The

Oncologist ®

Gastrointestinal Cancer
Resection of the Primary Colorectal Cancer Is Not Necessary in
Nonobstructed Patients with Metastatic Disease

NEVENA DAMJANOV, JARED WEISS, DANIEL G. HALLER

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University of Pennsylvania, Abramson Cancer Center, Philadelphia, Pennsylvania, USA

Key Words. Colorectal neoplasms • Chemotherapy • Colectomy • Review literature

Disclosures: Nevena Damjanov: Honoraria: Amgen, Sanofi-Aventis, Genentech, Bristol-Myers Squibb; Jared Weiss: None;
Daniel G. Haller: None.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from
commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer
reviewers.

ABSTRACT
Asymptomatic patients with metastatic colorectal cancer
do not routinely need to undergo resection of the primary
tumor. Although several retrospective analyses suggest
that patients who undergo resection of the primary tumor
live longer, most of these reviewed data prior to the advent
of modern polychemotherapy and are subject to consider-
able bias, as patients who were considered able to undergo
surgery likely had better overall prognoses than those who
were not. In addition to significant prolongation of overall
survival, current combinations of systemic chemothera-
peutic agents and targeted agents have allowed improved
local and distant tumor control, decreasing the likelihood
of local tumor-related complications requiring colon re-
section. The Oncologist 2009;14:963–969

INTRODUCTION: METASTATIC
COLORECTAL CANCER
In 2009, there will be approximately 150,000 new diag-
noses of colorectal cancer (CRC) in the United States. In
that same time period, approximately 49,960 will die from
cancer of the colon and rectum. Between 20% and 25% of
patients diagnosed with CRC will present with metastases
at the time of initial diagnosis [1]. Therefore, appropriate
management of patients who present with metastatic dis-
ease from a synchronous colorectal cancer is a significant
oncologic issue.
Modern polychemotherapy combined with targeted
agents has improved median survival from less than 1 year
with single-agent fluoropyrimidines to almost 2 years [2].
Nonetheless, less than 10% of patients diagnosed with met-
astatic CRC (mCRC) are alive at 5 years, with most patients
dying from their cancer [1]. Consequently, in patients with
a limited life expectancy, in addition to improving survival,
the potential morbidity of treatment and the treatment’s im-
pact on patient quality of life must be considered.
In patients with symptomatic primary CRC, the goals of
resection of the primary lesion are to decrease cancer-
related morbidity related typically to bleeding, obstruction,
or perforation. In addition, in selected patients, resection of

Correspondence: Nevena Damjanov, M.D., University of Pennsylvania, Abramson Cancer Center at Penn Presbyterian Medical Center, 51
North 39th Street, Philadelphia, PA 19104, USA. Telephone: 215-662-9801; Fax: 215-243-3249; e-mail: nevena.damjanov@uphs.upenn.edu
Received February 9, 2009; accepted for publication September 10, 2009; first published online in The Oncologist Express on
October 9, 2009; available online without subscription through the open access option. ©AlphaMed Press 1083-7159/2009/
$30.00/0 doi: 10.1634/theoncologist.2009-0022

The Oncologist 2009;14:963–969 www.TheOncologist.com

964
all sites of metastatic disease can offer improvement in
long-term survival. Surgical resection rapidly palliates
symptomatic primary colon lesions. However, resection of
the colon in mCRC patients is associated with a 1%– 6%
perioperative mortality [3– 6] and postoperative morbidity
of 20%–30% [3, 6, 7]. In patients who have resectable stage
I, II, or III cancer, any perioperative mortality and morbid-
ity is balanced by the potential for cure, but in patients with
incurable cancer, the benefit, if it exists, is much more mod-
est. In particular, two groups of patients can be identified
who benefit most from a nonsurgical initial approach. First
are those patients with bulky, aggressive metastatic disease
who require immediate relief of symptoms by systemic
therapy. Second is the patient with limited liver metastases,
for whom neoadjuvant therapy followed by hepatic resec-
tion is often favored over concurrent colectomy and hepatic
metastasectomy.
RETROSPECTIVE ANALYSES
No prospective randomized clinical trials exist to guide
treatment in patients with asymptomatic primary colorectal
lesions and diffuse metastatic disease at presentation. Sev-
eral retrospective analyses report a benefit from primary
cancer resection; these are summarized in Table 1. Al-
though each of these studies reports a numerically higher
survival for patients who underwent resection compared
with patients who did not, the analyses are subject to sub-
stantial selection bias. Patients were not randomly assigned
to treatment groups; rather, they were treated based on the
standard practice of their physician. The choice to perform
surgery on a given patient reflected a lower burden of dis-
ease, higher performance status, and younger age. This se-
lection bias is reflected in, but not completely elucidated by,
reported differences in population characteristics, partly
summarized in the fifth column of Table 1. As a conse-
quence of these differences, patients selected for surgery
likely had a better prognosis and their survival advantage
may be unrelated to surgery.
Retrospective studies concluding against resecting
the asymptomatic primary tumor suffer from these same
confounding factors. Indeed, two of the studies [10, 11]
must be credited for not only recognizing and discussing
these biases, but going so far as to conclude that their
data did not support resection despite numerically higher
survival in the resected group. These studies are summa-
rized in Table 2.
RESPONSE OF PRIMARY TUMOR
TO CHEMOTHERAPY
Patients given chemotherapy in the preceding retrospective
trials mostly received regimens of single-agent fluoropyri-
Nonobstructed mCRC: Primary Resection Unnecessary
midine therapy. Modern chemotherapy regimens incorpo-
rating the novel cytotoxic agents oxaliplatin and irinotecan
as well as the biologic agents bevacizumab and cetuximab
have improved both response rates and survival. The nega-
tive consequence of delaying chemotherapy to allow for
surgery may therefore be increased in an era of better che-
motherapy. Furthermore, if chemotherapy is able to better
shrink the primary lesion, the risk/benefit ratio of surgical
morbidity to palliative benefit may lean further toward risk
than before. Table 3 summarizes the outcome results of sev-
eral of the key trials that define the standard of care for mod-
ern chemotherapy. A discussion of the details of these
studies is beyond the scope of this review; rather, the table
aims to demonstrate the high efficacy of state-of-the-art
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chemotherapy.
The efficacy of neoadjuvant chemotherapy suggests
that the high response rates reported in chemotherapy tri-
als are not limited to metastatic sites. For example, in
2006, Chau et al. published a report of a phase II study
evaluating the effect of neoadjuvant chemotherapy on 77
patients with poor-risk rectal cancer [17]. Neoadjuvant
chemotherapy was followed by chemoradiotherapy, total
mesorectal excision, and adjuvant chemotherapy. En-
rolled patients received 12 weeks of capecitabine and ox-
aliplatin prior to capecitabine with radiation. During the
neoadjuvant chemotherapy, patients were assessed for
evidence of rectal bleeding, pelvic pain, tenesmus, diar-
rhea, and constipation. The objective response rate after
12 weeks of neoadjuvant capecitabine and oxaliplatin
was 88%, and 86% of the patients with symptoms had
symptomatic improvement. Specifically, pelvic pain/
tenesmus was decreased in 71% of patients, 90% had im-
provement in diarrhea/constipation, 100% had reduced
rectal bleeding, and 93% had weight stabilization or
weight gain. The median time to symptom resolution was
32 days. These results were compared with the 28% re-
sponse rate in the previously reported study of neoadjuvant
protracted infusion 5-fluorouracil and mitomycin-C, also in
patients with rectal cancer [18].
PALLIATION OF INTESTINAL COMPLICATIONS BY
NONSURGICAL METHODS
Endoscopic techniques may be very effective in managing
intestinal hemorrhage or malignant obstruction. Endolumi-
nal stents inserted by surgeons, gastroenterologists, or in-
terventional radiologists are able to restore patency in many
patients with malignant bowel obstruction. In a report by
Camúñez et al., more than 90% of stents remained patent
for 6 months or more following placement [19]. Clinically
significant bleeding is present in only 10% of patients with
mCRC [2] and endoscopic laser therapy, cryotherapy, radi-
Damjanov, Weiss, Haller
Table 1. Retrospective studies of patients with metastatic colorectal cancer supporting the benefit of resection of the
primary tumor
Study
Ruo et al. (2003) [4]
Cook et al. (2005) [8]
Konyalian et al. (2007) [9]
Galizia et al. (2008) [6]
Abbreviations: 5-FU, 5-fluorouracil; LDH, lactate dehydrogenase; Med, median; Met, metastases; mo, months; NR, not
resected; R, resected.
www.TheOncologist.com
965
Perioperative Key differences in
n (Initial morbidity (surgery Survival, population
resection/no group)/Later surgery resected vs. characteristics,
initial needed (no surgery not resected vs. not
resection) group) resected resected Key concerns
209 20.5% 16 mo ● Site in right colon ● Imbalances in patient
103 29% 9 mo -46% R characteristics.
-28% NR ● Patients with liver-only disease
● Single site included in analysis; some of the
metastatic disease patients in the surgical arm may
-68% R have been cured via
-53% NR metastasectomy. Importance of this
● Met to liver only imbalance confirmed in analysis of
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-56% R prognostic factors showing extent
-41% NR of liver disease as only significant
● Comorbidity prognostic variable.
-32% R ● Chemotherapy used in the NR
-20% NR group was predominantly 5-FU
● LDH above normal without oxaliplatin, irinotecan, or
-52% R biologic agents.
-64% NR
17,657 Not reported 11 mo ● Med age ● Imbalances in patient
9,097 2 mo -67.1 R characteristics.
-70.3 NR ● No data available on performance
● Site primary R status.
-R colon 75.3% ● No data available on comorbidity.
-L colon 73.0% ● Patients operated upon with
-Rectum 45.6% metastatic disease discovered at
surgery included in surgery group.
● No data available on need for
surgery for symptom control.
62 14% R 20% NR (17/47 375 days ● Use of ● 64% of patients in NR group
47 NR patients had 138 days chemotherapy presented with symptoms of
nonresective surgery) -58% R uncontrolled bleeding, obstruction,
0% but 4.3% later -42% NR or perforation. 23 of 47 required a
required stent procedure that included
nonresective surgery in 17.
● No data on performance status.
● Data on many important
comorbidities not presented.
42 43% 26 mo ● Rate of complete ● 4/42 patients in R group were
23 30% 17 mo hepatic resection brought to surgery with curative
-11.9% R intent and found to have metastases
-4.3% NR at surgery; they likely had a lower
burden of disease.
● Complete hepatic metastasectomy
can be curative. More patients
received complete hepatic resection
in the resection group, perhaps
secondary to the last bullet point.
● Low response rate to chemotherapy
likely reflects use of older
regimens; better results can be
expected with modern regimens.
966 Nonobstructed mCRC: Primary Resection Unnecessary

Table 2. Retrospective studies of patients with metastatic colorectal cancer refuting the benefit of resection of the primary
tumor
n (Initial Perioperative
surgery/ Survival, morbidity (surgery
Not Key differences in resected vs. group)/Later
initially population not surgery needed (no
Study resected) characteristics resected surgery group) Key concerns
Scoggins et al. 66 ● Rectal site of primary 14.5 mo 30.3% ● 10 patients in NR group
(1999) [3] 23 -21.2% R 16.6 mo 4.6% received radiation or
-47.8% NR chemoradiation. The
● Use of radiation or NR group contained 11
chemoradiation patients with rectal
-0% R cancer; radiation is
-43.5% NR particularly effective for
local control of this site.
Tebbutt et al. 280 ● Gender 14.0 mo ● 13.2% obstruction ● Unresected group

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(2003) [10] 82 -40% female R ● 5% total needed included patients whose
-27% female NR repeat surgery primary tumors were
● Performance status ⱖ2 8.2 mo ● 13.4% obstruction symptomatic.
-20% R ● 9.8% total needed ● Surgical group included
-38% NR surgery patients who were not
● Rectal site of primary known to harbor
-33% R metastatic disease until
-46% NR the time of surgery.
● Mean alkaline ● Multiple imbalances in
phosphatase known prognostic
-179 U/l R factors.
-329 U/l NR
● Mean albumin
-38.7 g/l R
-34.5 g/l NR
● Mean CEA
-809 ␮g/l R
-3139 ␮g/l NR
Stelzner et al. 128 Demographic details of 11.4 mo 11.7% surgical ● Surgery performed
(2005) [11] 58 R vs. NR groups not 4.6 mo mortality R whenever possible.
presented. Reasons for inclusion in
NR group included
advanced tumor spread,
multiple concomitant
disease, and patient
choice.
● 42/58 patients in NR
group were operated
without resection for
intestinal diversion,
formation of a
colostomy, or
diagnostic laparotomy.
Abbreviations: CEA, carcinoembryonic antigen; mo, months; NR, not resected; R, resected.

ation therapy, and photodynamic therapy may be effective
in controlling bleeding symptoms [20, 21]. Radiation therapy
is also useful in palliating perineal pain from local invasion
seen in some patients with locally advanced rectal cancer.
In the event that nonsurgical methods are unsuccessful,
operative interventions, including colonic diversion, lapa-
roscopic or open colectomy, or abdominoperineal resec-
tion, may be performed. In the recently published Memorial
Sloan-Kettering Cancer Center (MSKCC) study, 16 pa-
tients underwent emergent surgery following the initiation
of chemotherapy [22]. Of those, two (12.5%, or 0.8% of the
total study population) died in the 30 days following surgery.
Median survival of patients who underwent emergent surgery
was 6 months, compared with 13 months for the 152 patients
who did not require any intervention for their primary cancer.
PROSPECTIVE TRIALS EVALUATING THE VALUE OF
PRIMARY RESECTION
Unfortunately, no randomized controlled trials have been
reported to provide level I evidence to answer this question.
Damjanov, Weiss, Haller
Table 3. Modern chemotherapy regimens for colorectal cancer
Study
N016966: FOLFOX or XELOX ⫹ bevacizumab [12]
FOLFOX-4 ⫹ cetuximab [13]
CRYSTAL: FOLFIRI ⫹ cetuximab [14]
BRiTE tumor registry, bevacizumab past progression group [15]
GONO: FOLFOXIRI [16]
Abbreviations: FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin;
FOLFOXIRI, leucovorin, 5-fluorouracil, oxaliplatin, and irinotecan; GONO: Gruppo Oncologico Nord Ovest; N/A, not
available; OS, overall survival; RR, relative risk; XELOX, capecitabine and oxaliplatin.
However, one trial is ongoing. National Surgical Adjuvant
Breast and Bowel Project (NSABP) C-10, a phase II trial of
5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6)
chemotherapy plus bevacizumab for patients with unresect-
able stage IV colon cancer and a synchronous asymptomatic
primary tumor, has been designed to prospectively accrue 90
patients with unresected primary colon tumors and radio-
graphically confirmed, surgically unresectable metastases.
The primary aim of the study is to determine the rate of ma-
jor morbidity for patients who are treated with mFOLFOX6
with bevacizumab, without resection of the primary tumor.
Major morbidity will be defined as any event related to the
intact primary tumor necessitating surgery or resulting in
patient death. Additional aims of this study are to evaluate
local complications and determine the rate of specific
events related to the intact primary tumor requiring hospi-
talization or a major intervention, but not requiring surgery.
In addition to overall survival, the study will monitor the
rate of grade 3/4 toxicities related to study therapy prior to
disease progression. The trial is powered to determine out-
comes relative to the primary tumor, with an incidence of
events less than 25% considered a therapeutic success. In
addition, documentation will be made of how many patients
with initially unresectable metastases develop resectable
disease. Accrual is ongoing [23].
DISCUSSION
Prospective randomized clinical trials support the use of
systemic polychemotherapy in patients with diffuse metas-
tases from mCRC. Patients who are fit enough to receive
modern chemotherapeutic regimens that combine standard
antineoplastic agents with targeted therapy have a median
survival close to 2 years [2]. Response rates in the first-line
setting with modern combination chemotherapy range from
more than 20% with 5-fluorouracil and leucovorin, to more
than 50% with FOLFOX and 5-fluorouracil, leucovorin,
and irinotecan (FOLFIRI) [24, 25]. The addition of bevaci-
zumab improves response rates of combination chemother-
www.TheOncologist.com
967
n RR OS
899 38% 21.3
337 46% (61% in kRAS wild type) N/A
1198 47% (59% in kRAS wild type) 24.9
642 48% 31.8
122 60% 22.6
apeutic regimens in most phase III trials [26 –28], as does
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the addition of cetuximab [13, 14, 29, 30]. In patients who
receive a combination of chemotherapy and biologic ther-
apy, there is an increased risk of grade 3 or 4 toxicities. For
example, in the retrospective BRiTE registry, patients with
an intact primary tumor had a slightly increased risk (3.4%)
of gastrointestinal perforations [31]. However, as in other
bevacizumab trials, both perforations as well as sites of
bleeding could occur at sites away from the original tumor.
Therefore, resecting the primary tumor would not eliminate
the risk of perforation or bleeding. Targeting the metastases
as well as the primary tumor with systemic therapy is likely
to offer the greatest benefit to a patient with unresectable
cancer.
Bevacizumab is commonly added to primary chemo-
therapy for metastatic CRC. All of the available studies
with bevacizumab precluded entry by patients who had an
identified bleed within the preceding 6 months. Therefore,
prospective data for the use of bevacizumab in patients with
a bleeding primary CRC are not available. However, in the
MSKCC study [22], bevacizumab was incorporated into
the first-line therapy for 112 (48%) patients. No episodes of
intractable bleeding that required surgery were docu-
mented. Therefore, in the setting of unresected primary
CRC, barring uncontrolled bleeding, the potential benefit of
bevacizumab-based polychemotherapy outweighs the
small risk of bleeding or perforation.
There is no evidence that response rates of the primary
tumor are inferior to that of the metastases; on the contrary,
the data from Chau et al. in a prospective trial demonstrate
that primaries may be even more responsive than metastatic
disease [17]. In asymptomatic patients, potential complica-
tions from an intact primary tumor range from 10% to 20%
for intestinal obstruction, 4% for gastrointestinal hemor-
rhage, and 4% for fistula formation [3, 4, 10, 32]. In the
study by Tebbutt et al., the risk of colonic obstruction was
13%, whether the tumor was resected or not, because pa-
tients who underwent surgery may develop adhesions that
968
cause bowel obstruction or obstruction due to peritoneal re-
currences [10]. Resection of an asymptomatic primary tu-
mor risks surgical complications and may postpone the
administration of chemotherapy that may offer systemic (as
opposed to just local) control. Most of the published retro-
spective studies reflect systemic treatment prior to the
availability of oxaliplatin, irinotecan, bevacizumab, panitu-
mumab, or cetuximab. In addition, these retrospective stud-
ies do not address case selection bias, availability or
administration of active chemotherapeutic agents, the per-
formance status, or a prospective evaluation of the initial
burden of metastatic disease. Most patients will succumb to
metastatic disease before developing symptoms from their
unresected primary colorectal lesion [3]. In patients with a
limited life expectancy, the morbidity and mortality of un-
necessary surgery or surgery that does not improve quality
of life or survival should be carefully evaluated, preferably
in prospective, multicenter clinical trials. With the avail-
ability of effective combination chemotherapy and biologic
agents, systemic therapy for the treatment of life-threaten-
ing metastases should be paramount.
CURRENT RECOMMENDATIONS
(a) Patients with evidence of perforation, significant ob-
struction, or uncontrolled bleeding should undergo resec-
tion of the symptomatic lesion.
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AUTHOR CONTRIBUTIONS
Collection/assembly of data: Nevena Damjanov, Jared Weiss, Daniel G.
Haller
Data analysis and interpretation: Nevena Damjanov, Jared Weiss, Daniel G.
Haller
Manuscript writing: Nevena Damjanov, Jared Weiss, Daniel G. Haller
Final approval of manuscript: Nevena Damjanov, Jared Weiss, Daniel G.
Haller
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