Prognostic Indicators of Colon Tumors

The Gastrointestinal Tumor Study Group Experience

SETH M. STEINBERG, PHD,* JAMIE S. BARKIN, MD,t RICHARD S. KAPLAN, MD,*

AND DONALD M. STABLEIN, PHD

This study sought to replicate and expand findings reported by the National Surgical Adjuvant Breast
and Bowel Project (NSABP) on prognostic factors in resectable colon cancer. Mantel-Haenszel tests and
the Cox model were used to analyze prognostic significance and effect of primary disease symptoms and
tumor location in 572 patients from the Gastrointestinal Tumor Study Group (GITSG), with resected
Dukes B2 and C colon cancer. Tumor location (left, right, and rectosigmoid/sigmoid)was of low prognostic
importance (P > 0.10), and did not effect survival or disease-free survival (P > 0.10). Obstruction was
an important indicator of prognosis, independent of Dukes stage (P = 0.03). Bowel perforation is associated
with poor prognosis in disease-free survival (P = 0.001). Rectal bleeding had a positive impact on survival
(P = 0.08). Thus, obstruction, perforation, and rectal bleeding (but not location) are found to be prognostic
factors in patients with Dukes B2 or C colon cancer.
Cancer 57:1866-1870, 1986.

T HE PROGNOSTIC SIGNIFICANCE of tumor location in

patients with Dukes B and C colorectal cancer was
recently investigated by Wolmark el al. The data were
from 1021 patients who had been entered into two Na-
tional Surgical Adjuvant Breast and Bowel Project
(NSABP) trials. Location of the tumor within the colon
was determined to be an important prognostic factor. Pa-
tients with descending colon tumors demonstrated the
most favorable prognosis, whereas those with tumors lo-
cated in the rectosigmoid and rectum had the worst. The
presence of bowel obstruction was also shown to have
prognostic importance; obstruction of the right colon was
associated with a significantly diminished disease-free
From *The EMMES Corporation, Potomac, Maryland, ?The Uni-
versity of Miami, Miami, Florida, and the $University of Maryland Can-
cer Center, Baltimore, Maryland.
Supported by Contract No. NOI-CM-87193 and Grant No. UIO-CA-
34 169 of the National Cancer Institute.
Address for reprints: Dr. Seth M. Steinberg, The EMMES Corporation,
I I325 Seven Locks Road, Potomac, MD 20854.
The following member institutions of the Gastrointestinal Tumor
Study Group have participated in this study: University of Miami, Miami,
Florida; Dana-Farber Cancer Institute, Boston, Massachusetts; The
EMMES Corporation, Potomac, Maryland; Mayo Clinic, Rochester,
Minnesota: Roswell Park Memorial Institute, Buffalo, New Y o r k
Georgetown University Medical Center, Washington, D. C.; Albany
Medical College, Albany, New Y o r k Mount Sinai Medical Center, New
York, New York; University of California, Los Angeles, California; Uni-
versity of Chicago, Chicago, Illinois; Istituto Nationale Tumori, Milan,
Italy: Memorial Sloan-Kettering, New York, New Y o r k University of
Southern California, Los Angeles, California; Yale University, New
Haven, Connecticut.
Accepted for publication July 22, 1985.
survival, whereas obstruction in the left colon had no effect
on prognosis. These differences were not attributable to
differences in the number of positive regional nodes. The
prognostic significance of Dukes stage was confirmed,
whereas age and sex were not important. This informa-
tion, if found to be reproducible, has important clinical
applications. This study was undertaken to analyze, in a
similar fashion, data from patients who have surgically
resectable colon cancer who had been treated on a Gas-
trointestinal Tumor Study Group (GITSG) protocol.
Material and Methods
The data are derived from 572 patients who were en-
tered into a four treatment arm GITSG protocol that
evaluated adjuvant treatment of patients with resectable
Dukes B2 (serosal involvement, no affected nodes) and
C (involved regional lymph nodes) stage colon, but not
rectal. carcinomas (the NSABP study included both colon
and rectal lesions). The GITSG has modified the Dukes
staging system to define C , tumors as those with 1 to 4
positive regional lymph nodes, and C2 as those with more
than 4 positive nodes, regardless of tumor penetration.
The study found no statistically significant survival or re-
currence differences among patients in the control group
or receiving any of the therapies.2
Tumor location was ultimately determined by the sur-
geon. Tumor location was grouped in the same fashion
as in the NSABP study. Tumors located in the transverse
colon, splenic flexure, and descending colon above the

1866
No. 9 INDICATORSOF COLONTUMORS
PROGNOSTIC - Sreinberg et al. 1867

sigmoid colon were classified as left colonic tumors. Those
located in the hepatic flexure, ascending colon, and cecum
were grouped as the right colonic tumors. Those in the
rectosigmoid and sigmoid were combined in the analyses
when such a grouping simplified presentation of findings.
The distribution of tumor location in our patient popu-
lation, compared to that in the NSABP, is shown in Table
1 , which reveals that the two studies had patient distri-
butions by site which were quite similar.
The prognostic significance of tumor location was de-
termined through Mantel-Haenszel tests for differences
in survival or disease-free ~ u r v i v a lAnalyses
.~ stratified for
differences in age, sex, and number of nodes, as well as
unstratified analyses, were performed.
The 13 primary disease symptoms and findings that
are reported in the GITSG on-study form for colorectal
studies were analyzed (Table 2). Age and sex were not
considered as they were previously identified as being
nonsignificant for prognosis.* Each primary disease
symptom was first evaluated independently for prognostic
importance by means of Mantel-Haenszel tests. Those
variables which were of at least borderline significance Primary Disease Symptoms
(below P = 0.10) in prognosis were tested for their degree
of association with each other and with Dukes stage. The
symptoms, number of patients, and the effect of each
symptom on survival or disease-free survival (not ac-
counting for Dukes stage or any other possible factors)
are listed in Table 2. Five possible prognostic factors were
found utilizing these criteria. Since Dukes stage has al-
ready been identified as a strong prognostic factor in these
study patients, any additional factors should have prog-
nostic importance after adjusting for Dukes stage.2 The
Cox Proportional Hazards Model was selected to deter-
mine the effects of location and primary disease symp-
toms, adjusting for Dukes stage.4
TABLE1. Distribution of Colonic Tumor Sites by Study
Tumor Site NSABP Studies GITSG Study
Left colon 184 (24.2%) 139 (24.6%)
Right colon 294 (38.6%) 215 (38.0%)
Sigmoid 246 (32.5%) 166 (29.3%)
Rectosigmoid 36 (4.7%) 46 (8.1%)
Total 760 (100%) 566 (100%)
NSABP: National Surgical Adjuvant Breast and Bowel Project; GlTSG:
Gastrointestinal Tumor Study Group.
of whether three locational groupings or four were in-
cluded in the analyses.
Figures 1 and 2, respectively, illustrate the small dif-
ferences in disease-free survival and survival curves of
patients with left, right, and rectosigmoid, or sigmoid co-
lon tumors. The disease-free curves for left colonic loca-
tion are slightly (nonsignificantly) superior to those for
patients with right colon tumors, or rectosigmoid and sig-
moid tumors.
Obstruction, bowel perforation, nausea and vomiting,
and abdominal distention were determined to have sta-
tistical importance, while melena or rectal bleeding ap-
proached significance (Table 2). The association of these
factors with each other and with Dukes stage was ex-
amined using multiple contingency tables. Any symptoms
which were of importance would need to be shown of
consequence independent of Dukes stage. All of the po-
tentially prognostic primary symptom variables were
found to be well associated with each other, so each of
the symptoms might be of nearly identical importance in

Results TABLE2. Primary Disease Symptoms Examined

for Prognostic Significance
Tumor Location
Mantel-Haenszel
Colonic tumor location in the GITSG study was of no P-values
No. of
prognostic importance. When one compares the groupings patients with Disease-free
of left versus right versus rectosigmoid and sigmoid colon Primary symptom symptoms survival Survival
tumors, the Mantel-Haenszel test for a difference in dis-
Obstruction 80 0.0 I * 0.003*
ease-free survival yielded an unimpressive P = 0.42. Ex- Bowel perforation 14 0.0 I * 0.14
amining differences in survival also failed to show a dif- Nausea and vomiting 97 0.02* 0.01*
ference (P = 0.44). Abdominal distention 73 0.12 0.01*
Melena or rectal bleeding 246 0.19 0.06
Tumor location was further classified into four cate- Weakness 149 0.11 0.10
gories: left, right, rectosigmoid, and sigmoid. As in prior Change in bowel habit 247 0.19 0.12
analyses, there was no statistical effect due to location on Abdominal pain 306 0.34 0.18
Anorexia 102 0.24 0.22
either survival or disease-free survival. Unstratified Man- Rectal or pelvic pain 32 0.2 1 0.29
tel-Haenszel tests for both survival and disease-free sur- Tenesmus 43 0.37 0.25
vival differences resulted in P values on the order of 0.6. Diarrhea 131 0.64 0.40
Obstipation or constipation 146 0.88 0.78
Using the Cox model, the effect of tumor location, ad-
justed for Dukes stage, was of little importance regardless * Statistically significant, P < 0.05.
1868 CANCERMay 1 1986 Vol. 51

LEGEND TABLE3. Prognostic Importance of Primary Disease Symptoms

After Adjusting for Dukes Stage (Using Cox Model)
RECTOSIGMOID 8 SIGMOID
RIGHT COLON
................................................................. Disease-free
survival Survival
LEFT COLON
Primary disease Relative P Relative P
80 symptom N* risk? value risk value
W
W 70 Obstruction 80 1.40 0.034 1.41 0.034
t
Y Bowel perforation 14 3.40 0.001 2.09 0.041
LL
I 60 Nausea and
vomiting 91 1.38 0.068 1.43 0.022
Abdominal
distention 73 1.22 0.320 1.41 0.043
Melena or rectal
30 bleeding 246 0.85 0.264 0.80 0.081
s
20 * N is the number of patients with the condition present at time of
placement onto study.
t Relative risk z I .O implies harmful factor; relative risk < I .O implies
helpful factor: relative risk = 1 .O implies no importance whatsoever.
I 1 1 1 I 1 I I
o i 2 3 t 5 6 7 e
YEARS both for survival and disease-free survival, differ by
FIG. I . Probability of disease-free survival by location of primary tumor. whether or not there is bowel obstruction. Mantel-Haen-
szel tests performed demonstrated significant disease-free
survival ( P = 0.01) and survival ( P = 0.003) differences.
prognosis. In order to determine prognostic importance These effects are consistent after adjusting for age, sex,
adjusting for Dukes stage, the identified symptoms each and Dukes stage. For illustrative purposes, separate plots
were included in a separate Cox model that included of survival and disease-free survival, for Dukes B2 and C
Dukes stage. The results of the analysis appear in Table patients appear as Figures 5 and 6.
3. Relative risks obtained from the Cox model are included Since bowel obstruction has been shown to be of im-
to indicate the negative or positive effect that each factor portance, it is worthwhile to examine the distribution of
has on the chance of recurrence or ofsuccumbing to death. obstructed patients by treatment and Dukes stage. Pro-
It is apparent that many ofthe primary disease symptoms, portions obstructed range from 12% to 16.4% among
considered individually, are of some importance, even treatments, and were 13.4% for Dukes B2, 12.6% for
when Dukes stage is taken into account. Dukes C, with one to four positive lymph nodes, and
Bowel obstruction is an important prognostic factor
independent of Dukes stage (Figs. 3 and 4). The curves,
LEGEND
NOT OBSTRUCTED
90
OBSTRUCTED
.............................................
l
90 oon

-1
Y;.
.... *- _
.......... -\__ ._- .....:I L
(f
>
U
60
.._
-. ------
...................
......
>
I
r
2
i

301
. . 40

ti
LEGEND
RECTOSIGMOID SIGMOID s
20 RIGHT COLON 20
.................................................................
10

0 :
0
I
1 2
LEFT COLON
I 1
3
YEARS
4
I I
5 6
I I
7
I
8
lo
0 1
0 1 2 3
YEARS
4 5 6 7 8

FIc;. 2. Probability of survival by location of primary tumor. FIG.3. Probability of disease-free survival by bowel obstruction
No. 9 PROGNOSTIC
INDICATORS
OF COLONTUMORS - Steinberg et ul. 1869

LEGEND LEGEND
NOT OBSTRUCTED NOT OBSTRUCTED
OBSTRUCTED
............................................. OBSTRUCTED
.............................................
90

W
w
CK
a 60 -
t
> I
Y W
-c. 0
............ a
............ W
(J-J 40 .............. cn
H
*\ 0
s

10

I I I I 1 I I 1 01 I I I I I I 1 1
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
YEARS YEARS
FIG.4. Probability of survival by bowel obstruction. FIG. 6. Probability of disease-free survival in Dukes C patients by
bowel obstruction.

19.0% for Dukes C2 with five or more positive lymph When analyses were performed to identify any inter-
nodes. It is also of interest to learn whether presence or action between tumor location and obstruction, none
absence of obstruction is associated with site of recurrence could be found. Relative risks computed for the effect of
(Table 4). Proportions obstructed did not differ by site of obstruction on disease-free survival, by means of the
recurrence. If, on the other hand, we consider failure sites Mantel-Haenszel procedure as used in the NSABP study,
as a percentage of total patients, we find that 34% of ob- were 1.64 ( P = 0.14) for left tumors, 1.49 ( P = 0.73) for
structed patients had at least one distant failure site com- right tumors, and 1.74 ( P = 0.06) for those in the recto-
pared with 23% of nonobstructed patients, while 12.5%
of obstructed patients had only local failure compared TABL.E
4. Bowel Obstruction and Effect on Sites
with 9.5% of nonobstructed patients. of Recurrence, by Treatment
Not
Treatment Site of recurrence Obstructed obstructed
Control Local only 3 11
Distant only 5 21
Local and distant 4 I
Any site 12 39
...................
Methyl-CCNU Local only 3 10
+ 5-FU Distant only 6 19
Local and distant 1 11
Any site 10 40
MER Local only 2 16
Distant only 5 28
LEGEND Local and distant 0 2
Any site 7 46
s NOT OBSTRUCTED +

q
30{ MER Methyl- Local only 2 10
OBSTRUCTED
............................................. CCNU 5- + Distant only 5 21
FU Local and distant I 6
Any site 8 37
I
Total Local only 10 (27%) 47 (29%)
0 Distant only 21 (57%) 89 (55%)
0 1 2 3 4 5 6 7 8 Local and distant 6 ( 16%) 25 (16%)
YEARS ~~
All sites 37 (lOO%) 161 (100%)

FIG. 5. Probability of disease-free survival in Dukes R2 patients by 5-FU: 5-fluorouracil; MER: methanol extraction residue of bacillus
bowel obstruction. Calmette-Gutrin.
1870 CANCERMay 1 1986
sigmoid and sigmoid. The values were quite similar for
survival as well. To be certain that the lack of interaction
was not an artifact from the particular grouping, additional
proximal versus distal groupings were constructed, all re-
sulting in similar findings.
Obstruction is not the only primary disease symptom
of major prognostic importance. When a Cox regression
model, including Dukes stage and the other symptoms
with prognostic significance, was examined, bowel per-
foration was quite significant ( P = 0.01), but none of the
other symptoms yielded a parameter different from zero
(all P values between 0.3 and 0.8).
Analyses performed indicated that the prognostic out-
look following perforation is poor, after adjustment for
Dukes stage and obstruction. When abdominal disten-
tion, nausea and vomiting, and rectal bleeding, are in-
cluded in the model along with obstruction, however,
these latter factors are not significant, and the prognostic
significance of obstruction is also reduced. Only when
jointly considered with rectal bleeding does obstruction
remain significant. A clinical association among the
symptoms is a plausible explanation for these observa-
tions. Finally, presence of melena or rectal bleeding, mar-
ginally prolongs survival time ( P = 0.08), even after con-
sidering the effect of Dukes stage.
Discussion
It is clinically important to identify the prognostic fac-
tors in a patient with colon carcinoma. Dukes staging is
accepted as the major fdctor.s Recently, the NSABP re-
ported that tumor location and bowel obstruction are two
important prognostic factors in patients with Dukes B2
and C colorectal carcinoma. Another recent study of pat-
terns of failure in colonic carcinoma conducted at the
Massachusetts General Hospital indicated that nonob-
structed patients had a 28% S-year survival advantage.6
These findings might be considered in the design and
analysis of therapeutic trials in colon cancer.
The GITSG study was unable to confirm the statistical
importance of tumor location within the colon, when lo-
cation was grouped according to left, rectosigmoid, sig-
moid, or right. Neither total survival nor disease-free sur-
vival were statistically affected. Whereas the NSABP re-
ported a 1470 difference at 3 years between disease-free
curves for left versus right colon, the difference shown in
the GITSG data is approximately 2% (Fig. 1).
Bowel obstruction was shown in our study to be an
important prognostic factor independent of Dukes stage.
The NSABP study noted that bowel obstruction in the
right colon was associated with significantly reduced dis-
ease-free survival, whereas left colon obstruction did not
VOl. 57
alter survival. The GITSG data failed to confirm an in-
teraction between location and obstruction.
The GITSG also demonstrated that nausea, vomiting,
and distention were major factors of importance, inde-
pendent of Dukes stage. For each, significance is ap-
proximately equal to that of bowel obstruction, but each
adds little prognostic information when considered jointly
with obstruction. Since nausea, distention, and later,
vomiting are caused by obstruction, these symptoms add
nothing to the prognostic information if obstruction is
known to be present.
In the GITSG experience, nearly one-third of patients
identified as obstructed received primary diverting colos-
tomies (consistent with NSABP data). How patients with
partial obstruction in our series (and in the NSABP stud-
ies) were stratified into obstructed and nonobstructed
groups is uncertain since partial obstructions were not
separately identified.
Bowel perforation was shown to have substantial prog-
nostic ability, far outweighing obstruction in terms of pre-
dicting disease-free survival. The main factor limiting its
impact on a large study is that only 14 of 572 (2.5%) study
patients presented with perforation. This is far fewer than
any of the other symptoms, and so rare as to be of limited
use as a prognostic variable. This finding raises the ques-
tion as to whether patients with perforations should be
excluded from future studies, as 57% (8 of 14) obstructed
compared with 34% (190 of 558) of all others had recur-
rences.
Finally, by confirming its prognostic effect, one of the
primary disease symptoms has been provided with ad-
ditional support as an important method of cancer de-
tection. Rectal bleeding or melena is associated with longer
survival, but has little effect on stage-adjusted disease-free
survival. One could speculate that the noted effect might
be the result of earlier diagnosis.
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