Download modern staging and adjuvant approaches in colon cancer

PROCEEDINGS
MODERN STAGING AND ADJUVANT APPROACHES
IN COLON CANCER*
—
John L. Marshall, MD†
ABSTRACT
DIAGNOSTIC TOOLS
Staging of colorectal cancer (CRC) is based on
the degree of tumor invasion into tissues of the
colon, the number of lymph node metastases, and
the presence or absence of distant metastasis. It is
particularly important to distinguish between stage
II and stage III CRC because patients in stage III
most certainly will benefit from chemotherapy,
whereas there is considerable debate as to whether
it is worth the resources to similarly treat patients in
stage II. Several clinical trials have established that
only perhaps 5% of patients with stage II CRC benefit from chemotherapy, either because the cancer
has been totally removed by resection or the patient
is unresponsive to the therapy. Several advances
are likely to increase the accuracy of staging.
Identification of lymph node metastases is of primary importance. If resources are available to
examine all lymph nodes recovered after resection,
studies have shown that this will increase the likelihood of finding one or more positive lymph nodes.
Current guidelines recommend a minimum of 12
lymph nodes to be assessed per resected specimen
in order to have the cancer adequately staged.
Identification of sentinel lymph nodes may decrease
this workload, allowing for microsectioning of only
a few nodes per resection. Genetic screening is
becoming increasingly important. At present, loss
of chromosome 18q and microsatellite stability are
among the most useful markers of patients with
higher risk in stage II. Work is continuing on other
genetic markers, which, in the future, may further
improve our ability to stage these patients.
(Adv Stud Med. 2007;7(2):33-38)
*Based on a presentation given by Dr Marshall at a
satellite symposium held in conjunction with the 2006
International Society of Gastrointestinal Oncology
Conference on September 22, 2006, in Arlington, Virginia.
†Associate Professor, Lombardi Comprehensive Cancer
Center, Washington, DC.
Address correspondence to: John L. Marshall, MD,
Associate Professor, Lombardi Comprehensive Cancer Center,
3800 Reservoir Road, NW, Washington, DC 20007.
E-mail: [email protected].
Johns Hopkins Advanced Studies in Medicine
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Early stage colorectal cancer (CRC) can be curable
by surgical resection. Unfortunately, at this stage the
cancer is often asymptomatic. The right side of the
colon is especially large, allowing tumors to reach an
appreciable mass before any obstruction results in
noticeable symptoms. As lesions in the ascending
colon ulcerate, blood loss in the stool causes patients
to present with symptoms of anemia, such as fatigue
and palpitations. This has led clinicians to consider a
CRC workup for any adult presenting with an iron
deficiency anemia, with the exception of menstruating
women. There exists a certain inconsistency, however,
in preoperative workups in some areas of the United
States, suggesting a need to discuss an appropriate
staging strategy. There is general agreement among
clinicians that a complete colonoscopy is an important
preoperative procedure. A complete examination of
the colon from the anus to the cecum is possible in
95% of patients with less than a 0.5% complication
rate resulting in the detection of 90% to 95% of polyploidy lesions.1 In addition, endoscopic ultrasound
(EUS) has increasingly been incorporated into procedures for patients with rectal cancer. Although somewhat operator dependent, EUS is capable of
determining the extent to which a tumor has penetrated through the bowel wall, thus contributing to the
ability of the clinician to accurately stage the tumor.
Lymph node assessment is less accurate by EUS.
Abdominal and pelvic imaging, such as computed
tomography (CT), have become common, but their
ability to accurately identify early stages of CRC is
poor.2 These studies are most useful for determining
the presence or absence of metastatic disease. Whereas
chest X rays are often performed, seldom does one see
a preoperative chest CT ordered. Positron emission
tomography (PET) scans may occasionally be useful
for diagnostic purposes; however, in most cases, PET
scans do not contribute to the diagnosis. The measure
of carcinoembryonic antigen (CEA) protein is useful
33
PROCEEDINGS
as a baseline study for subsequent surveillance. CEA
protein is expressed by over 90% of CRC tumors and
presence of CEA in the serum is useful as a marker for
metastatic disease.3 Genetic screening is also underutilized. Hereditary nonpolyposis colorectal cancer
(HNPCC) accounts for 3% to 4% of all CRC and can
easily be detected as mutations in certain DNA mismatch repair genes.4 The surgical strategy can change
depending on whether the patient has HNPCC.
WHO SHOULD RECEIVE ADJUVANT CHEMOTHERAPY?
Staging clearly plays a critical role in assessing treatment. Patients with stage III CRC, for example, are routinely given adjuvant chemotherapy, whereas patients in
stage II are not. The American Joint Committee on
Cancer/TNM staging scale is shown in the Table. The
T-scale refers to the extent of tumor invasion through
the colon wall and clearly correlates with the possibility
of metastasis. Lymph node involvement also serves as an
important measure of prognosis. Categories include no
nodal involvement (N0), 1 to 3 nodes (N1), and 4 or
more nodes (N2). The M-scale denotes absence (M0) or
presence (M1) of distant metastatic disease. Together
the T, N, and M are used to establish the stage of the
cancer as shown in the Table.
Lymphovascular invasion (LVI) is another important parameter. Indeed, a recent study presented at the
2006 American Society of Clinical Oncology annual
meeting showed LVI to be predictive of metastasis.5
Perforation and obstruction of the colon are also associated with a poor prognosis.6 All these factors play
into the decision as to whether adjuvant chemotherapy should be given postoperatively.
It is important to note that although a large number of patients are exposed to chemotherapy, only a
relatively small number of those patients will benefit
from this treatment. In part, this is because of the
complete removal of the cancer by the surgeon.
Obviously, this group will never benefit from
chemotherapy because their cancer has already been
cured. The second group will experience a return of
the cancer unless it is eradicated by the chemotherapy.
As improved efficacy equates to an increased number
of cures, this is the highest priority task facing us at
this time. At present we cannot distinguish between
patients who are cured by surgery and who will benefit from chemotherapy. Additionally, we do not yet
know who is more likely to respond to chemotherapy
34
assuming that they still have remnants of the cancer
remaining. Another issue is toxicity. Adjuvant
chemotherapy for CRC is relatively mild in terms of side
effects. Few patients lose much of their hair or experience
a debilitating side effect that keeps them from pursuing
their daily activities. However, for a few patients
chemotherapy has significantly decreased quality of life;
thus, we need to address the toxicity issue. Certainly, a
great deal of effort has gone into the development of
more efficacious chemotherapeutic regimens. There are
now several available regimens, and work is under way to
develop screening methods to assess which population
will most benefit from a specific regimen.
Table. Staging of Colorectal Cancer by the American
Joint Committee on Cancer (TNM classification)*
Stage 0
Tis† N0 M0‡
Carcinoma in situ; negative nodes
Stage I
T1, T2 N0 M0
Tumor invades submucosa; negative nodes
Stage IIA
T3 N0 M0
Tumor invades through muscularis propria into subserosa
or into nonperitonealized pericolic or perirectal tissues;
negative nodes
Stage IIB
T4 N0 M0
Tumor perforates the visceral peritoneum and/or directly
invades other organs or structures; negative nodes
Stage IIIA T1–T2 N1 M0
Tumor invades submucosa or muscularis propria with 1–3
pericolic or perirectal lymph nodes involved.
Stage IIIB
T3–T4 N1 M0
Tumor invades through the muscularis propria into the
subserosa or into nonperitonealized pericolic or perirectal
tissues, or tumor directly invades other organs or structures, and/or perforates visceral peritoneum and 1–3 pericolic or perirectal lymph nodes involved.
Stage IIIC Any T N2 M0
Any T stage with ≥4 pericolic or perirectal lymph nodes
involved.
Stage IV
Any T Any N M1
Any invasion of bowel wall with or without lymph node
metastasis, but with evidence of distant metastasis.
*Based on American Joint Committee on Cancer Staging Manual. 6th ed.
New York, NY: Springer-Verlag; 2002.
†T-scale measures the extent of tumor spread through the layers of the wall of
the colon. T1 = extends into the submucosa; T2 = the muscularis propria; T3 =
the subserosa; T4 = spread to nearby tissues.
‡M-scale measures metastasis. M0 = absence of metastasis; M1 = metastasis
observed.
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PROCEEDINGS
Figure 1. Adjuvant Oxaliplatin: MOSAIC Trial (3year data)
FOLFOX4 (1100 pts)
77.8%
T3, T4 N0 = 40% (87% vs 84%)
Tx, N1, N2 = 60% (72% vs 65%)
72.9%
Johns Hopkins Advanced Studies in Medicine
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A
Disease-free
survival probability
For the patient with stage II CRC, one might predict that 3% to 6% will actually benefit (ie, achieve a
cure) from chemotherapy. From a population healthcare perspective, one might ask if it is a waste of
resources to treat this population. Consider the
Multicenter International Study of Oxaliplatin/5Fluorouracil (5-FU)/Leucovorin in the Adjuvant
Treatment of Colon Cancer (MOSAIC) trial.7 This
study involved approximately 2200 patients of which
40% were stage II and 60% were stage III. The overall
benefit for patients in stage II was approximately 3%,
whereas the benefit for patients in stage III was
approximately 7% as shown in Figure 1. The results of
this study have led to the combination of FOLFOX
(5-FU, leucovorin, and oxaliplatin) as the standard of
care for stage III CRC. Its use in patients with stage II
CRC continues to be debated; these patients are still
being followed. The relative benefits appear to be
holding at 5 years with 3.5% for patients with stage II
CRC and 8.6% for patients with stage III CRC
(Figure 2).8 If one considers markers of poor prognosis
(defined as T4, and/or bowel obstruction, and/or tumor
perforation, and/or poorly differentiated tumor,
and/or venous invasion, and/or <12 examined lymph
nodes), the numbers for patients with stage II CRC
improves somewhat to 5.4% (Figure 2).8 These small
differences indicate the necessity of a large trial to
establish their significance. It is estimated that 3000 to
4000 patients would need to be assessed to power a
study to establish a significant difference of 3%. This
was accomplished with the Quick and Simple and
Reliable (QUASAR-1) trial.9 A total of 3289 patients
with stage II CRC were randomized to receive weekly
Figure 2. MOSAIC Trial Data as of January 16, 2005
1.0
0.9
} 3.5%
0.8
FOLFOX4
LV5FU2
0.7
0.6
0.0
0
6
12
18
24
30
36
42
48
54
60
66
M o n th s
B
1.0
Disease-free
survival probability
FOLFOX4 = 5-fluorouracil, leucovorin, and oxaliplatin; LV5FU2 = 5-fluorouracil/leucovorin; MOSAIC = Multicenter International Study of
Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon
Cancer; pts = patients.
FOLFOX4
LV5FU2
0.9
0.8
0.7
} 8.6%
0.6
0.0
0
6
12
18
24
30
36
42
48
54
60
66
M o n th s
C
Disease-free
survival probability
LV5FU2 (1100 pts)
P <.01
bolus 5-FU/leucovorin or observation only. Five-year
recurrence rates in the treatment versus observation arms
were 22.2% and 26.2%, respectively (relative risk, 0.78;
95% confidence interval, 0.67–0.91; P = .001).
Another ongoing study that is considering patients
with stage II CRC is the National Surgical Adjuvant
Breast and Bowel Project (NSABP) C-07 trial. Here
2709 patients with stage II and stage III CRC were
randomized to receive 5-FU/leucovorin or FLOX (5-
1 .0
0 .9
} 5.4%
0 .8
FOLFOX4
LV5FU2
0 .7
0 .6
0
6
12
18
24
30
36
42
48
M o n th s
A, Stage II CRC: FOLFOX4 = 451 patients; LV5FU2 = 448 patients; HR, 0.82;
95% CI, 0.6–1.13. B, Stage III CRC: FOLFOX4 = 672 patients; LV5FU2 = 675
patients; HR, 0.75; 95% CI, 0.62–0.89. C, Patients with high-risk stage II CRC:
FOLFOX4 = 286 patients; LV5FU2 = 290 patients; HR, 0.76.
CI = confidence interval; CRC = colorectal cancer; FOLFOX4 = 5-fluorouracil,
leucovorin, and oxaliplatin; HR = hazard ratio; LV5FU2 = 5-fluorouracil/leucovorin; MOSAIC = Multicenter International Study of Oxaliplatin/5Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer.
Reprinted with permission from de Gramont 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: 2005 American Society of Clinical Oncology
Meeting; May 13-17, 2005; Orlando, Fla. Abstract 3501.8
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PROCEEDINGS
FU/leucovorin and oxaliplatin). The complete
results have not yet been published; however several
interesting findings have emerged. The 5-FU/leucovorin was administered as a bolus and surprisingly, the same benefit was observed as in the MOSAIC
trial.10 The 3-year interim results from this study are
a disease-free survival of 71.6% for the Roswell Park
arm and 76.5% for the FLOX arm with less neurotoxicity because of the reduced number of oxaliplatin doses.10
MOLECULAR STAGING TOOLS
There exist several potential molecular markers for
increased risk. Chromosome 18q is often mutated in
CRC and contains the tumor suppressor gene DCC.13
A study from 1994 performed a retrospective examination of the relationship between loss of chromosome
18q and 5-year survival in patients with stage II and
stage III resected CRC.14 If TNM staging alone was
considered, 5-year survival was 74% for patients in
stage II and 42% for patients in stage III. However,
when the status of chromosome 18q was considered,
the numbers changed markedly. The survival rate for
patients in stage II with an intact chromosome 18q
was 93% and 54% for the group of patients in stage II
with a mutated chromosome 18q. Stage III statistics
did not change appreciably.
Because HNPCC has been associated with mutations in DNA mismatch repair genes, screening for
these mutant alleles will be informative.4 Additionally,
as DNA mismatch repair genes serve as a sort of “spell
check” for DNA during replication, loss of this function results in microsatellite DNA instability, which
also can be assessed.15 In some ways, this may be more
efficient because there are several potential mismatch
repair genes that must be assessed for mutation, any
one of which can result in microsatellite instability.
Other markers such as p53, k-ras, and thymidylate
synthase have been examined in retrospective studies;
NODAL SAMPLING
Percentage with metastases
If we could refine the staging process we could better identify the patients with stage II CRC who are
high risk. Perhaps the most important criteria currently to be considered is nodal assessment. In a study of
2427 resected T3 tumor specimens, the number of
lymph nodes evaluated was compared to the number
of positive lymph nodes found and the 5-year survival
statistics for the patient population.11 As the number of
recovered lymph nodes increased, the probability of
finding a positive lymph node also increased. Given
that adjuvant therapy is usually only offered to
patients with nodal metastasis, it is of paramount
importance to find those metastases if they exist.
Figure 3 shows the relationship between the number of
lymph nodes recovered and the number of specimens
in which metastatic lymph nodes were found.
However, the evaluation of so many lymph
nodes requires tremendous resources. One new
concept that may save much work is that of the
sentinel lymph node. The sentinel lymph node
Figure 3. Lymph Nodes Associated with Increasing Percentage
is defined as that lymph node to which the priof Specimens with Lymph Node Metastases
mary tumor drains. If any lymph nodes were to
become metastatic, one would predict that this
would be the first. The technique developed to
identify the sentinel lymph node involves the
injection of isosulfan blue dye or fluorescein
around the tumor. The draining lymph nodes
are then stained and can be identified, removed,
and carefully sectioned to look for micrometastases. In a retrospective study, Saha et al found
that only 7% of the patients who underwent
sentinel lymph node mapping had disease recurRecovered lymph nodes
rence after resection as compared with 25% of
An increasing number of lymph nodes were significantly associated with an increasing perthe patients who had standard node staging percentage of specimens with lymph node metastases. The steepest increase was between 2 and
formed.12 The results are intriguing and warrant
12 recovered lymph nodes.
further study.
Reprinted with permission from Goldstein. Am J Surg Pathol. 2002;26:179-189.
11
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PROCEEDINGS
at present, only microsatellite instability is associated
with better survival, but perhaps less responsive to
chemotherapy, in retrospective studies.16 Another molecular marker that is receiving attention currently is
guanylyl cyclase C (GCC). This gastrointestinal tractspecific enzyme is normally expressed in apical membranes of intestinal epithelial cells and also is
overexpressed in colorectal tumors but not in other tissues or tumors.17 Polymerase chain reaction detection
of GCC has recently been clinically validated as a
reproducible measure of lymph node micrometastases
and is being used in a prospective clinical trial.18
APPLICATION OF BIOLOGICAL AGENTS IN STAGE II CRC
Currently, several clinical trials are in progress
focusing on the use of the new biological agents in
stage II and stage III CRC. Eastern Cooperative
Oncology Group 5202 is a phase III trial comparing
FOLFOX4 to FOLFOX4 plus bevacizumab in
patients with stage II CRC with loss of chromosome
18q and microsatellite stability. N0147 is a phase III
randomized study of a different variant of the FOLFOX regimen (FOLFOX6) with or without the addition of cetuximab. This study is focused on stage III
CRC. This will be a fairly large study with approximately 2300 patients accrued. The NSABP C-08
study is comparing FOLFOX6 with or without bevacizumab and will consider patients with both stage II
and stage III CRC. Each arm of the study will enroll
1316 patients for a total of 2632. The AVANT study
is examining bevacizumab in combination with FOLFOX6 or XELOX (also known as CAPOX
[capecitabine and oxaliplatin]) regimens in the treatment of stage III CRC. The 3 arms of the study are
FOLFOX6, FOLFOX6 plus bevacizumab, and
XELOX plus bevacizumab. Each arm will recruit 1150
patients. Results from this trial will further help us
define the role of adjuvant chemotherapy in stage II
CRC.
CONCLUSIONS
Staging of CRC is of paramount importance
because it will determine the course of treatment.
Currently, the primary challenge is to determine which
patients with stage II CRC are high risk and should be
treated with chemotherapy in addition to resection
and which patients with stage II CRC can be treated
Johns Hopkins Advanced Studies in Medicine
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with resection alone followed by observation. This is
compounded by the problem that only 3% to 6% of
patients with stage II CRC will benefit from
chemotherapy as demonstrated by several studies, such
as the MOSAIC and QUASAR-1 clinical trials. LVI,
perforation, and obstruction all have been shown to
correlate with decreased survival and thus, are useful
risk factors for the patient with stage II CRC.
Improving nodal assessment will improve staging,
however, it can be technically challenging and resource
consuming. Molecular tumor evaluation is another
strategy that may identify patients with high-risk stage
II CRC. Loss of chromosome 18q and microsatellite
stability have been shown to mark a higher risk population. Molecular testing for GCC also shows promise
as a means to identify metastasis and thus, direct the
patient with stage II CRC to adjuvant chemotherapy.
Currently, the most attractive adjuvant regimen is one
combining 5-FU and oxaliplatin, such as FOLFOX.
However, several clinical trials are currently examining
the role of the newer biological agents, bevacizumab
and cetuximab, in adjuvant chemotherapy.
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