Documentos de Académico
Documentos de Profesional
Documentos de Cultura
* Corresponding author.
E-mail address: todd.d.shuster@lahey.org (T.D. Shuster).
0039-6109/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.suc.2006.06.002 surgical.theclinics.com
1024 NATARAJAN & SHUSTER
Newer agents
Because first-generation 5-FU/LV regimens result in only a modest re-
sponse rate and improvement in survival, attempts to improve these out-
comes has led to incorporation of novel chemotherapeutic agents as well
as biologic agents in combination with 5-FU. These agents include the che-
motherapy drugs irinotecan, capecitabine, and oxaliplatin. The biologic tar-
geted therapies include bevacizumab, a humanized vascular endothelial
growth factor (VEGF) antibody, and cetuximab, a monoclonal antibody
that binds to the epidermal growth factor receptor (EGFR).
Irinotecan (Camptosar) is a camptothecin that gets hydrolyzed to its ac-
tive metabolite SN-38, and exerts its cytotoxic effects through interaction
with topoisomerase-1 [10]. Its primary toxic effects include diarrhea, bone
marrow suppression, nausea, vomiting, and alopecia. Randomized single-
agent irinotecan studies in patients who were refractory to 5-FU showed
a 2- to 3-month improvement in median overall survival (OS) as compared
with best supportive care or infusional 5-FU [11,12]. Subsequently, irinote-
can in combination with 5-FU/LV was evaluated in two randomized phase
III trials as first-line treatment for metastatic colorectal cancer. The first
study, led by Saltz, used a weekly bolus schedule of the combination
(IFL), which resulted in a statistically significant improvement in response
rate (39% versus 21%; P ! .001), progression-free survival (7 months ver-
sus 4.3 months; P ¼ 0.004) and OS (14.8 months versus 12.6 months; P ¼ 0.04)
[13]. The European infusional regimen, folinic acid, fluorouracil and irinote-
can (FOLFIRI), using infusional 5-FU and bolus irinotecan every other week,
also demonstrated a statistically significant improvement in response rate
(35% versus 22%; P ! .005), progression-free survival (6.7 months versus
TREATMENT OF COLON CANCER 1025
4.4 months; P ! .001), and OS (17.4 months versus 14.1 months; P ¼ .031)
[14]. The addition of irinotecan to 5-FU increases the likelihood of diarrhea
and myelosuppression, and patients need to be selected carefully. Oral cape-
citabine may replace intravenous 5-FU safely with comparable response rates
and OS [15], with potential ease of administration (as described below).
Capecitabine (Xeloda) is a prodrug that undergoes a three-step enzymatic
conversion to fluorouracil, with the final step occurring at the level of the
tumor. The side effect profile predominantly includes hand-foot syndrome
but also bone marrow suppression and gastrointestinal toxicity. Two ran-
domized clinical trials [16,17] that compared oral capecitabine with intrave-
nous 5-FU/LV demonstrated that capecitabine was associated with
significantly higher response rates and a better toxicity profile. The incidence
of grade 3 or 4 diarrhea, stomatitis, nausea, and neutropenic sepsis was sig-
nificantly less with capecitabine. Based on these results, oral capecitabine
has been approved for first-line treatment of metastatic colorectal cancer.
Combination regimens of oral capecitabine with irinotecan or oxaliplatin
are more efficacious; single-agent capecitabine typically is reserved for
patients with a poor performance status or patients whose disease does
not warrant combination chemotherapy.
Oxaliplatin (Eloxatin) is a third-generation platinum derivative that
forms bulky DNA adducts. The major toxicity of oxaliplatin is neuropathy,
which can be in the form of an acute sensory toxicity that is precipitated by
exposure to cold temperature and causes dysesthesias of the extremities and
oropharynx, or a chronic cumulative peripheral sensory neuropathy that of-
ten is reversible after stopping therapy. Hypersensitivity reactions and cyto-
penias also can be associated with oxaliplatin therapy.
Single-agent oxaliplatin has only limited efficacy when administered in
metastatic colorectal cancer; however, by down-regulating thymidylate syn-
thase, it works synergistically with 5-FU [18]. Addition of oxaliplatin to in-
fusional 5-FU/LV (FOLFOX) significantly increases response rates and
time to disease progression in the first-line and in the second-line settings
[19–22]. The first trial, by de Gramont and colleagues, compared infusional
5-FU/LV with the same regimen in combination with oxaliplatin. This trial
showed a significantly higher objective response rate (22% versus 51%) and
longer progression-free survival (6.2 months versus 9 months), but the
median OS did not reach statistical significance. More recently, the North
Central Cancer Treatment Group 9741 three-arm study compared FOLFOX,
IFL, and a combination of irinotecan and oxaliplatin. This important trial
demonstrated an improved median time to progression, response rate, and
median survival with the FOLFOX regimen. FOLFOX also had a tolerable
toxicity profile [23]. As a result of these studies, FOLFOX has been adopted
as a standard first-line therapy by many oncologists in the United States.
Bevacizumab (Avastin) is a humanized monoclonal antibody against the
VEGF that reduces the availability of the VEGF ligand and impairs recep-
tor activation. The main toxicities include hypertension, proteinuria,
1026 NATARAJAN & SHUSTER
rate [28]. Encouraged by these results, Cunningham and colleagues [29] ran-
domly assigned 329 patients to irinotecan with cetuximab or cetuximab
alone in a 2:1 schema. A nearly identical 22.9% response rate was observed
in the irinotecan/cetuximab arm, with a time to progression of 4.1 months.
This trial led to the approval of this drug in combination with irinotecan in
the salvage setting after progression on irinotecan. Cetuximab also is ap-
proved for use as a single agent in patients who are intolerant of irinotecan.
No randomized first-line phase III trials of cetuximab have been re-
ported, although phase II studies using cetuximab in combination with ef-
fective chemotherapy regimens, such as FOLFOX or FOLFIRI, have
resulted in response rates of up to 81% [30,31]. Phase III studies are ongoing
to confirm these results, but until those studies are completed, use of this
drug in the first-line setting should be considered investigational.
FOLFOX or FOLFIRI
+
Bevacizumab
FOLFOX or FOLFIRI
Metastatic +
Colorectal Cancer Cetuximab
FOLFOX or FOLFIRI
+
Bevacizumab/Cetuximab
who have stage II disease have been subdivided into IIa (T3N0) and IIb
(T4N0), and patients who have stage III have been subdivided into stage
IIIa (T1/2N1), IIIb (T3/4N1), and IIIc (TxN2) [35]. Using surveillance,
epidemiology and end results data from 1991 to 2000, with approximately
120,000 patients who had colon cancer, 5-year colon cancer–specific survival
by stage was determined (Table 1) [2]. Of particular interest is the finding
that patients who have stage IIIa disease have a statistically significant
improvement in survival compared with patients who have stage IIb disease,
possibly because of the use of adjuvant therapy in patients who have stage
III disease, but not in patients who have stage II disease, as recommended in
the National Institutes of Health’s 1990 Consensus Conference guidelines
[36]. Surgical technique, without en bloc resection in patients who have stage
II disease, inadequate or inaccurate staging, or real differences in biology
also may explain these differences in survival.
Web-based prognostic and predictive tools are available that allow in-
formed and shared decision making when considering adjuvant therapies
for patients who have resected colon cancer. The Mayo Clinic site [37]
uses patient age, T and N stage, and grade to estimate disease-free survival
(DFS) and OS with surgery alone and with adjuvant therapy. Another use-
ful tool incorporates patient age, comorbidity, T and N stage, grade, and the
number of lymph nodes examined to determine prognosis with surgery
alone or with the addition of a fluorouracil- or FOLFOX-based adjuvant
regimen [38]. The example shown in Fig. 2 illustrates the data regarding
prognosis and predictive value of treatment for a 72-year-old gentleman
in good general health with a resected T3N1 moderately differentiated tu-
mor with adequate lymph node sampling. These graphs can be printed
and provided to patients during an office visit following surgical staging
to facilitate discussions regarding prognosis and the absolute benefit
expected with adjuvant therapy.
Table 1
Five-year colon cancer–specific survival by stage
AJCC stage T stage N stage M stage Survival
I T1 or T2 N0 M0 93%
IIa T3 N0 M0 85%
IIb T4 N0 M0 72%
IIIa T1 or T2 N1 M0 83%
IIIb T3 or T4 N1 M0 64%
IIIc Any T N2 M0 44%
IV Any T Any N M1 8%
Abbreviations: AJCC, American Joint Committee on Cancer. T1, tumor invades submucosa;
T2, tumor invades muscularis propria; T3, tumor invades through the muscularis propria into
the subserosa or nonperitonealized pericolic tissues; T4, tumor directly invades other organs/
structures or perforates visceral peritoneum; N0, no regional lymph node involvement; N1,
one to three positive nodes; N2, four or more positive nodes; M0, no distant metastasis; M1,
distant metastasis present.
1030 NATARAJAN & SHUSTER
Historical perspective
Benefit with adjuvant therapy for stage III colon cancer was reported ini-
tially in the 1980s based on trials using a combination of 5-FU and the pur-
ported immunostimulatory agent levamisole [39,40]. Randomization in
Intergroup trial 0035 was to observation, levamisole, or 1 year of 5-FU
and levamisole. The combined regimen reduced the risk for cancer recur-
rence by 40% (P ! .0001) and the overall death rate by 33% (P !
.0007), and this regimen became the standard of care for adjuvant treatment
of stage III colon cancer from 1989 until 1996. In 1996, the results of Inter-
group trial 0089 were released in abstract, which again changed the standard
of care for adjuvant treatment [41]. In 3700 patients who had stage II or III
disease, 5-FU and levamisole was compared with a 6-month regimen of
5-FU with low-dose (Mayo Clinic) or high-dose (Roswell Park) LV. There
was a fourth arm that used all three drugs (5 FU, LV, and levamisole).
The regimens that contained LV (5-year OS 66%) proved to be as effective
as the levamisole regimen (5-year OS 63%) and could be administered
over 6 months instead of 12 months; there was no advantage to a three-
drug regimen. A new standard of care for stage III adjuvant therapy was es-
tablished, and the choice of 5-FU with low-dose or high-dose LV was based
primarily on anticipated toxicities (myelosuppression and mucositis versus
diarrhea). These regimens remained the standard of care for nearly a decade,
and they continue to remain a therapeutic choice for many patients in the ad-
juvant setting.
TREATMENT OF COLON CANCER 1031
1032
Trial (patients-stage) Arms 3-y DFS 3-y OS 4-y DFS 4-y OS 5-y DFS 5-y OS
INT-0035 Observation 43% 47%
(929-III) Lev 44% 49%
5-FU/Lev (1-y) 61% 60%
P ¼ .0001 P ¼ .0007
INT-0089 5-FU/Lev (1-y) 56% 63%
(3759-II/III) 5-FU/LV (high) 60% 66%
5-FU/LV (low) 60% 66%
5-FU/LV/Lev 60% 67%
MOSAIC LV5FU2 72.9% 86.6% 69.8% 82.8%
(2246-II/III) FOLFOX 78.2% 88.2% 76.4% 84.9%
P ¼ .002 NS P ! .001 NS
St II only LV5FU2 84.3% 81.3%
results of C-07 were similar to those seen in the MOSAIC trial, which con-
firmed the benefit of a combination regimen. Three-year DFS was increased
from 71.6% to 76.5% with FLOX, which corresponded to a 21% relative
risk reduction in recurrence or death; this was comparable to the 23%
risk reduction that was seen in the MOSAIC trial with FOLFOX.
Complete toxicity data have not been presented from C-07, although
there seems to be a higher rate of diarrhea but a lower rate of neutropenia
and neuropathy with the FLOX regimen compared with FOLFOX. Aside
from differences in toxicity, the convenience of bolus therapy instead of in-
fusional treatment by way of a portable pump makes FLOX an attractive
option. A switch from an infusional FOLFOX regimen to bolus FLOX as
adjuvant treatment for colon cancer remains premature until the complete
data set has been presented.
Capecitabine
Recently, the results of the Xeloda in Adjuvant Colon Cancer Therapy
trial, which was conducted in Europe and Canada, were published [50]. Ap-
proximately 2000 patients who had stage III disease were randomized to
1034 NATARAJAN & SHUSTER
04), and pooled and compared outcomes for patients on the ‘‘superior’’ arm
with those on the ‘‘inferior’’ arm of each trial [52]. When data from all four tri-
als were examined in a combined analysis, the mortality reduction was 30%
for patients who had Dukes’ B colon cancer and 18% for patients who had
Dukes’ C colon cancer. The investigators concluded, ‘‘patients with Dukes’
B colon cancer benefit from adjuvant chemotherapy and should be presented
with this treatment option,’’ regardless of clinical prognostic factors.
The Quick and Simple and Reliable (QUASAR) trial randomized more
than 3200 patients with ‘‘uncertain indications’’ for adjuvant treatment
(92% had stage II disease) to chemotherapy or observation. With a median
follow-up of 4.5 years, there was a statistically significant improvement in
freedom from recurrence (77.8% versus 73.8%; P ¼ .001) and in 5-year sur-
vival (80.3% versus 77.4%; P ¼ .02) [53].
In the MOSAIC study, a subgroup analysis of patients who had stage II
disease did not demonstrate a significant DFS advantage; however, the study
was not powered to detect such differences. In 2004, ASCO published
guidelines recommending against routine treatment with adjuvant therapy
for average risk patients who have stage II disease. It was suggested, how-
ever, that chemotherapy be considered for patients who have high-risk fea-
tures (T4 disease, perforation, high-grade tumors, or fewer than 12 lymph
nodes examined) [54].
Regarding adjuvant therapy for patients who have stage II disease, the
National Comprehensive Cancer Network, an alliance of 19 of the leading
cancer centers in the United States, offers some guiding principles [55]. Sev-
eral elements need to be considered when determining whether adjuvant
therapy should be administered: number of lymph nodes examined, poor
prognostic features (high-grade tumor, lymphatic or vascular invasion,
bowel obstruction), and assessment of comorbidities. For patients who
have low-risk T3N0 disease, observation or a clinical trial is recommended.
Adjuvant therapy is an option, however, for high-risk patients who have T3
or T4 disease using 5-FU/LV or a FOLFOX regimen. Patients should be in-
formed of the potential risks and benefits of therapy, and it should be rec-
ognized that the absolute survival benefit does not exceed 2% to 5%.
Although the improvement seems to be small, this is similar to the magni-
tude of benefit that is seen with the use of adjuvant chemotherapy in patients
who have node-negative breast cancerdan accepted practice in academic
and community oncology.
A randomized phase III trial in stage II colon cancer is being conducted
by the Intergroup, led by the Eastern Cooperative Oncology Group. In
E5202, risk stratification is performed prospectively by tumor analysis for
microsatellite instability status (MSI) and loss of heterozygosity (LOH) at
chromosome 18q. Patients who have high-risk tumors, defined as having mi-
crosatellite stability [56] and 18q LOH [57], are randomized to FOLFOX
with or without bevacizumab. The low-risk patients will be assigned to an
observation arm and followed (Fig. 3).
1036 NATARAJAN & SHUSTER
FOLFOX
Plus
High Risk Group Bevacizumab
ECOG 5202 18q LOH plus
MSS or MSI-L
Fig. 3. Adjuvant study for stage II colon cancer. MSI-H, microsatellite instability high; MSI-L,
microsatellite instability low; MSS, microsatellite stability.
Current trials
Based on the results that were observed in the metastatic setting, future
directions in adjuvant therapy focus on the integration of new biologic
agents (cetuximab and bevacizumab). The Intergroup N0147 study will en-
roll patients who have stage III colon cancer with randomization to FOL-
FOX or FOLFOX plus cetuximab. NSABP C-08 is comparing FOLFOX
with FOLFOX plus bevacizumab in patients who have stage II or III colon
cancer (Fig. 4).
Assessment of molecular markers and gene expression is another active
area of research to facilitate selection of patients for adjuvant therapies. Ge-
netic polymorphisms in dihydropyrimidine dehydrogenase and the
UGT1A1 gene predict increased toxicity with 5-FU and irinotecan, respec-
tively, because of diminished clearance of the chemotherapeutic agent or its
1038 NATARAJAN & SHUSTER
N0147 Intergroup
FOLFOX
Resected
Stage III
FOLFOX +
Cetuximab
NSABP C-08
FOLFOX
Resected
Stage II/III
FOLFOX +
Bevacizumab
AVANT
FOLFOX
Resected FOLFOX +
Stage II/III Bevacizumab
XELOX +
Bevacizumab
Fig. 4. Current adjuvant trials in colon cancer. AVANT, Avastin adjuvant study.
active metabolite (SN38). In addition to 18q LOH and MSI being used to
assess prognosis in stage II disease, MSI also may be a predictor of benefit
with adjuvant therapy [65]. Ultimately, as is being done in breast cancer,
gene microarray technology will be used to determine prognosis and to pre-
dict response to individual chemotherapy agents.
Summary
There has been a dramatic improvement in outcomes for patients who
have colon cancer over recent years. These improvements have come about
TREATMENT OF COLON CANCER 1039
References
[1] Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55(1):
10–30.
[2] O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new Amer-
ican Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004;96(19):
1420–5.
[3] Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by leucovorin in patients
with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol 2004;22(18):
3766–75.
[4] Grothey A, Sargent D, Goldberg R, et al. Survival of patients with advanced colorectal can-
cer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in
the course of treatment. J Clin Oncol 2004;22(7):1209–14.
[5] Sobrero A, Guglielmi A, Grossi F, et al. Mechanism of action of fluoropyrimidines: rele-
vance to the new developments in colorectal cancer chemotherapy. Semin Oncol 2000;27
(5)(Suppl 10):72–7.
[6] Buroker TR, O’Connell MJ, Wieand HS, et al. Randomized comparison of two schedules of
fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol
1994;12(1):14–20.
[7] Wang WS, Lin JK, Chiou TJ, et al. Randomized trial comparing weekly bolus 5-fluorouracil
plus leucovorin versus monthly 5-day 5-fluorouracil plus leucovorin in metastatic colorectal
cancer. Hepatogastroenterology 2000;47(36):1599–603.
[8] de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing monthly low-dose
leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil
bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study.
J Clin Oncol 1997;15(2):808–15.
[9] Jager E, Heike M, Bernhard H, et al. Weekly high-dose leucovorin versus low-dose leucovorin
combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter
trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1.
J Clin Oncol 1996;14(8):2274–9.
[10] Iyer L, Ratain MJ. Clinical pharmacology of camptothecins. Cancer Chemother Pharmacol
1998;42(Suppl):S31–43.
[11] Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus support-
ive care versus supportive care alone after fluorouracil failure for patients with metastatic co-
lorectal cancer. Lancet 1998;352(9138):1413–8.
[12] Rougier P, Van Custem E, Bajetta E, et al. Randomised trial of irinotecan versus fluorouracil
by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer.
Lancet 1998;352(9138):1407–12.
[13] Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic
colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343(13):905–14.
1040 NATARAJAN & SHUSTER
[14] Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil com-
pared with fluorouracil alone as first line treatment for metastatic colorectal cancer: a multi-
centre randomised trial. Lancet 2000;355(9209):1041–7.
[15] Patt YZ, Liebmann J, Diamandidis D, et al. Capecitabine (X) plus irinotecan (XELIRI) as
first-line treatment for metastatic colorectal cancer (MCRC): final safety findings from
a phase II trial. Presented at the 2004 American Society of Clinical Oncology Annual Meet-
ing. New Orleans, June 5–8, 2004.
[16] Van Custem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous
fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large
phase III study. J Clin Oncol 2001;19(21):4097–106.
[17] Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous fluo-
rouracil plus leucovorin as first line treatment in 605 patients with metastatic colorectal can-
cer: results of a randomized phase III study. J Clin Oncol 2001;19(8):2282–92.
[18] Raymond E, Faivre S, Chaney S, et al. Cellular and molecular pharmacology of oxaliplatin.
Mol Cancer Ther 2002;1(3):227–35.
[19] de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without ox-
aliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18(16):
2938–47.
[20] Giacchetti S, Perpoint B, Zindani R, et al. Phase III multicenter randomized trial of oxali-
platin added to chronomodulted fluorouracil-leucovorin as first-line treatment of metastatic
colorectal cancer. J Clin Oncol 2000;18(1):136–47.
[21] Grothey A, Deschler B, Kroening H, et al. Phase III study of bolus 5-Fluorouracil (5-FU)/
folinic acid (FA) (Mayo) vs weekly high-dose 24h 5-FU infusion/FA þ oxaliplatin (OXA)
(FUFOX) in advanced colorectal cancer (ACRC). Presented at the 2002 American Society
of Clinical Oncology Annual Meeting. Orlando, May 18–21, 2002.
[22] Rothenberg ML, Oza AM, Bigelow RH, et al. Superiority of oxaliplatin and fluorouracil-
leucovorin compared with either therapy alone in patients with progressive colorectal cancer
after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol
2003;21(11):2059–69.
[23] Goldberg RA, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil
plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously un-
treated metastatic colorectal cancer. J Clin Oncol 2004;22(1):23–30.
[24] Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing
bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with
metastatic colorectal cancer. J Clin Oncol 2003;21(1):60–5.
[25] Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil
and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335–42.
[26] Hochster HS, Welles L, Hart L, et al. Safety and efficacy of bevacizumab (Bev) when added
to oxaliplatin/fluoropyrimidine (O/F) regimens as first-line treatment of metastatic colorec-
tal cancer (mCRC): TREE 1 and 2 studies. Presented at the 2005 American Society of Clin-
ical Oncology Annual Meeting. Orlando, May 13–17, 2005.
[27] Giantonio BJ, Catalano PJ, Meropol NJ, et al. High dose bevacizumab improves sur-
vival when combined with FOLFOX4 in previously treated advanced colorectal cancer:
results from the Eastern Cooperative Oncology Group (ECOG) study E 3200. Presented
at the 2005 American Society of Clinical Oncology Annual Meeting. Orlando, May
13–17, 2005.
[28] Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is ac-
tive in CPT-11 refractory colorectal cancer (CRC) that expresses epidermal growth factor
receptor (EGFR). Presented at the 2001 American Society of Clinical Oncology Annual
Meeting. San Francisco, May 12–15, 2001.
[29] Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus iri-
notecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351(4):
337–45.
TREATMENT OF COLON CANCER 1041
[30] Diaz Rubio E, Tabernero J, van Cutsem E, et al. Cetuximab in combination with oxaliplatin/
5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients
with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer:
an international study Presented at the 2005 American Society of Clinical Oncology Annual
Meeting. Orlando, May 13–17, 2005.
[31] Seufferlein T, Dittrich C, Riemann J, et al. A phase I/II study of cetuximab in combination
with 5-fluorouracil (5-FU)/folinic acid (FA) plus weekly oxaliplatin (L-OHP) (FUFOX) in
the first-line treatment of patients with metastatic colorectal cancer (mCRC) expressing epi-
dermal growth factor receptor (EGFR). Preliminary results. Presented at the 2005 American
Society of Clinical Oncology Annual Meeting. Orlando, May 13–17, 2005.
[32] Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse
sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol
2004;22(2):229–37.
[33] Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of
bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colo-
rectal cancer. J Clin Oncol 2005;23(16):3706–12.
[34] Greene FL, Balch CM, Fleming ID, et al, editors. AJCC cancer staging handbook. 6th edi-
tion. New York: Springer-Verlag; 2002.
[35] Greene FL, Stewart AK, Norton HJ. A new TNM staging strategy for node-positive (stage
III) colon cancer: an analysis of 50,042 patients. Ann Surg 2002;236(4):416–21.
[36] NIH Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer.
JAMA 1990;264(11):1444–50.
[37] Health tools: adjuvant systemic therapy for resected colon cancer. Available at: http://
www.mayoclinic.com/calcs. Accessed February 1, 2006.
[38] Adjuvant! for colon cancer. Available at: http://www.adjuvantonline.com. Accessed Febru-
ary 1, 2006.
[39] Laurie JA, Moertel CG, Fleming TR, et al. Surgical adjuvant therapy of large-bowel carci-
noma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The
North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 1989;7(10):
1447–56.
[40] Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant
therapy of resected colon carcinoma. N Engl J Med 1990;322(6):352–8.
[41] Haller DG, Catalano PJ, Macdonald JS, Mayer RJ. Fluorouracil (FU), leucovorin (LV) and
levamisole (LEV) adjuvant therapy for colon cancer: four-year results of INT-0089. Pre-
sented at the 1997 American Society of Clinical Oncology Annual Meeting. Denver, May
17–20, 1997.
[42] de Gramont A, Banzi M, Navarro M, et al. Oxaliplatin/5-FU/LV in adjuvant colon cancer:
results of the international randomized MOSAIC trial. Presented at the 2003 American So-
ciety of Clinical Oncology Annual Meeting. Chicago, May 31–June 3, 2003.
[43] Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as ad-
juvant treatment for colon cancer. N Engl J Med 2004;350(23):2343–51.
[44] de Gramont A, Boni C, Navarro M, et al. Oxaliplatin/5FU/LV in the adjuvant treatment of
stage II and stage III colon cancer: efficacy results with a median follow-up of 4 years.
Presented at the 2005 American Society of Clinical Oncology Annual Meeting. Orlando,
May 13–17, 2005.
[45] Sargent DJ, Wieand S, Benedetti J, et al. Disease-free survival (DFS) vs. overall survival as
a primary endpoint for adjuvant colon cancer studies: individual patient data from 12,915
patients on 15 randomized trials. Presented at the 2004 American Society of Clinical Oncol-
ogy Annual Meeting. New Orleans, June 5–8, 2004.
[46] Wolmark N, Wieand HS, Kuebler JP, et al. A phase III trial comparing FULV to FULV þ
oxaliplatin in stage II or III carcinoma of the colon: results of NSABP protocol C-07. Pre-
sented at the 2005 American Society of Clinical Oncology Annual Meeting. Orlando, May
13–17, 2005.
1042 NATARAJAN & SHUSTER
[47] Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan plus fluorouracil/leucovorin (IFL) ver-
sus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trail CALGB
C89803). Presented at the 2003 American Society of Clinical Oncology Annual Meeting.
Chicago, May 31–June 3, 2003.
[48] Van Cutsem E, Labianca R, Hossfeld D, et al. Randomized phase III trial comparing infused
irinotecan/5-fluorouracil (5-FU)/folinic acid (IF) versus 5-FU/FA (F) in stage III colon can-
cer patients (pts). (PETACC 3). Presented at the 2005 American Society of Clinical Oncology
Annual Meeting. Orlando, May 13–17, 2005.
[49] Ychou M, Raoul J, Douillard J, et al. A phase III randomized trial of LV5FU2 þ CPT-11 vs.
LV5FU2 alone in adjuvant high risk colon cancer (FNCLCC Accord02/FFCD9802). Pre-
sented at the 2005 American Society of Clinical Oncology Annual Meeting. Orlando, May
13–17, 2005.
[50] Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III
colon cancer. N Engl J Med 2005;352(26):2696–704.
[51] International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Inves-
tigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol
1999;17(5):1356–63.
[52] Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant chemotherapy
in patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical
Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin On-
col 1999;17(5):1349–55.
[53] Gray RG, Barnwell J, Hills R, et al, for the QUASAR Collaborative Group. QUASAR:
a randomized study of adjuvant chemotherapy (CT) vs. observation including 3238 colorec-
tal cancer patients. Presented at the 2004 American Society of Clinical Oncology Annual
Meeting. New Orleans, June 5–8, 2004.
[54] Benson AB III, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology rec-
ommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004;
22(16):3408–19.
[55] Engstrom P. Update: NCCN colon cancer clinical practice guidelines. J Natl Compr Canc
Netw 2005;3(Suppl 1):S25–8.
[56] Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in
young patients with colorectal cancer. N Engl J Med 2000;342(2):69–77.
[57] Shibata D, Reale MA, Lavin P, et al. The DCC protein and prognosis in colorectal cancer.
N Engl J Med 1996;335(23):1727–32.
[58] Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver re-
section for hepatic colorectal metastases. Ann Surg 2002;235(6):759–66.
[59] Langer B, Bleiberg H, Labianca R, et al. Fluorouracil (FU) plus l–leucovorin (l-LV) versus
observation after potentially curative resection of liver or lung metastases from colorectal
cancer: results of the ENG (EORTC/NCIC CTG/GIVIO) randomized trial. Presented
at the 2002 American Society of Clinical Oncology Annual Meeting. Orlando, May 18–21,
2002.
[60] NCCN practice guidelines on treatment of colon cancer, version 2. 2006. Available at: http://
www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed January 15, 2006.
[61] Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after
resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341(27):
2039–48.
[62] Delaunoit T, Alberts SR, Sargent DJ, et al. Chemotherapy permits resection of metastatic
colorectal cancer: experience from Intergroup N9741. Ann Oncol 2005;16(3):425–9.
[63] Bilchik AJ, Poston G, Curley SA, et al. Neoadjuvant chemotherapy for metastatic colon can-
cer: a cautionary note. J Clin Oncol 2005;23(36):9073–8.
[64] Fernandez FG, Ritter J, Goodwin JW, et al. Effect of steatohepatitis associated with irino-
tecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll
Surg 2005;200(6):845–53.
TREATMENT OF COLON CANCER 1043
[65] Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite instability status as a predictor
of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med
2003;349(3):247–57.
[66] Desch CE, Benson AB III, Somerfield MR, et al. Colorectal cancer surveillance: 2005 update
of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2005;23(33):
8512–9.