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S M
C
INTRODUCTION
Surgical resection is the primary curative treatment for patients with
localized colorectal cancer. e most accurate prognostic indicator
of colon cancer is its stage at diagnosis, and in patients with locally
advanced disease, chemotherapy has a role in decreasing the risk for
recurrence or metastasis.
Staging of colorectal cancer is based on the depth of penetration
of the tumor into the bowel wall, the involvement of regional lymph
nodes, the involvement of adjacent organs, and the presence or
absence of distant metastasis. Surgery performed according to oncologic principles is designed to resect the cancer with clear margins,
provide the most accurate staging possible, and preserve function.
e purpose of this chapter is to describe these surgical techniques as
applied to cancer of the colon.
EPIDEMIOLOGY
Colorectal cancer is the third most frequently diagnosed cancer in
men and women and the second leading cause of cancer death in the
United States. In 2013, there were an estimated 102,480 new cases of
colon cancer and 40,340 new cases of rectal cancer, with an estimated
5830 deaths from colon and rectal cancers combined. However, mortality from colorectal cancer has decreased by almost 35% from 1990
to 2007, likely because of earlier diagnosis through screening and
improvements in management.
Prognostic Factors
Oncologic outcomes of colon cancer resection include survival and
recurrence. Survival is usually reported as overall survival including deaths from all causes, or age-adjusted survival, controlling for
deaths from causes unrelated to the colon cancer. Recurrence is classied as local recurrence, distant recurrence or metastasis, or both.
e most important prognostic factor aer resection for colon cancer
is the stage of disease at presentation. Survival is usually reported by
stage, according to the American Joint Committee on Cancer staging
system, as follows: stage I: overall survival is well above 90%; stage
II: overall survival is 65% to 90%; stage III: overall survival 45% to
75%; and stage IV: overall survival is 10% to 20%. For patients with
high-risk stage II and stage III disease, adjuvant chemotherapy can
reduce the risk of recurrence and improve survival. Adjuvant 5-uorouracil (5-FU) and leucovorin (LV) provides an approximately 25%
to 30% relative risk reduction for recurrence and approximately 10%
absolute improvement in survival at 8 years. Capecitabine is an oral
uoropyrimidine and has been shown to be equivalent to 5-FU/LV
in patients with stage III colon cancer. e addition of oxaliplatin
to 5-FU/LV also improves risk for recurrence and survival with an
C
In Ja Park and George J. Chang
approximately 20% incremental risk reduction for recurrence among
stage III patients when compared with 5-FU alone. e role of radiation therapy for colon cancer is limited by the potential for radiation-induced injury to adjacent structures such as the small intestine.
Other prognostic factors include the tumor-related complications
of obstruction or perforation and histologic features such as signet
ring cells, high tumor grade (poor dierentiation), and vascular, lymphatic, or perineural invasion.
PREOPERATIVE EVALUATION
Preoperative assessment of the patient with colon cancer should
include staging, an assessment of operative risk, and a thorough family history that documents colorectal cancer and extracolonic cancers
associated with syndromes of inherited colorectal cancer. e overall
physiologic status of the patient is assessed with preoperative laboratory studies such as a complete blood cell count, urinalysis, chemistry
panel, electrocardiogram, and chest radiograph. Nutritional status is
assessed clinically. Scoring systems that combine physical activity,
symptoms, and laboratory results to assess perioperative risk have
been described, including that of the American Society of Anesthesiologists and the Physiological and Operative Severity Score for the
enUmeration of Mortality and morbidity (POSSUM) and the Portsmouth (p)-POSSUM scores.
A complete staging workup includes a total colonoscopy with
biopsy (with consideration given to immunohistochemistry to detect
mismatch repair gene expression and/or microsatellite instability
testing to detect mismatch repair dysfunction that might suggest
Lynch syndrome), carcinoembryonic antigen (CEA), and baseline
computed tomography (CT) scans of the chest, abdomen, and pelvis.
If questionable abnormalities are seen on the CT or magnetic resonance imaging (MRI) scan, a positron emission tomography/CT scan
may be considered to further delineate the abnormality, particularly
if more denitive information will change management.
Accurate localization of the tumor is important, especially if the
cancer is small and the operation will be performed using the laparoscopic technique. Ideally, the referring colonoscopist has tattooed the
colon near the tumor. An accurate family history and the results of
preoperative tumor immunohistochemistry/microsatellite instability
testing are important in deciding the extent of the resection.
PREOPERATIVE PREPARATION
e role of mechanical bowel preparation remains controversial;
however, most surgeons continue to recommend bowel preparation
prior to a routine colectomy. One potential benet is to decrease the
weight and distension of the colon for minimally invasive mobilization. e use of prophylactic oral antibiotics during mechanical
301
Surgical ManageMent of cancer of the colon302
preparation is also controversial. A recent evaluation of 24 hospitals
in the Michigan Surgical Quality Collaborative Colectomy Best Practices Study showed that mechanical preparation was used in 86% of
patients and that the addition of oral antibiotics reduced the risk for
surgical site infections (4.5% vs 11.8%, P = .0001) and the risk for
prolonged ileus (3.9% vs 8.6%, P = .011) without increasing the risk
for Clostridium dicile colitis. Evidence consistently supports the use
of intravenous antibiotics prior to making an incision to reduce the
rate of wound infections.
Prophylaxis against deep venous thrombosis should be performed
prior to the induction of anesthesia and may include subcutaneous
heparin or one of the low molecular weight heparin agents. In addition, graded lower extremity compression stockings and sequential
pneumatic compression devices also should be applied intraoperatively and their use should be continued postoperatively until the
patient is walking.
5–10
5
10
5
5–10
OPERATIVE PRINCIPLES AND TECHNIQUES
Surgery is the primary treatment of localized colon cancer and in
many cases will be the only treatment that is necessary. e surgical
principles for resectable, nonmetastatic colon cancer include colectomy with complete, en bloc removal of regional lymph nodes following the principles of oncologic resection. ese principles are:
1. Resection of the cancer-containing bowel and the wedge of
mesentery associated with the arterial supply of the aected
segment, including the regional lymph nodes
2. Ligation of the feeding vessel at its origin
3. Removal or biopsy of suspicious lymph nodes that are located
outside the eld of resection
4. Unresected positive lymph nodes indicate an incomplete re-
section
5. Minimum proximal and distal resection margins are 5 cm
6. A minimum of 12 mesenteric lymph nodes should be found
and examined for accurate staging
No specic margin is recommended for clearance of the terminal ileum for patients with right colon cancer undergoing resection
other than that dened by vascular supply because mural spread to
the ileum is rare.
Exploration
Whether laparotomy or a minimally invasive technique is chosen,
the presence of metastatic disease must be carefully assessed, with
particular attention directed to the liver, peritoneal surfaces, and pelvis. In women, the ovaries should be examined not only for metastatic deposits but also for synchronous primary neoplasms. Next,
the resectability of the primary tumor should be determined. If the
cancer is adherent to an adjacent organ, it should be removed with
an en bloc resection.
5
FIGURE 61-1 Approach for laparoscopic resection for colon cancer.
Surgical Treatment of Right Colon Cancer
Our preferred approach to colon resection is laparoscopic. A number of variations for the placement of the ports and the sequence of
the steps for vascular dissection and bowel mobilization have been
described; our preferred port placement is shown in Figure 61-1. is
approach optimizes the port placement to be contralateral to the disease. e sequence of dissection (e.g., vascular or bowel rst) is at
the discretion of the operating surgeon; however, vascular control is
facilitated by a medial to lateral approach, which takes advantage of
the native attachments of the colon to facilitate exposure of the vascular anatomy. On the other hand, bowel mobilization may be preferred
FIGURE 61-2 Extent of resection for right colectomy.
during open surgery, allowing the bowel to be elevated to expose the
central vessels.
Cancers that are located in the cecum or the ascending colon
should be removed by a right hemicolectomy, which encompasses the
bowel served by the ileocolic, right colic, and, as necessary, the right
branch of the middle colic vessels (Fig. 61-2). If the lesion is located
in the area of the hepatic exure, the right branch of the middle colic
vessels should be routinely divided. An extended right colectomy
COLON 303
FIGURE 61-4 Proximal ligation of the ileocolic artery and vein.
FIGURE 61-3 Extent of resection for extended right colectomy.
includes ligation and division of the main middle colic arterial trunk
and is performed for any lesion in the transverse colon beyond the
hepatic exure (Fig. 61-3).e splenic exure may need to be released
for a tension-free anastomosis.
A right hemicolectomy should begin by gaining access to
the retroperitoneum, which can be accomplished via dierent
approaches. e medial and lateral approaches are most common during laparoscopy. With the medial to lateral approach, the
ileocolic pedicle is identied and elevated. e peritoneum on the
caudal side of the pedicle is incised and the retroperitoneum is
entered. e ileocolic artery and vein are isolated aer rst clearly
identifying their relationship to the superior mesenteric artery
and vein. During the course of this dissection, the lymphoadipose
tissue overlying the ileocolic vessels should be swept distally and
included with the resection specimen. e duodenum should be
identied during this maneuver because the ileocolic vessels are
elevated away from the duodenum and pancreatic head. e ileocolic artery and vein should be divided at their origins from superior
mesenteric vessels (Fig. 61-4). e ileocolic vein typically courses
behind the artery before draining into the superior mesenteric vein
(SMV), but care should be taken to clearly delineate the anatomy
because signicant variation may exist. Continuing the dissection
along the superior mesenteric artery (SMA) reveals the right colic
and middle colic arteries. is maneuver is facilitated by completing the mobilization of the proximal transverse colic mesentery
away from the pancreatic head.
Alternatively, the colon can be mobilized from inferior to superior
by elevating the cecum and base of small bowel mesentery cephalad. e lateral approach should begin by incising the lateral peritoneal attachments of the colon beginning at the cecum and elevating
the colon away from the retroperitoneum. Regardless of how the
retroperitoneum is accessed, the principles of the resection remain
the same. e right colon mesentery is lied away from the retroperitoneum, and the duodenum and pancreatic head are identied
FIGURE 61-5 Exposure of the duodenum during medial-to-lateral
mesocolic mobilization.
(Fig. 61-5). e lateral attachments are incised and the hepatic ex-
ure is fully mobilized. In cases of locally advanced tumors, the bowel
mobilization should remain widely clear of the tumor to avoid the
potential for perforation.
Certain dangers must be avoided for safe and eective mobiliza-
tion of the right colon.
1. Anatomic variation is found in both the arterial supply and the
venous drainage of the right colon. e origin of the right colic
artery is quite variable. It may arise from the SMA, the middle
colic artery, or the ileocolic artery, or it may be entirely absent.
e venous drainage through the right colic vein typically joins
the right gastroepiploic vein and/or the pancreaticoduodenal
vein to form the gastrocolic trunk of Henle (Fig. 61-6). e
right branch of the middle colic vein also may drain into the
common trunk.
2. e veins in the proximal transverse mesentery are fragile and
prone to avulsion, which results in serious bleeding.
3. Care should be taken to avoid injury to the duodenum as the
mesentery is mobilized o of the duodenum and the head of
the pancreas. Small venous tributaries are present along the
edge of the pancreatic head, and dissection in the incorrect
plane can lead to bleeding.
4. At the base of the transverse colon mesentery, the SMA and
SMV are at risk for injury.
5. Inadvertent mobilization of the duodenum and right kidney
and injury to the right ureter or gonadal vein should be avoided. Routine deliberate dissection of the ureter as a means to
identify it and protect it from injury is discouraged unless it
Surgical ManageMent of cancer of the colon304
cannot be seen through the thin veil of retroperitoneal tissue
and denitive visualization of the ureter is required. In some
cases, the ureter can be identied where it crosses the iliac vessels and it can be followed into the retroperitoneum.
Upon completion of the mobilization, the terminal ileum should
be divided approximately 10 cm proximal to the ileocecal valve,
protecting its mesentery. e transverse colon is divided according to the location of the tumor. An ileocolic anastomosis can then
be performed aer conrming adequate blood supply through
seeing or feeling pulsatile ow in the marginal vessels, or Doppler
interrogation.
Surgical Treatment of Transverse Colon Cancer
e best surgical procedure is determined by the location of the
tumor and the need to remove the regional lymphatics. Resection is
based on arterial supply and the associated mesentery. us a proximal lesion may require resection of the middle colic and ileocolic
arteries (Fig. 61-7), whereas several options may be appropriate for a
more distal lesion. A cancer in the middle of the transverse colon may
be treated by transverse colectomy, including the root of the middle
colic artery, although an extended right colectomy with an anastomosis to the proximal descending colon is an alternative option
(Fig. 61-8). Tumors located further distally may need to be treated
with an extended le colectomy.
Based on the observation that transverse colon cancers represent a uniquely challenging subgroup where mesenteric dissection
and resection is more dicult, patients with transverse lesions were
excluded from the COST, COLOR, CLASICC, and Barcelona trials.
However, surgical instrumentation and techniques have improved
since the initiation of these trials, and thus it is appropriate to treat
these patients laparoscopically.
Surgical Treatment of Splenic Flexure and Descending Colon Cancer
A le colectomy is usually performed for lesions located in the distal transverse colon, splenic exure, or descending colon. is procedure involves removal of the distal half of the transverse colon
and the descending colon, with a transverse to sigmoid anastomosis. e le colon can be mobilized in either a medial-to-lateral or
a lateral-to-medial fashion. For the medial-to-lateral approach, the
small bowel mesentery is mobilized to the right upper quadrant to
expose the origin of the inferior mesenteric artery located just caudal
to the third portion of the duodenum. e limit of the vascular dissection depends on the exact location of the tumor. Tumors located
along the distal transverse colon may be treated with an extended le
colectomy that includes the middle colic arterial and venous trunks
and the le colic artery. Tumors located at the splenic exure may be
treated with resection of the le branch of the middle colic artery and
the associated venous tributary.
To perform the medial dissection, the inferior mesenteric vein
(IMV) is identied above the origin of the inferior mesenteric artery
(IMA), the peritoneum is incised behind the IMV, and the retroperitoneum is entered. Continuing the mobilization caudally will reveal
the IMA and its branches. e most proximal branch is the ascending
le colic artery, which can be isolated and divided at its origin from
the IMA. e medial to lateral dissection is completed by elevating
the descending and transverse mesocolon toward the abdominal wall
FIGURE 61-6 Gastrocolic trunk of Henle.
MCA
SMA
SMV
FIGURE 61-7 Exposure of the middle colic artery (MCA) at its origin
from the superior mesenteric artery (SMA) adjacent to the superior
mesenteric vein (SMV).
Stomach
Pancreas
FIGURE 61-8 Extent of resection for transverse colectomy.
COLON 305
AB
until the pancreatic tail is identied and the lesser sac is entered just
anterior to the pancreas (Fig. 61-9). Mesenteric dissection can be
continued in a counter-clockwise fashion from the IMV to divide the
transverse mesocolon and expose the middle colic artery and vein
at their origin and termination, respectively. Division of the IMV at
the inferior border of the pancreas facilitates entry into the lesser sac,
but the vein will need to be divided again at the le colic artery. An
alternative approach preserves the IMV and divides the proximal lesided tributary (usually from near the splenic exure).
Bowel mobilization may be performed by incising the lateral peritoneal refection from the sigmoid colon to the splenic exure. e le
colon mesentery is elevated from the retroperitoneum and the le
Stomach
(lesser sac)
Pancreas
FIGURE 61-9 Exposure of the lesser sac along the distal pancreas dur-
ing medial-to-lateral mobilization of the splenic flexure.
Descending mesocolon
ureter is visualized as the colon and its mesentery are brought to the
midline. Splenic exure mobilization is completed by elevating the
omentum away from the transverse colon along the avascular embryonic fusion plane or by dividing the gastrocolic omentum to resect the
omentum en bloc in the case of a transverse colon tumor. As the splenic
exure is approached, the splenocolic ligament is divided to fully release
the splenic exure. If the splenic exure is high, the transverse colon
should also be mobilized and the splenic exure approached from both
proximal and distal directions. Excessive traction on the splenic exure
or omentum should be avoided or an avulsion of the inferior tip of the
spleen may occur. e le branch of the middle colic artery, the le
colic artery, and the rst sigmoidal vessels, depending on the level of
the lesion, are ligated. e anastomosis should be performed between
the distal transverse and sigmoid colon.
Surgical Treatment of Sigmoid Colon Cancer
It was previously thought that a radical le hemicolectomy was
required for all sigmoid colon cancers. However, such an extended
resection is not necessary because an impact on oncologic outcomes has not been demonstrated. e extent of the resection thus
depends on the location of the tumor within the sigmoid colon
and the lymphovascular distribution of the tumor-bearing segment
(Fig. 61-10). Tumors located within the mid or distal sigmoid colon
may be treated by anterior resection with resection on the rectum
with at least a 5 cm bowel margin, sparing the descending colon,
whereas more proximally located tumors may require a formal
le colectomy. e splenic exure is mobilized when necessary to
decrease tension on the anastomosis, depending on the location of
the lesion and redundancy of the sigmoid colon.
e surgical approach may begin either medially or laterally. e
medial dissection of the IMA is initiated by incising the peritoneum
at the base of the sigmoid mesentery to open the avascular plane
FIGURE 61-10 Anterior resection for tumor of the sigmoid colon (A) and left colectomy for descending and proximal sigmoid colon cancer (B).
Surgical ManageMent of cancer of the colon306
behind the superior rectal artery and vein. e IMA is then identied, isolated, and ligated at its origin from the aorta or distal to the
le colic branch, depending on the extent of resection (Fig. 61-11),
with care being taken to rst identify and preserve the le ureter. e
inferior mesenteric vein is then mobilized and divided, usually at the
level of the IMA ligation. Bowel mobilization should be initiated by
mobilization of the descending and sigmoid colon from its embryonic attachments. e lymph nodes around the root of IMA may be
dissected to complete the excision. e anastomosis should then be
performed according to the surgeon’s preference.
LAPAROSCOPIC COLECTOMY
Laparoscopic colectomy for colon cancer has been widely performed in the United States since the COST trial was reported in
2004. e Barcelona trial, which was the rst randomized trial comparing open and laparoscopic approaches, reported that a laparoscopic approach showed faster recovery and a shorter hospital stay
and was associated with a modest trend toward a survival benet.
Later, the COLOR trial included 1248 patients with colon cancer
and showed a 2% improvement in the 3-year disease-free survival
rate for patients undergoing a laparoscopic approach. is dierence was not statistically signicant. In the CLASSICC study, no
statistically signicant dierences between laparoscopic and open
colectomy in the 3-year disease-free survival, overall survival, and
local recurrence rates were observed.
ese trials were designed as noninferiority studies, not to demonstrate improved oncologic outcomes from laparoscopy. However,
they did show many of the short-term benets of laparoscopy, such
as faster return of bowel function, shorter length of stay, and less
use of narcotics. ese benets did not translate into improved
quality of life. Aer a median 7-year follow-up, the COST trial
demonstrated similar 5-year recurrence and overall survival rates
aer open and laparoscopic-assisted colectomy. is study and
several subsequent meta-analyses have shown that laparoscopic
approaches for colon cancer are associated with long-term outcomes that are at least similar to that of open surgery. However, in
a subgroup analysis of the COLOR trial, it was observed that case
volume aected many of the parameters of the study. High-volume
centers (>20 cases/year) had more favorable short-term outcomes
such as shorter operative times, fewer conversions, and fewer complications than did medium-volume (10 to 20 cases/year) and lowvolume (<10 cases/year) centers.
A laparoscopic approach is better when performed by surgeons
with adequate experience. Under these circumstances, a laparoscopic colectomy for colon cancer is safe and has better short-term
and similar long-term oncologic outcomes compared with an open
colectomy (Table 61-1). An open approach is better for tumors with
adjacent organ invasion and in patients with severe abdominal
adhesions.
SPECIAL CONSIDERATIONS
Obstruction and Perforation
About 15% of patients with colon cancer present as an emergency
with intestinal obstruction, perforation at the site of tumor, or a
combination of both when perforation occurs in the distended
colon proximal to the obstructing cancer. Emergency resection
for a complicated cancer of the right colon means a primary ileo-
LCA
IMV
colic anastomosis in almost all cases because there is no concern
about size discrepancy in the bowel ends. An obstructed left
IMA
colon cancer is more tricky to anastomose because of the widely
dilated proximal colon and the normal or small-caliber distal
Aorta
bowel. Comparisons of left- and right-sided resections with primary anastomosis in the setting of obstruction have not shown
significant differences in leakage rates (left, 6.9% vs right, 5.2%) or
FIGURE 61-11 Vascular anatomy of the left colon demonstrating the
inferior mesenteric artery (IMA), the ascending left colic artery (LCA),
the inferior mesenteric vein (IMV), and the aorta.
mortality rates (left, 8.9% vs right, 7.3%). These are selected cases,
however, and diversion or resection with stoma and mucus fistula are safer options under certain circumstances. Intraoperative
TABLE 61-1: Results of Randomized Controlled Trials Comparing Laparoscopic with Open Colectomy for
Colon Cancer
Study Published Study Period No.
Barcelona 2005 1993-1998 Laparoscopic: 106
Open: 102
COST 2007 1994-2001 Laparoscopic: 435
Open: 428
Mean Follow-up
Duration, Mo
95 11
53 21
Postoperative
Morbidity, %
29
20
Overall Recurrence, %
18
28
19.4
21.8
Disease-Free
Survival, %
—
—
69.2
68.4
Overall
Survival, %
64
57
76.4
74.6
COLOR 2005 1997-2003 Laparoscopic: 534
Open: 542
CLASICC 2007 1996-2002 Laparoscopic: 230
Open: 118
ALCCaS 2012 1998-2005 Laparoscopic: 290
Open: 297
84 21
20
62.9 35
35
62 37.8
45.3
19.6
16.9
23.8
22.2
13.7
14.8
76.2
74.2
57.6
64.0
72.3
71.7
84.2
81.8
55.7
62.7
77.7
76.0
COLON 307
colonic lavage has been advocated as an adjunct to resection in
treating the obstructed colon. A number of cohort studies have
demonstrated the safety and efficacy of this approach for avoiding a colostomy without increasing leakage rates (<5%) or sepsis. More recently, colonic stenting has been used and can serve
as a bridge to elective surgery, converting an emergency procedure into an elective one in patients with operable cancers.
Stenting has been used largely for left-sided lesions. The clinical success rate of stenting has been reported to be greater than
90%, and nonrandomized trials have advocated for use of stenting as a bridge to surgery to help reduce operative mortality,
postanastomotic leakage rates, wound infection rates, and
in-hospital length of stay. However, the Dutch Stent-in randomized trial of colonic stenting as a bridge to elective surgery or emergency surgery for patients with acute obstructive
left-sided colorectal cancers was closed prematurely when stentrelated complications crossed the safety threshold for early study
termination. No difference was recorded between treatment
groups in 30-day mortality, overall mortality, morbidity, and
stoma rates at latest follow-up.
Prophylactic Oophorectomy
e risk of micrometastatic implants in the ovary increases with
tumor stage and may approach 10%. Debate regarding the relative risks and benets of prophylactic bilateral oophorectomy in
women with colon cancer is ongoing. A comparison of cohorts of
women with and without prophylactic oophorectomy did not demonstrate a survival advantage. Prophylactic oophorectomy has not
been shown to improve survival but may be considered in postmenopausal women at high risk for the development of ovarian
metastases.
ASSESSMENT OF QUALITY OF
COLECTOMY
Recently, increased attention has been directed to the quality of colectomy for cancer. Currently, the quality standard of a minimum of
12 lymph nodes in the specimen remains the only nationally recognized measure for colon cancer surgery in the United States and is
endorsed by the National Quality Forum. In a systematic review of
17 studies from 9 countries with 61,371 patients, 16 studies showed
a positive association between the number of lymph nodes evaluated and survival among patients with stages II and III disease. An
analysis of patients from the Intergroup Trial INT-0089 showed that
the number of examined lymph nodes had a positive association
with survival in both node-negative and node-positive disease. e
reason for this association is likely multifactorial. A more complete
assessment of lymph nodes facilitates more accurate staging, but
this eect does not completely explain the ndings of improved
survival. Alternatively, it has been suggested that lymph nodes in
patients with a strong anticancer immune response are easier to
locate and that such patients have an improved prognosis. Although
the number of assessed lymph nodes can be inuenced by the individual completeness and quality of surgery and of the pathologic
evaluation, its role as a hospital-based quality measure continues
to be debated.
e principles of complete lymph node clearance have been promoted by the Japanese Society for Cancer of the Colon and Rectum and more recently elaborated by Western proponents of central
vascular ligation (total mesocolic resection). Both techniques
include extended lymph node resection to include the root nodes
(e.g., superior mesenteric artery lymph nodes for right colon cancer). A number of technical challenges exist for routine extended
lymph node dissection, and the potential exists for increased morbidity. Moreover, the reported rates of tumor involvement of the
root nodes are low (approximately 3% to 7%). However, given the
advances in modern chemotherapy and the potential for improved
survival with complete resection of regional and distant metastatic
disease, extended resection should be considered for patients with
clinically evident disease in the absence of unresectable distant
metastasis.
Finally, there has been increased recent emphasis on the completeness of resection of the bowel and associated mesocolon
as determined by pathologic assessment of the resection specimen (total mesocolic excision). A retrospective observational
study found significant variability in the integrity of the primary
resection specimen among patients with colon cancer. Surgery
performed in the mesocolic plane compared with the intramesocolic or the muscularis propria plane has been associated with
improved survival. Pre- and postimplementation evaluation of
a training program for colon cancer surgery has been shown to
improve the pathologically assessed quality of the resection specimen, highlighting both the high degree of variability in surgical
quality that currently exists and the potential to improve outcomes for patients with colon cancer patients through standardization, audit, and feedback.
is interest in the quality of colon cancer surgery emphasizes the
need for both standardization of surgical technique and emphasis on
the oncologic principles for colon cancer surgery.
POSTOPERATIVE SURVEILLANCE
A major goal of follow-up and surveillance is the detection of
treatable recurrence and the identification of metachronous
tumors while they are in a preinvasive stage. Although an advantage for intensive follow-up of patients with all stages of colon
cancer has been suggested, a recent randomized trial comparing intensive follow-up with routine imaging or routine carcinoembryonic antigen testing with or without imaging to minimal
follow-up showed no significantly measurable difference in survival between the study arms. However, patients undergoing routine surveillance by any modality were more likely to have their
recurrence resected with curative intent when compared with the
patients in the minimum follow-up arm. Thus controversy still
exists regarding the optimal surveillance strategies for patients
after curative surgery. Currently, a number of consensus guidelines regarding recommended surveillance exist internationally through a variety of leading organizations (Table 61-2).
However, there is little agreement regarding the optimal followup strategies. Based on the existing evidence, it can be argued
that at minimum, at least one surveillance CT scan should be
performed along with office visits and CEA level determination for patients with a history of a preoperatively elevated
CEA. In addition, follow-up colonoscopy can help identify metachronous neoplasia. However, surveillance recommendations will
continue to evolve as new evidence regarding the optimal strategies emerge. Finally, a good reason for regular follow-up is for the
individual surgeon to be aware of the outcomes of surgery as a
quality audit.
SUMMARY
e primary treatment of localized colon cancer is surgery. e
principles of treatment include a thorough preoperative evaluation,
including tumor staging. e extent of resection is determined by the
tumor location and its associated blood supply and is not aected by
the use of a minimally invasive approach. With appropriate surgery,
locoregional recurrence is rare. Although the most important determinant of long-term outcomes is stage of disease at presentation and
appropriate use of adjuvant chemotherapy, the quality of surgery is
also important.
Surgical ManageMent of cancer of the colon308
TABLE 61-2: Surveillance Recommendations after Curative Treatment of Colorectal Cancer
Abdominal Imaging
Organization Clinic Visits (Mo) Serum CEA (Mo)
ASCO* Year 1-3: every 3-6
Year 1-3: every 3 CT abdomen (pelvis)
Year 4-5: every 6
(Mo) Chest Imaging Colonoscopy
CT chest annually At year 3, then every
annually
5 yr
CCO Stage I
Ye a rl y
Stage II-III
Year 1-3: every 6
Year 4-8: every 12
ESMO Year 1-3: every 3-6
Year 4-5: every 6-12
NCCN Year 1-2: every 3-6
Year 3-5: every 6
Year 1-3: every 6
Year 4-8: every 12
Year 1-3: every 3-6
Year 4-5: every 6-12
Year 1-2: every 3-6
Year 3-5: every
Liver US or CT
Year 1-3: every 6
Year 4-8: every 12
Years 1-3: CT/US
every 6-12
Years 1-5:
CT annually
Chest radiograph at
each visit
Years 1-3: CT every
6-12
Years 1-5:
CT annually
Within 6 mo, then
every 3-6 yr
At year 1, then every
3-5 yr
At year 1, then every
3-5 yr
NHS* Year 1-3: every 6 Year 1-3: every 6 CT 2× within 3 yr CT 2× within 3 yr At year 1, then every
5 yrs
*Stage II-III
ASCO, American Society of Clinical Oncology; CCO, Cancer Care Ontario; CEA, carcinoembryonic antigen; CT, computed tomography; ESMO, European
Society of Medical Oncology; NCCN, National Comprehensive Cancer Network; NHS, National Health Service; US, ultrasound.
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-
M
M C
INTRODUCTION
Colorectal cancer is currently the third most common cancer in the
United States, and in 2015 it is estimated that 140,000 persons will
be diagnosed with this disease. More than 50,000 patients die from
colorectal cancer each year, making it second only to lung cancer
as a cause of cancer-related death. Risk factors for colorectal cancer
include inammatory bowel disease, tobacco, consumption of red
and processed meats, alcohol, diabetes, inactivity, and obesity. Inherited genetic syndromes account for fewer than 10% of new cases.
Colorectal cancer can spread by lymphatics or blood vessels, or by
transperitoneal or direct spread. e most common site of hematogenous dissemination is the liver, followed by the lungs and bone. Rectal cancer can initially metastasize to the lungs as a result of inferior
rectal vein drainage into the inferior vena cava. Approximately 20%
of patients with colorectal cancer are found to have metastatic disease
at the time of presentation. Most of these patients cannot be cured.
In the past three decades we have seen great progress in treatment
options for metastatic disease. In the 1990s, 5-uorouracil (5-FU) was
the only agent approved for this indication, and median survival was
less than 1 year. Now, with nearly 10 agents approved, median survival in the most recent randomized trials is approaching 30 months.
is progress is a result of new cytotoxic agents and biomarker-based
therapies targeting specic molecules, including vascular endothelial
growth factor (VEGF) and epidermal growth factor receptor (EGFR).
One major advance in the treatment of metastatic colorectal cancer
involves a greater understanding of sequential systemic and local therapies, including resection in patients with oligometastatic disease. For
such patients, some estimates suggest that 20% to 25% can be oered
potentially curative treatment with the combination of surgical resection and chemotherapy. Furthermore, improvements in response rates
with chemotherapy have allowed patients who present with unresectable disease to be downstaged, and some patients eventually may be
oered curative resection. However, the timing and sequence of treatment remains an art, and data from large clinical trials are lacking. In
this chapter we will review the management of patients with metastatic
disease, focusing on systemic chemotherapy and potentially curative
approaches incorporating liver-directed therapy.
CHEMOTHERAPY
e standard rst-line approach for patients with metastatic colorectal cancer is systemic chemotherapy, which is given with the intent to
palliate symptoms and prolong life. Initial treatment is composed of
several standard cytotoxic drugs given as the chemotherapy “backbone” that are oen combined with more recently approved targeted
agents. ese conventional agents are 5-FU, capecitabine, oxaliplatin,
and irinotecan, as depicted in Table 62-1.
C
Marcus S. Noel and Alok A. Khorana
5-Fu
5-FU has remained an integral part of the treatment in colorectal cancer aer its rst approval more than 50 years ago. 5-FU is a
prodrug that requires multiple enzymatic steps prior to its conversion into the active phosphorylated form. e key metabolite is
5- uorodeoxyuridylate monophosphate (F-dUMP), which is a competitive inhibitor of thymidylate synthase (TS). TS is an obligatory
step in the synthesis of thymidine, and its inhibition has a potent
eect on DNA synthesis. 5,10-Methylene tetrahydrofolate (leucovorin; LV) accentuates the inhibition of TS therapy by stabilizing the
ternary complex, thus enhancing the activity of 5-FU. 5-FU is administered in several ways, including bolus and continuous infusion.
Capecitabine
Capecitabine is a uoropyrimidine carbamate, a prodrug of 5-FU
designed to be dihydropyrimidine dehydrogenase (DPD) resistant. Once
absorbed into the gastrointestinal tract, it undergoes a three-step activation process into 5-FU. Capecitabine was rst compared with bolus
5-FU/LV in a randomized trial of patients with metastatic disease. It was
found to have a superior response rate and was equivalent with respect to
progression-free survival (PFS) and overall survival (OS). Capecitabine
was also studied in a European trial and found to be equivalent to 5-FU.
e current standard of care for rst-line treatment in metastatic
colon cancer involves administration of either 5-FU and LV in combination with oxaliplatin (FOLFOX) or 5-FU and LV in combination
with irinotecan (FOLFIRI) (Fig. 62-1). Several versions of FOLFOX
exist, distinguished by the dosing schedule of individual drugs. Alternatively, capecitabine can be substituted for 5-FU and LV and combined with either oxaliplatin or irinotecan.
Irinotecan
Irinotecan, a semisynthetic derivative of the plant alkaloid camptothecin, works by inhibiting topoisomerase I, which is necessary for DNA
self-replication and RNA transcription. Inhibition of topoisomerase
I results in DNA strand breaks and cytotoxicity. Initial clinical trials
with irinotecan were notable for response rates of up to 25% and clinical benet in patients previously treated with uoropyrimidines. Two
randomized clinical trials led to U.S. Food and Drug Administration
approval of irinotecan in 1996. In one trial, nearly 300 patients were
randomized to irinotecan versus best supportive care, and the treatment group was found to have an increase in 1-year survival (36% vs.
14%, P = .0001). In the second trial, 267 refractory patients were randomized to either irinotecan or infusional 5-FU; survival in the irinotecan group was increased at 1 year from 32% to 45% (P = .035).
309
ManageMent of Metastatic colorectal cancer310
TABLE 62-1: Conventional Chemotherapy Agents
Category Mechanism Adverse Effects
Fluoropyrimidines (5-uorouracil/capecit-
abine)
A pyrimidine analog antimetabolite that interferes
with DNA and RNA synthesis
Mucositis
Diarrhea
Hand-foot syndrome
Irinotecan Converted by carboxylesterase to its active metabolite
(SN38), which binds reversibly to topoisomerase
1-DNA complex, preventing regulation of the
cleaved DNA strand
Oxaliplatin An alkylating agent that binds DNA, forming cross-
links that inhibit DNA replication and transcription
Metastatic colorectal cancer
Neoadjuvant or conversion
Potentially
resectable
No
“Extended” WT RAS “Extended” mutant RAS
FOLFOX/CAPOX
+ anti-EFGR antibody
or bevacizumab
Consider maintenance therapy (5-FU ± bevacizumab)
in responders/stable disease
Yes
+ anti-EFGR antibody
or bevacizumab
Multidisciplinary
evaluation
FOLFIRI
therapy for resectable
patients followed by
resection and consideration
for additional therapy
FOLFOX/CAPOX or FOLFIRI
Consider maintenance therapy (5-FU ± bevacizumab)
in responders/stable disease
Diarrhea
Alopecia
Neurotoxicity
+ bevacizumab
FOLFIRI/irinotecan
+ aflibercept or
bevacizumab
OR anti-EGFR (if naïve)
Anti-EGFR ± irinotecan (if anti-EFGR naïve)
FIGURE 62-1 Proposed algorithm for selection of systemic treatment and integration with surgical resection in patients with metastatic colorectal
FOLFIRI/CAPOX
+ bevacizumab or
aflibercept
OR anti-EGFR
(if naïve)
Regorafenib
FOLFIRI/irinotecan
+
aflibercept or
bevacizumab
FOLFOX
+ aflibercept or
bevacizumab
carcinoma, based on available clinical and molecular data. EGFR, Epidermal growth factor receptor; 5-FU, 5-fluorouracil; CAPOX, capecitabine and
oxaliplatin; FOLFIRI, irinotecan, 5-fluorouracil, and leucovorin; FOLFOX, oxaliplatin, 5-fluorouracil, and leucovorin; WT, wild type. (From Mi K, Kalady MF,
Quintini C, Khorana AA. Integrating systemic and surgical approaches to treating metastatic colorectal cancer. Surg Oncol Clin North Am. 2015;24:199-214.
Reprinted with permission.)
Once irinotecan was established as an active agent in colorectal
cancer, the next step was to combine it with 5-FU with the hope of
increasing response rates and survival. Aer successful completion
of phase 1 trials, two large randomized studies were conducted in
rst-line metastatic disease. e rst study randomized 387 patients
to irinotecan plus 5-FU versus 5-FU alone. Response rates increased
from 31% to 49% (P <.001), PFS increased from 4.4 to 6.7 months
(P <.001), and OS increased from 14.1 to 17.4 months (P = .031).
e second trial, based in North America, randomized 683 patients
to one of three groups: irinotecan combined with 5-FU and LV,
5-FU and LV alone, or irinotecan alone. e combination regimen
was superior to both 5-FU and LV and single-agent irinotecan with
regard to the response rate (50% vs. 28% vs. 29%, P <.001), PFS (7.0
vs. 4.3 vs. 4.2 months, P = .004), and OS (14.8 vs. 12.6 vs. 12 months,
P = .04). Although manageable, the combination regimen is notable
for toxicity, including diarrhea and neutropenia.