preoperative chemotherapy for resectable
liver metastases has not been established (CQ-9).
[Treatment methods other than resection]
Systemic chemotherapy or hepatic arterial infusion
therapy with anticancer drugs is performed alone or in
combination for patients with unresectable liver metas-
tases (CQ-10).
2. Treatment strategies for lung metastases
Treatment of lung metastases consists of pulmonary
resection and chemotherapy.
Pulmonary resection is considered if the metastatic lung
tumor is resectable.
Pulmonary resection consists of systematic resection
and partial (nonsystematic) resection.
Indication criteria for pulmonary resection
(1) The patient is capable of tolerating surgery,
(2) the primary tumor has been controlled or can be
controlled,
(3) the metastatic lung tumor can be completely resected,
(4) there are no extrapulmonary metastases, or they can
be controlled,
(5) the function of the remaining lung will be adequate.
123
Int J Clin Oncol (2012) 17:129
Systemic chemotherapy is considered for patients with
unresectable lung metastases whose general condition
can be maintained at a certain level or higher.
Even if the patient cannot tolerate surgery, stereotactic
radiotherapy is considered if the primary tumor and
extrapulmonary metastases are controlled or can be
controlled and the number of lung metastases is no
more than three or four.
If the patients general condition is poor, appropriate
BSC is provided.
3. Treatment strategies for brain metastases
Brain metastases are often detected as a part of a sys-
temic disease, and surgical therapy or radiotherapy is
considered for lesions in which treatment can be
expected to be effective.
The optimal treatment method is selected after consid-
ering the patients general condition and the status of
other metastatic tumors, and evaluating the sizes and
locations of metastatic tumors and the number of lesions.
Radiotherapy is considered for patients with unresec-
table metastases.
[Surgical therapy]
Indications criteria for removal of brain metastases [17]
(1) The patient has a life expectancy of at least several
months,
(2) resection will not cause significant neurologic symptoms,
(3) there are no metastases to other organs, or they can be
controlled.
[Radiotherapy]
The purpose of radiotherapy is to relieve symptoms,
such as cranial nerve symptoms and intracranial
hypertension symptoms, and to prolong survival time
by reducing locoregional relapse.
Whole-brain radiotherapy is considered for patients
with multiple brain metastases and for patients with a
solitary brain metastasis for which surgical resection is
not indicated.
Stereotactic irradiation is considered when the number
of brain metastases is no more than three or four and the
maximum diameter of each metastasis does not exceed
3 cm.
4. Treatment strategies for hematogenous metastases
to other organs
Resection is also considered for other hematogenous
metastases, such as to the adrenal glands, skin, and
Int J Clin Oncol (2012) 17:129
spleen, if they are resectable. However, patients with
such metastases often have metastasis to more than one
organ, and chemotherapy or radiotherapy is often
indicated.
Chapter 5: Chemotherapy
Chemotherapy consists of adjuvant chemotherapy to
prevent postoperative recurrence and systemic chemo-
therapy to treat unresectable colorectal cancer.
Commonly used anticancer drugs that have been
approved for the indication of colorectal cancer and
are covered by Japanese National Health Insurance are:
Oral drugs 5-FU, tegafur, UFT, doxifluridine (50 -
DFUR), carmofur (HCFU), S-1, UFT ?
leucovorin (LV), capecitabine, etc.
Injection drugs 5-FU, mitomycin C, irinotecan (CPT-11),
5-FU ? l-leucovorin (l-LV), oxaliplatin
(L-OHP), bevacizumab, cetuximab,
panitumumab, etc.
1. Adjuvant chemotherapy
Postoperative adjuvant chemotherapy is systemic che-
motherapy that is performed after surgery to prevent
recurrence and improve the prognosis of patients who
have undergone R0 resection [18].
General principles underlying the indications for sys-
temic chemotherapy
(1) Stage III colorectal cancer (colon and rectal cancer)
for which R0 resection has been performed
(2) The function of major organs is maintained
Bone marrow: peripheral blood WBC count [4,000/
mm3; platelet count [100,000/mm3.
Liver function: total bilirubin \2.0 mg/dL; AST/ALT
\100 IU/L.
Renal function: serum creatinine concentration no higher
than the upper limit of the normal at the institution.
(3) Performance status (PS) of 0 or 1 (CQ-11),
(4) the patient has recovered from postoperative compli-
cations, if any
(5) the patient has provided written informed consent,
(6) the patient has no serious complications (in particular:
no intestinal obstruction, diarrhea, or fever).
For patients who have stage II colorectal cancer with a
high risk of recurrence, the indications for adjuvant
13
chemotherapy are considered after obtaining informed
consent [19, 20] (CQ-12).
Recommended therapies (listed in the order of the date
of their coverage by Japanese National Health Insurance)
5-FU?l-LV
UFT ? LV
Capecitabine
FOLFOX4 or mFOLFOX6 (CQ-14)
Recommended administration period (CQ13)
In principle, the administration period is 6 months.
Comments
Randomized controlled trials conducted in Europe and
the United States have shown that the combination of
intravenous infusion of 5-FU ? LV and L-OHP (FOL-
FOX4 and FLOX) used as postoperative adjuvant
chemotherapy for stage III colon cancer provides an
additional benefit in terms of prevention of recurrence
and survival time [2124]. FOLFOX has also been
approved in Japan for the postoperative adjuvant
therapy of stage III colon cancer, and it became
available in August 2009. Although combinations of
oral anticancer drugs and L-OHP have been reported to
be useful in Europe and the United States, as of July
2010 no such combinations had been approved in Japan
[25] (CQ-14).
Note The Roswell Park Memorial Institute (RPMI)
method of 5-FU ? LV therapy as an adjuvant
chemotherapy (drip infusion of l-LV 250 mg/m2
administered for 2 h; intravenous infusion of 5-FU
500 mg/m2 slowly administered within 3 min at 1 h
after the start of administration of l-LV; once-weekly
administration for 6 consecutive weeks followed by a
2-week rest period, 3 cycles every 8 weeks [26]).
2. Chemotherapy for unresectable colorectal cancer
(Fig. 6)
In the absence of chemotherapy, the median survival
time (MST) of patients with unresectable colorectal
cancer has been reported to be approximately 8 months.
Although their MST has been extended to approxi-
mately 2 years as a result of recent chemotherapy,
unresectable colorectal cancer is still difficult to cure.
The purpose of chemotherapy is to prolong survival time
and control symptoms by delaying tumor enlargement.
Phase III clinical trials in PS 0 to PS 2 patients have shown
significantly longer survival time in the chemotherapy
123
14 Int J Clin Oncol (2012) 17:129

<Treatment after first <Treatment after

<Initial therapy> progression> second progression>

FOLFIRI + bevacizumab**
or <KRAS wild-type>
CPT-11 CPT-11+ cetuximab
FOLFOX + bevacizumab* or
(1) or <KRAS wild-type> cetuximab/panitumumab
CapeOX + bevacizumab* *** monotherapy
FOLFIRI + cetuximab/panitumumab
or
CPT-11 + cetuximab

FOLFOX + bevacizumab**
(2) FOLFIRI + bevacizumab* or <KRAS wild-type>
CapeOX + bevacizumab** CPT-11+ cetuximab
or
FOLFIRI + bevacizumab* cetuximab/panitumumab
<KRAS wild-type> ***
(3) or monotherapy
FOLFOX + cetuximab/panitumumab
CPT-11

FOLFOX + bevacizumab*
<KRAS wild-type>
(4) or
FOLFIRI + cetuximab/panitumumab
CapeOX + bevacizumab*

To be determined based on the patient s

<KRAS wild-type>
5FU+LV + bevacizumab* condition. If possible, (1) and (2).
CPT-11+ cetuximab
(5) or or or
UFT+LV cetuximab/panitumumab
CPT-11 monotherapy

*: Administration of bevacizumab is recommended, but not when considered appropriate.

**: If bevacizumab was not administered as primary treatment, or if administration of bevacizumab
was discontinued because of toxicity of CPT-11 and L-OHP even though the primary treatment
was still effective, then, administration of bevacizumab is recommended as secondary treatment.
***: If anti-EGFR antibody drugs were not used in the secondary treatment.

Fig. 6 Chemotherapy for unresectable colorectal cancer

groups than in the best supportive care (BSC) groups that (6) The patient has no serious complications (especially,
did not receive anticancer drugs [2729]. no intestinal obstruction, diarrhea, or fever)
Unresectable colorectal cancer may become resectable
Initial therapy
after successful chemotherapy.
The following are regimens that have been shown to be
General principles underlying the indications for sys-
useful in clinical trials and that are available as initial
temic chemotherapy
therapies covered by Japanese National Health
(1) The clinical diagnosis or histopathological diagnosis Insurance.
has been confirmed The usefulness of cetuximab and panitumumab has been
(2) The metastatic or recurrent tumor can be confirmed demonstrated in KRAS wild-type tumors (CQ-16).
by imaging
(1) FOLFOX4 [30, 31] bevacizumab [32], CapeOX5
(3) Performance status (PS) is 02
bevacizumab [32, 33].
(4) The function of major organs is maintained
(2) FOLFIRI6 [34, 35] bevacizumab [36, 37]
1. Bone marrow: peripheral blood WBC count (3) FOLFOX cetuximab/panitumumab [38, 39]
[3,500/mm3; platelet count [100,000/mm3 (4) FOLFIRI cetuximab/panitumumab [40, 41]
2. Liver function: total bilirubin \2.0 mg/dL; AST/ (5) 5-FU ? LV [42] bevacizumab [43, 44] or
ALT \100 IU/L UFT ? LV [45]
3. Renal function: serum creatinine concentration
no higher than the upper limit of the normal 4
FOLFOX is infusional 5-FU ? LV ? L-OHP.
range at the institution 5
CapeOX is capecitabine ? L-OHP.
6
(5) The patient has provided written informed consent FOLFIRI is infusional 5-FU ? LV ? CPT-11.

123
Int J Clin Oncol (2012) 17:129
Therapy after the first or second progression
The following regimens are considered as chemother-
apy for secondary or follow-up treatment (CQ-15).
The usefulness of cetuximab and panitumumab has
been demonstrated in KRAS wild-type tumors (CQ-
16).
(a) For patients whose cancer has become resistant to a
regimen that includes L-OHP:
(1) FOLFIRI [34] bevacizumab,
(2) FOLFIRI (or CPT-11 alone) cetuximab/pani-
tumumab [46, 47].
(b) For patients whose cancer has become resistant to a
regimen that includes CPT-11:
(1) FOLFOX [34, 48] bevacizumab [49], Ca-
peOX2 [50] bevacizumab,
(2) CPT-11 ? cetuximab [51].
(c) For patients whose cancer has become resistant to a
regimen that includes 5-FU, L-OHP, and CPT-11:
(1) CPT-11 ? cetuximab [51],
(2) Cetuximab/panitumumab monotherapy [5255].
Comments
Careful attention must be paid when using CPT-11 to
treat patients with constitutional jaundice, such as
caused by Gilberts syndrome, or to treat patients with
high serum bilirubin values. Relationships between
genetic polymorphisms of enzymes that metabolize
CPT-11 and toxicity have been suggested (see Side
Memo 2).
Chapter 6: Radiotherapy
Radiotherapy is used to treat patients with locally
advanced rectal cancer, either as an adjuvant therapy
after surgery to prevent recurrence, or before surgery to
reduce tumor volume and preserve the anal sphincter,
and also as palliative care to relieve the symptoms and
prolong the survival times of patients with unresectable
colorectal cancer who have symptomatic lesions.
1. Adjuvant radiotherapy
Adjuvant radiotherapy is classified into three catego-
ries, according to the timing of surgery and radiation
therapy: preoperative radiotherapy, intraoperative
radiotherapy, and postoperative radiotherapy.
The purpose of adjuvant radiotherapy is to improve the
local control rate and the survival rate of rectal cancer
15
patients. In addition the purpose of preoperative
radiotherapy is to improve the anal sphincter preserva-
tion rate and resection rate.
Preoperative radiotherapy is indicated for patients with
T stage clinically diagnosed as invasion depth cSS/cA
or deeper or cN-positive; postoperative radiotherapy
is indicated for patients with T stage pathologically
diagnosed after surgery as invasion depth pSS/pA or
deeper or pN-positive; and intraoperative radiotherapy
is indicated for surgical dissection plane positive
(RM?) cancer or cancer with invasion close to the
dissection plane (RM).
Radiotherapy is delivered with a linear accelerator, with
electron beams being used for intraoperative radiother-
apy and photon beams for external radiotherapy.
Comments
Preoperative radiotherapy (CQ-17).
1. Preoperative radiotherapy has the following advanta-
ges: seeding during surgery can be prevented by inac-
tivating lesions with irradiation; a high percentage of
tumor cells are normo-oxic and radiosensitive, because
blood flow to the tumor is maintained; the small bowel
is not fixed within the pelvic cavity, thereby resulting in
low radiation-induced delayed toxicity, which means
less toxic than postoperative setting; improvements in
the resection rate and anal sphincter preservation can be
expected because of tumor size reduction [56].
2. Preoperative radiotherapy has the following disadvan-
tages: early-stage patients may be subjected to over-
treatment and postoperative complications may
increase.
3. Twelve phase III clinical trials of preoperative radio-
therapy (without chemotherapy) have been reported
[56], and in 5 of the 12 trials the local control rate in
the group that received preoperative radiotherapy was
significantly higher than that in the surgery-alone
group. However, an improvement in the survival rate
was observed in only 1 trial [57].
4. Two meta-analyses of radiotherapy showed improve-
ment in the local control rate and improvement in the
survival rate in the groups that received doses of 30 Gy
or more. However, there is controversy as to whether
there is improvement in the survival rate [58, 59].
5. Trials of short-course radiotherapy with 5 Gy per
fraction have been conducted, mainly in Europe [57,
60]. Because the late effects of radiation depend on the
fraction size, long-term follow-up for late adverse
effects, such as anal dysfunction and bowel dysfunc-
tion, is necessary.
6. In the Dutch CKVO 95-04 trial, which compared
preoperative radiotherapy (25 Gy delivered in five
123
16
fractions in 1 week) ? TME with TME alone to
investigate the significance of adding short-course
radiotherapy to TME, the 5-year local control rate was
significantly higher in the combination therapy group
but there was no significant difference between the two
groups in the 5-year survival rate [60, 61]. The
incidences of sexual dysfunction and bowel dysfunc-
tion were higher in the preoperative radiation combi-
nation therapy group than in the surgery-alone group
[62, 63].
7. The effect of preoperative radiotherapy in reducing the
size of the primary tumor may enable sphincter
preservation. When the purpose of the preoperative
radiotherapy is sphincter preservation, it is recom-
mended to perform surgery after allowing an appro-
priate period for the tumor to decrease in size
(68 weeks after the completion of radiotherapy) [64].
8. In Europe, three phase III clinical trials, including the
EORTC trial, were performed to investigate the
usefulness of adding chemotherapy to preoperative
radiotherapy. The incidence of acute-phase adverse
events was significantly higher in the preoperative
chemoradiotherapy groups, but the pathologic com-
plete response rates (pCR) were significantly higher
than in the preoperative radiotherapy alone groups. In
two trials (the exception being the short-course
radiotherapy trial), the local recurrence rate was
significantly lower in the preoperative chemoradio-
therapy group, and there was no significant difference
between the two groups in terms of sphincter preser-
vation or survival rate [6567].
9. In a phase III clinical trial that compared preoperative
chemoradiotherapy and postoperative chemoradiother-
apy, there was no significant difference in the 5-year
survival rate, but the local recurrence rate and incidence
of grade 3 or higher adverse events were significantly
lower in the preoperative chemoradiotherapy group.
Among the patients in whom abdominoperineal resec-
tion (APR) was considered necessary at the time of
enrollment, the percentage of patients in whom sphincter
preservation was possible was significantly higher in the
preoperative chemoradiotherapy group [68].
2. Palliative radiotherapy
a. Intrapelvic lesions (CQ-18)
The purpose of palliative radiotherapy for intrapelvic
lesions is to relieve symptoms such as pain, hemor-
rhage, and bowel movement disorders caused by
intrapelvic tumors.
The target volume includes the tumor that is causing
the symptoms.
123
Int J Clin Oncol (2012) 17:129
[Dose and fractionation]
A total dose of 4550 Gy is administered in 1.82.0 Gy
per fraction.
Depending on the patients general condition, such as
performance status, and the severity of the symptoms,
radiotherapy may be completed in a shorter term with a
larger fraction size, for example 30 Gy in 10 fractions
over 2 weeks.
b. Extrapelvic lesions
(1) Bone metastases
The purpose of palliative radiotherapy for bone
metastases is to achieve pain relief, prevent pathologi-
cal fractures, and prevent and treat spinal cord
paralysis.
The target volume includes the metastatic bone lesions
causing the symptoms.
[Dose and fractionation]
Local field radiotherapy, such as 30 Gy in 10 fractions
and 20 Gy in 5 fractions, is widely performed.
(2) Brain metastases
See Chapter 4: Treatment strategies for hematogenous
metastases.
[Dose and fractionation]
When whole brain radiotherapy is performed, 30 Gy in
10 fractions is the standard treatment. If long-term
survival is expected, prolonged fractionated radiother-
apy, such as 37.5 Gy in 15 fractions and 40 Gy in 20
fractions, is considered.
When stereotactic radiosurgery is performed, a periph-
eral dose of 1625 Gy is delivered in a single fraction.
Chapter 7: Palliative care
Palliative care is a general term for palliative treatment
of various mental and physical symptoms related to
cancer.
Palliative care extends from the time the diagnosis of
cancer is made to the end stage, and the care provided
should depend on the disease stage and symptoms.
In principle, cancer treatment should be performed
under conditions in which symptom relief is achieved
[69], and palliative care should be started at the same
time as surgical treatment and chemotherapy.
Palliative care to improve the QOL of patients with
end-stage colorectal cancer includes:
(1) pain relief,
(2) surgical treatment,
Int J Clin Oncol (2012) 17:129 17

No. of years and months after

1 year 2 years 3 years 4 years 5 years
surgery
3m 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12
Colon cancer and
RS cancer
Interview and
examination
Tumor marker
Chest CT
Abdominal CT
Colonoscopy
Rectal cancer
Interview and
examination
Tumor marker
Digital rectal
examination
Chest CT
Abdominal and
pelvic CT
Colonoscopy
: Performed for Stage I to Stage III colorectal cancer.
: Performed for Stage III colorectal cancer. Can be omitted in Stage I and Stage II colorectal cancer.
Diagnostic imaging of the chest: CT is desirable, but plain chest X-ray is acceptable.
Diagnostic imaging of the abdomen: CT is desirable, but abdominal ultrasound is acceptable.

Fig. 7 An example of a surveillance schedule after curative resection of stage I to stage III colorectal cancer

(3) chemotherapy, retrospective investigation of factors such as the

(4) radiotherapy, common sites and the incidence of recurrence and the
(5) counseling for psychiatric symptoms. efficacy of treatment (Fig. 7).

Chapter 8: Surveillance after surgery for colorectal 2. Surveillance after curability B resection of colorectal
cancer cancer and after resection of recurrent tumors

1. Surveillance for recurrence after curability A resection The same surveillance method as for stage III colorectal
of colorectal cancer cancer is used. It should be noted that recurrence and
re-recurrence are common in organs that were previ-
Surveillance is not required for stage 0 (pM cancer) if ously operated on.
the resection margin is cancer-free. However, when
evaluation of the resection margin is difficult, colon-
3. Surveillance of metachronous multiple cancer
oscopy is performed 6 months to 1 year later to deter-
mine whether local recurrence is present.
Colonoscopy is performed for surveillance of metach-
In principle, the duration of surveillance is 5 years after
ronous multicentric colorectal cancer.
surgery, but the surveillance examinations are scheduled
at shorter intervals during the first 3 years after surgery. Comments
It should be noted that there is a high incidence of lung [Aim of surveillance]
metastasis and local recurrence after surgery for rectal
The aim of surveillance is to improve the patients
cancer.
prognosis by early detection and treatment of recur-
As a general rule, the duration of surveillance for
rences. Meta-analyses of RCTs conducted in Europe
anastomotic recurrence is until 3 years after surgery.
and the United States have shown that surveillance after
The following is an example of a surveillance schedule
curative surgical resection of colorectal cancer contrib-
after curative resection of stage I to stage III colorectal
utes to improving the resection rate of recurrent tumors
cancer that was designed on the basis of the results of a
and to improving the prognosis [7074] (CQ-19).

123
18 Int J Clin Oncol (2012) 17:129

[Recurrence rate, sites of recurrence, times of recurrence] More than 95% of the anastomotic recurrences
were detected within 3 years after surgery.
The results of a review of the project study by the
Local recurrence and lung recurrence were more
JSCCR are shown in Figs. 8, 9 and Tables 7, 8, 9, 10.
frequent in rectal cancer than in colon cancer.
The subjects were patients who underwent curative
There have been reports regarding recurrences
resection of colorectal cancer between 1991 and 1996
after curative resection in Europe and the United
at the 14 institutions that participated in the project, and
States showing that approximately 50% of the
the follow-up period was 611 years.
recurrences were detected within 1 year after
(1) Times of the recurrences and sites of the recurrences surgery, that approximately 70% of the recur-
(Fig. 9; Tables 7, 9, 10). rences were detected within 2 years after surgery
[75, 76]; and that in most patients the recurrences
More than 80% of the recurrences were detected
were detected within 5 years after surgery [76].
within 3 years after surgery, and more than 95%
of the regcurrences were detected within 5 years (2) Characteristics according to stage (Fig. 8; Tables 7, 8)
after surgery.
1. Stage I
The overall incidence of recurrence more than
5 years after surgery was less than 1%. The recurrence rate of pSM cancer was
Among lung recurrences, 5% of recurrences were approximately 1% in both colon cancer and
detected more than 5 years after surgery. rectal cancer.
The overall recurrence rate of pMP cancer
1 was 6.4%, and it was 5.0% in colon cancer
Cumulative incidence of

and 8.3% in rectal cancer.

.8
Two-thirds of the recurrences were detected
recurrence

Stage I 1367 patients

.6 Stage II 1912 patients
within 3 years after surgery, and the overall
Stage III 1951 patients incidence of recurrence more than 5 years after
.4
surgery was less than 0.2% among all patients.
.2
2. Stage II, Stage IIIa, and Stage IIIb
0 P<0.0001
The recurrence rate increased with the stage.
0 2 4 6 8 10 7890% of recurrences were detected within
(Years after surgery) 3 years after surgery, and the overall inci-
Fig. 8 Graph of the cumulative incidence of recurrence according to dence of recurrence more than 5 years after
stage. (Project study by the JSCCR: patients in years 19911996) surgery was less than 1% among all patients.

Fig. 9 Graphs of the 1

Cumulative incidence of

cumulative incidence of .8
recurrence according to the site
recurrence

of recurrence. (Project study by .6

Liver metastases 373 patients
the JSCCR: patients in years .4 Lung metastases 250 patients
19911996)
.2
P<0.0001
0
0 2 4 6 8 10 (Years after
surgery)
Liver recurrence / lung recurrence

1 1 199 patients
Cumulative incidence of

Cumulative incidence of

.8 .8
recurrence

recurrence

.6 .6

.4 Local recurrence 209 patients .4

Anastomotic recurrence 22
.2 patients .2
0 P=0.4560 0

0 2 4 6 8 10 (Years after 0 2 4 6 8 10 (Years after

surgery) surgery)
Local recurrence / anastomotic Other recurrences
recurrence

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Int J Clin Oncol (2012) 17:129 19

Table 7 Recurrence rate after curative resection of colorectal cancer according to stage and cumulative incidence of recurrence according to the
number of years after surgery
Stage (no. of Recurrence rate Cumulative incidence of recurrence Percentage of patients
patients) (no. of patients according to the number of years after surgery experiencing recurrence more than
with recurrence) (cumulative no. of patients with recurrence) 5 years after surgery among all
patients (no. of patients)
3 years 4 years 5 years

I 3.7% 68.6% 82.4% 96.1% 0.15%

(1,367) (51) (35) (42) (49) (2)
II 13.3% 76.9% 88.2% 92.9% 0.94%
(1,912) (255) (196) (225) (237) (18)
III 30.8% 87.0% 93.8% 97.8% 0.67%
(1,957) (600) (522) (563) (587) (13)
All 17.3% 83.2% 91.6% 96.4% 0.63%
(5,230) (906) (753) (830) (873) (33)
Project study of the JSCCR: patients in years 19911996

Table 8 Recurrence rate of

Stage I No. of No. of patients Recurrence p value
stage I colorectal cancer (RS
patients with recurrence rate (%)
cancer was counted as colon
cancer) Tumor location
Colon 891 24 2.7 0.0056
Rectum 476 27 5.7
Depth of tumor invasion
SM 714 9 1.3 \0.0001
MP 653 42 6.4
Tumor location and depth of tumor invasion
Colon
SM 528 7 1.3 0.0024
MP 363 17 4.7
Rectum
SM 186 2 1.1 0.0005
Project study of the JSCCR: MP 290 25 8.6
patients in years 19911996

Table 9 Recurrence rate according to the site of the first recurrence after curative resection of colorectal cancer and cumulative incidence of
recurrence according to the number of years after surgery
Site of first Recurrence rate (no. Cumulative incidence of recurrence according Percentage of patients
recurrence of patients with to the number of years after surgery experiencing recurrence more than
recurrence (cumulative no. of patients with recurrence) 5 years after surgery among all
(including overlaps) patients (no. of patients)
3 years 4 years 5 years

Liver 7.1% (373) 87.9% (328) 94.1% (351) 98.7% (368) 0.10% (5)
Lung 4.8% (250) 78.0% (195) 88.8% (222) 94.8% (237) 0.25% (13)
Local 4.0% (209) 80.9% (169) 90.4% (189) 96.2% (201) 0.15% (8)
Anastomotic 0.4% (22) 95.5% (21) 95.5% (21) 95.5% (21) 0.02% (1)
Other 3.8% (199) 79.4% (158) 91.0% (181) 95.5% (190) 0.17% (9)
All (5,230) 17.3% (906)
Project study of the JSCCR: patients in years 19911996

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20 Int J Clin Oncol (2012) 17:129

Table 10 Comparison between

Site of recurrence Colon cancer Rectal cancer p value
the recurrence rates of colon
(3,583 patients) (1,647 patients)
cancer and rectal cancer
according to the site of the first Liver 7.0% (252) 7.3% (121) NS
recurrence (RS cancer was
counted as colon cancer) Lung 3.5% (126) 7.5% (124) \0.0001
Local 1.8% (64) 8.8% (145) 0.0001
Anastomotic 0.3% (9) 0.8% (13) 0.0052
Other 3.6% (130) 4.2% (69) NS
Project study of the JSCCR: All 14.1% (506) 24.3% (400) \0.0001
patients in years 19911996

Fig. 10 Treatment strategies

for pSM cancer after endoscopic Positive vertical
Negative vertical margin margin
resection
Papillary Poorly differentiated
adenocarcinoma adenocarcinoma
Tubular Signet-ring cell
adenocarcinoma carcinoma
Mucinous carcinoma

Depth of invasion Depth of invasion

<1000 m >1000 m

Vascular invasion Vascular invasion

negative positive

Budding (G1) Budding (G2/3)

Surveillance Intestinal resection with lymph node dissection Intestinal resection with
is considered lymph node dissection

[Surveillance of metachronous multiple primary cancer]
A past medical history of colorectal cancer, regardless
of stage, is a risk factor for metachronous colorectal
cancer [77].
The recommended interval between colonoscopy ran-
ged from 1 to 5 years, depending on the report [78].
There was no evidence indicating the necessity of
periodic detailed examinations for cancer in other
organs (multiple cancer) after surgery for colorectal
cancer (CQ-19).
Clinical questions
CQ-1: Indication criteria for additional treatment
after endoscopic resection (Fig. 10)
Recommendation: Category B
Surgical resection is preferable when the vertical
margin is positive.
If any of the following findings is observed during
histological examination of the resected specimen,
intestinal resection with lymph node dissection is
considered as an additional treatment:
(1) Depth of SM invasion C1,000 lm,
(2) vascular invasion positive,
(3) poorly differentiated adenocarcinoma, signet-ring
cell carcinoma, or mucinous carcinoma [79],
(4) Grade 2/3 budding at the site of deepest invasion
[79].
Note:
Vertical margin-positive means that carcinoma is
exposed at the submucosal margin of the resected
specimen.
Depth of SM invasion is measured by the method
described in Side Memo 1 (Fig. 11).
Vascular invasion consists of lymphatic and venous
invasion (Figs. 12, 13, 14).
The method for assessing budding is described in
Fig. 15.
The principle for the treatment of pSM carcinomas,
which are invasive carcinomas, is intestinal resection with
lymph node dissection. However, some pSM carcinomas
have a very low risk of metastasis, and the purpose of these

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Int J Clin Oncol (2012) 17:129 21

Fig. 11 Method for measuring

depth of SM invasion. a When it a b
is possible to identify or
estimate the location of the
muscularis mucosae, depth of
SM invasion is measured from
the lower border of the
muscularis mucosae. b, c When
it is not possible to identify or
estimate the location of the
muscularis mucosae, depth of
SM invasion is measured from c d
the surface layer of the
muscularis mucosae. Sessile
lesion (b), pedunculated lesion
(c). d For pedunculated lesions
with tangled muscularis Head
mucosae, depth of SM invasion
is measured as the distance
between the point of deepest
invasion and the reference line, Baseline
which is defined as the
boundary between the tumor
head and the stalk. e Invasion by
pedunculated lesions that is Stalk
limited to within the head is
defined as head invasion.

An example of head invasion

e

Lower border of
cancer invasion

Head Baseline

Stalk

criteria is to minimize the need for additional resections
that eventually result in overtreatment of such patients.
While no diagnostic methods make it possible to predict
lymph node metastasis (pN) without fail, the degree of risk
of metastasis can be used as a basis for determining whe-
ther or not to perform additional treatment.
Factors such as the depth of submucosal invasion (SM
invasion depth) [80], histological type (such as poorly
differentiated adenocarcinoma, signet-ring cell carcinoma,
and mucinous carcinoma [79]), the presence of a poorly
differentiated area and muconodules at the site of deepest
invasion, budding, and vascular invasion have been
reported to be risk factors for regional lymph node
metastasis by pSM carcinoma [79, 81].
The above criteria for determining whether additional
treatment is indicated were prepared based on the follow-
ing 3 criteria for performing additional intestinal resection
of pSM carcinoma described in the Japanese Classification
of Colorectal Carcinoma (2nd edition, 1980): (1) obvious
intravascular carcinoma invasion; (2) poorly differentiated
adenocarcinoma or undifferentiated carcinoma; (3) mas-
sive carcinoma invasion extending to the vicinity of the
margin [82]. The description of massive carcinoma
invasion in the 4th edition of the Japanese Classification
of Colorectal Carcinoma was revised to the following more
specific description in the 5th edition (1994): invasion
deeper than very shallow invasion (e.g., invasion
exceeding approximately 200 to 300 lm) [83].

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22 Int J Clin Oncol (2012) 17:129

Fig. 12 Venous invasion (arrow in a). a Located in the vicinity of an artery (a). b Elastic fibers in the vein wall have been highlighted by
Victoria blue staining

Fig. 13 Lymphatic invasion (arrow in a). a A cancer cell nest is visible in the interstitial space. b Double staining for cytokeratin and D2-40.
Cancer cells are stained brown, and the lymphatic endothelium is stained purplish red

Subsequent case series studies in Japan have shown that
200300 lm can be extended to 1,000 lm [84].
According to the results of the project study by the JSCCR,
the lymph node metastasis rate of colorectal carcinoma
with an SM invasion depth of 1,000 lm or more was
12.5% (Table 11) [80, 84]. However, approximately 90%
of patients with a depth of invasion of 1,000 lm or more
did not have lymph node metastasis, and it is important to
determine whether additional treatment is indicated after
sufficiently considering other factors in addition to depth of
SM invasion, such as whether other risk factors for lymph
node metastasis are present, the physical and social back-
ground of the patient, and the patients wishes. Because
budding was demonstrated to be an important risk factor
for lymph node metastases in the project study by the
JSCCR, additional intestinal resection has been added to
the list of factors that should be considered in this revised
edition. None of the guidelines in other countries include
depth of invasion or budding as criteria for additional
treatment.
CQ-2: Endoscopic resection of cM carcinomas
and cSM carcinomas with a maximum diameter
of 2 cm or greater
Recommendation: Category B
Accurate preoperative endoscopic diagnosis is essential,
and whether resection by EMR, piecemeal EMR, or ESD
is indicated is determined after taking the operators skill
in performing endoscopic resection into consideration.

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Int J Clin Oncol (2012) 17:129 23

Fig. 14 Space formed by artifacts during preparation of the specimen (arrow in a). a A cancer cell nest is visible in the interstitial space.
b Double staining for cytokeratin and D2-40. The interstitial space is D2-40-negative

Fig. 15 Budding (arrows in b). a A cancer cell nest consisting of 1 or less than 5 cells that has infiltrated the interstitium at the invasive margin
of the cancer is seen. b is the square area in a

Table 11 Depth of invasion of sm cancer and lymph node metastasis (modified from [80])
sm invasion distance (lm) Pedunculated Nonpedunculated
Number of lesions n (?) (%) Number of lesions n (?) (%)

Head invasion 53 3 (5.7)

0 \ X \ 500 10 0 (0) 65 0 (0)
500 B X \ 1,000 7 0 (0) 58 0 (0)
1,000 B X \ 1,500 11 1 (9.1) 52 6 (11.5)
1,500 B X \ 2,000 7 1 (14.3) 82 10 (12.2)
2,000 B X \ 2,500 10 1 (10.0) 84 13 (15.5)
2,500 B X \ 3,000 4 0 (0) 71 8 (11.3)
3,000 B X \ 3,500 9 2 (22.2) 72 5 (6.9)
3,500 B X 30 2 (6.7) 240 35 (14.6)
The lymph node metastasis rate of patients with a depth of invasion of 1,000 lm or above was 12.5%
All 3 lymph node metastasis-positive patients with head invasion were ly positive

123
24
Side Memo 1
Method for measuring depth of SM invasion (Fig. 11):
When it is possible to identify or estimate the location
of the muscularis mucosae, depth of SM invasion is
measured from the lower border of the muscularis
mucosae of the lesion, regardless of the macroscopic
type.
When it is not possible to identify or estimate the
location of the muscularis mucosae, the depth of SM
invasion is measured from the surface of the lesion. The
phrase possible to identify or to estimate means that
there is no deformity (i.e., disarray, dissection,
rupture, fragmentation, etc.) of the muscularis mucosae
as a result of SM invasion. If a deformed muscularis
mucosa is used as the baseline of the measurement, the
depth of SM invasion may be underestimated.
Although judging whether there is a deformity is
not always straightforward, if a desmoplastic reaction is
present around the muscularis mucosae, it is assumed to
be deformed.
For pedunculated lesions with a tangled muscularis
mucosae, depth of SM invasion is measured as the
distance between the point of deepest invasion and the
reference line, which is defined as the boundary between
the tumor head and the stalk (the boundary between the
tumor area and the non-tumor area in the mucosa).
Invasion by pedunculated lesions that is limited to
within the head is defined as head invasion.
Method for assessing vascular invasion (Figs. 12, 13, 14):
Attention to arteries is a key factor in assessing venous
invasion. Venous invasion is highly likely when a
circular, semicircular, or oblong cancer cell nest with
regular margins is located in the vicinity of an artery
and distant from the main lesion. If such a cancer cell
nest is surrounded by venous wall structures (such as
internal elastic membrane or perivascular smooth
muscle), it can be concluded to represent venous
invasion. However, the venous wall structures are often
displaced or obliterated by the cancer cell nest, and it is
difficult to recognize in hematoxylin and eosin stained
sections.
The presence of cancer cells and cancer cell nests in the
interstitial space suggests lymphatic invasion. A space
filled with lymph and lymphocytes is especially likely
to be a lymph vessel. When endothelial cells are
identified around the space, the space can be concluded
to represent a lymph vessel. However, it is often
difficult to identify endothelial cells in specimens
123
Int J Clin Oncol (2012) 17:129
stained with hematoxylin and eosin, and spaces may
be artifacts created during the process of preparing the
specimen.
As stated above, evaluation of vascular invasion, which
is an important indicator for determining treatment
strategies for SM cancer, is often difficult in hematox-
ylin and eosin stained specimens. Special staining
methods are useful for evaluating vascular invasion,
such as elastica van Gieson staining or Victoria blue
staining for venous invasion, and D2-40 immunostain-
ing for lymphatic invasion.
Method for assessing tumor budding (Fig. 15):
[Definition of tumor budding] [79]
A cancer cell nest consisting of 1 or less than 5 cells that
infiltrates the interstitium at the invasive margin of the
cancer.
[Grade of budding]
After selecting one field where budding is the most
intensive, the number of buddings is counted in a field
measuring 0.785 mm2 observed through a 209 objective
lens (WHK 109 ocular lens). Depending on the number of
buddings, the grade of budding is defined as follows:
Grade 1: 04
Grade 2: 59
Grade 3: 10 or more
The lymph node metastasis rate associated with grade 2/3
tumors is significantly higher than that associated with
grade 1 tumors. A multi-center study conducted by the
Budding Investigation Project Committee (2005) of the
JSCCR in which grade 1 was defined as low grade and
grade 2/3 as high grade showed that high grade is an
independent predictor of lymph node metastasis.
CQ-3: Laparoscopic surgery for colorectal cancer
Recommendation: Category B
Since laparoscopic surgery requires surgical skills that
are different from those required for open abdominal
surgery, and an understanding of regional anatomy is
essential for laparoscopic surgery, the indication crite-
ria should be determined depending on the skills of the
surgical team.
Laparoscopic surgery is suitable for D2, D1 or D0
resection of colon and RS cancer, and is well indicated for the
treatment of cStage 0 to cStage I disease. Because laparo-
scopic colectomy with D3 dissection is difficult, whether
it is indicated for patients with cStage II to cStage III
Int J Clin Oncol (2012) 17:129
disease should be determined after carefully considering the
skills of the surgical team. Laparoscopic surgery is also
difficult in patients with transverse colon cancer, in severely
obese patients, and in patients with severe adhesions. The
efficacy and safety of laparoscopic surgery for rectal cancer
has not been sufficiently established.
CQ-4: Resection of the primary tumor in patients
with unresectable distant metastases
Recommendation: Category B
The initial resection of the primary tumor should be
determined based on the performance status of each
patient, such as the symptoms caused by the primary
tumor, the status of distant metastases, and the patients
general condition. Resection of the primary tumor is
often desirable when a patient has symptoms caused by
the primary tumor that cannot be well controlled by
other therapies, if the patient is sufficiently able to
tolerate surgery, and the resection can be accomplished
with acceptable morbidity.
CQ-5: Resection of peritoneal metastases
(carcinomatous peritonitis)
Recommendation: Category C
If patients with localized peritoneal dissemination (P1,
P2) have no other unresectable distant metastases and
resection will not result in excessive invasion, it is
preferable to resect the disseminated tumors at the same
time as the resection of the primary tumor.
CQ-6: Surgical treatment for local recurrence of rectal
cancer
Recommendation: Category B
Resection should be considered for local recurrence of
rectal cancer when R0 resection is considered possible.
CQ-7: Resection in patients with liver and lung
metastases
Recommendation: Category C
The efficacy of resection in patients who have liver and
lung metastases at the same time has been shown, and
thus resection should be considered for patients with
resectable liver and lung metastases.
However, there are insufficient data to determine the
indication criteria for surgery. It is necessary to obtain
25
informed consent after informing the patient of the rather
low cure rate and the absence of outcome predictors.
CQ-8: Adjuvant chemotherapy after curative resection
of liver metastases
Recommendation: Category B
The efficacy of adjuvant chemotherapy after hepatec-
tomy has not been established. It is desirable to
investigate its efficacy in clinical trials.
CQ-9: Preoperative chemotherapy for resectable liver
metastases
Recommendation: Category B
The safety of preoperative chemotherapy for resectable
liver metastases has not been established. It should be
evaluated in properly designed clinical trials.
CQ-10: Chemotherapy for unresectable liver metastases
Recommendation: Category B
Hepatectomy should be considered for liver metastases
that have become resectable after successful
chemotherapy.
No clear difference has been observed between hepatic
arterial infusion therapy and systemic chemotherapy in
terms of the prolongation of survival time of patients with
unresectable liver metastases.
CQ-11: Postoperative adjuvant chemotherapy and age
Recommendation: Category A
Even in patients 70 years old or older, postoperative
adjuvant chemotherapy can be performed if their PS is
good, if the function of major organs is adequate, and if
there are no complications that may be a risk for
performing chemotherapy.
CQ-12: Postoperative adjuvant chemotherapy for stage
II colorectal cancer
Recommendation: Category A
The usefulness of postoperative adjuvant chemotherapy
for stage II colorectal cancer has not been proven, and it
is not appropriate to routinely administer adjuvant
chemotherapy to all patients with stage II colorectal
cancer.
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26 Int J Clin Oncol (2012) 17:129

CQ-13: Duration of postoperative adjuvant the effect of anti-EGFR antibody drugs and the level of
chemotherapy EGFR expression assessed by immunostaining [91].
CPT-11 and UGT1A1 genetic polymorphism
Recommendation: Category A
SN-38 is an active metabolite of CPT-11 and the
Although no definitive conclusion regarding the dura-
UGT1A1 gene encodes an intrahepatic metabolizing
tion of postoperative adjuvant chemotherapy has been
enzyme which converts the active form SN-38 to the
reached, the current standard duration of treatment by
inactive form SN-38 G. In patients who are double het-
5-FU-based adjuvant chemotherapy is 6 months.
erozygotes for *6 and *28 or homozygotes for *6 or *28 of
the UGT1A1 gene, the glucuronic acid conjugation capacity
CQ-14: Oxaliplatin (L-OHP) in postoperative adjuvant of UGT1A1 is known to be decreased and the metabolism
chemotherapy of SN-38 to be delayed, and serious adverse drug reactions
such as neutropenia may occur as a result. It is especially
Recommendation: Category A desirable to test for a UGT1A1 genetic polymorphism
before administering CPT-11 to patients with a high serum
In August 2009, L-OHP was approved for postoperative
bilirubin level, elderly patients, patients whose general
adjuvant chemotherapy in Japan. When selecting target
condition is poor (e.g., PS2), and patients in whom severe
patients, the indication should be determined after
toxicity (especially neutropenia) developed after the last
obtaining sufficient informed consent regarding adverse
administration of CPT-11. On the other hand, because CPT-
events and medical care costs as well as the expected
11 toxicity cannot be predicted with certainty on the basis of
additional benefit in terms of survival time.
the presence of a UGT1A1 genetic polymorphism alone, it
is essential to monitor the patients general condition during
CQ-15: Molecular target drugs for secondary treatment treatment and manage adverse drug reactions carefully
regardless of whether a genetic polymorphism is detected.
Recommendation: Category B
CQ-17: Significance of preoperative
It is desirable to use bevacizumab as secondary
chemoradiotherapy for rectal cancer
treatment in patients who can be treated with bev-
acizumab and have not received it as primary treatment.
Recommendation: Category C
There is no clear evidence supporting the optimal dose
in this situation (5 or 10 mg/kg) [44, 49]. Preoperative chemoradiotherapy is standard treatment
for rectal cancer in Europe and the United States.
However, there is insufficient evidence in support of its
CQ-16: KRAS gene mutations and anti-EGFR antibody
efficacy and safety in Japan, and it needs to be
drugs
evaluated in properly designed clinical trials.
Recommendation: Category A
CQ-18: Chemoradiotherapy for unresectable locally
The usefulness of anti-EGFR antibody drugs has been
advanced and locally recurrent rectal cancer
reported in metastatic colorectal cancer without KRAS
gene mutations [3841, 47, 53, 55, 8590].
Recommendation: Category C
The indication for chemoradiotherapy aiming at complete
Side Memo 2
cure by R0 resection will also be considered for locally
advanced or locally recurrent, unresectable rectal cancer.
Anti-EGFR antibody drugs and EGFR immunostaining
Since most clinical research on cetuximab has been con-
CQ-19: Significance of surveillance after surgery
ducted on EGFR-positive patients, insurance coverage is
of colorectal cancer
limited to EGFR-positive patients. On the other hand, most
clinical research on panitumumab has also been conducted
19A: Diagnosis of recurrence
on EGFR-positive patients, and evidence in regard to
Recommendation: Category A
EGFR-negative patients is insufficient, but insurance cov-
erage has been restricted to EGFR-positive patients. A Early detection of recurrence has been shown to
recent report showed that there is no relationship between contribute to an improvement in outcome, and

123
Int J Clin Oncol (2012) 17:129
postoperative surveillance examinations should be
performed regularly. However, an optimal surveillance
protocol incorporating the health economical point of
view has not been sufficiently established.
19B: Multiple cancer
Recommendation: Category B
With the exception of hereditary colorectal cancer, a
past medical history of colorectal cancer has not been
demonstrated to be a risk factor for the development of
cancer in other organs, and it is unnecessary to
incorporate special surveillance for multiple cancer
into the surveillance performed after curative surgery
for colorectal cancer.
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