Sphincter Preservation with

Chemoradiation in Anal
Canal Carcinoma
Abdominoperineal Resection in Selected Cases?
Gerhard G. Grabenbauer, M.D.,* Klaus E. Matzel, M.D.,t
Ignaz H. F. Schneider, M.D.,-~ Martin Meyer, Ph.D.,~: Christian Wittekind, M.D.,]
Birgit Matsche, M.D.,~ Werner Hohenberger, M.D.,t Rolf Sauer, M.D.*
From the Departments of *Radiation Oncology, tSurgery, ~Biostatistics~ and ~Pathology, University Hospitals
of Erlangen-Narnberg, Erlangen, Germany

PURPOSE: This study contained herein assessed long-term
results, toxicity, and prognostic variables following com-
bined morality therapy of patients with International Union
Against Cancer Classification T1-4, NO-3, M0 squamous~ell
carcinoma of the anal canal. PATIENTS AND METHODS:
Between 1985 and 1996, 62 patients completed treatment
with combined modality therapy. A median total dose of 50
Gy was given to the primary, perirectal, presacral, and
inguinal nodes followed by a local boost in selected cases.
5-Fluorouracil was scheduled as a continuous infusion of
1,000 mg/m 2 per 24 hours on days 1 to 5 and 29 to 33 and
mitomycin C as a bolus of 10 mg/m 2 on days 1 and 29.
Routinely processed paraffmmmbedded sections were
stained using monoclonal antibodies for detection of prolif-
erating cell nuclear antigen and MIB1 (Ki-67) antigen to
determine the labeling index. In addition, DNA ploidy was
assessed after Feulgen staining. RESULTS: Actuarial cancer-
related survival, no evidence of disease survival, and colos-
tomy-free survival rates at five years were 81, 76, and 86
percent, respectively. In univariate analysis, T category
(T1/2 vs. T3/4) was predictive for no evidence of disease
survival (87 vs. 59 percent; P = 0.03) and colostomy-free
survival (94 vs. 73 percent; P = 0.05). N category (NO vs.
N1-3) influenced actuarial cancer-related survival (85 vs. 58
percent; P = 0.002) and no evidence of disease survival (80
vs. 53 percent; P = 0.02). A higher proliferative potential as
measured by the MIB1 labeling index was associated with a
better colostomy-free survival (90 vs. 50 percent; P = 0.04).
In multivariate analysis, actuarial cancer-related survival was
only influenced by the N category (P = 0.03) and no
evidence of disease survival by N category (P = 0.03) and
mitomycin C dose (P = 0.04). Salvage abdominoperineal
resection achieved long-term control in only four of seven
patients with local failures. CONCLUSION: Treatment with
a combination of radiotherapy and chemotherapy is s'fie
and effective for patients with anal canal carcinoma. Ab-
dominoperineal resection is indicated as a salvage proce-
dure in nonresponding and recurrent lesions and may be of
Supported by a grant from the Wilhelm Sander Foundation
(Nr. 94.061.1).
Presented at the European Cancer Conference (ECCO9), Hamburg,
Germany, September 14 to 18, 1997.
Address reprint requests to Dr. Grabenbauer: Department of Radi-
ation Oncology, UniversiD, Hospital, Universit~itsstrafge27, D-91054
Erlangen, Germany.
441
benefit ha a small subgroup of patients with poor prognostic
factors. [Key words: Anal canal cancer; Combination ther-
apy; Radiation; Chemotherapy; MIBI; Ploidy; Prognostic
factors]
Grabenbauer GG, Matzel KE, Schneider IHF, Meyer M,
Wittekind C, Matsche B, Hohenberger W, Saner R. Sphinc-
ter preservation with chemoradiation in anal canal carci-
noma: abdominoperineal resection in selected cases? Dis
Colon Rectum 1998;41:441-450.
h e p o t e n t i a l curative effects o f r a d i a t i o n ther-
T a p y 1-7 a l o n e o r r a d i o c h e m o t h e r a p y 8-2° in the
p r e s e r v a t i o n o f anal f u n c t i o n has b e e n w e l l estab-
l i s h e d in s q u a m o u s - c e l l c a r c i n o m a o f the anal canal.
T h e a b d o m i n o p e r i n e a l r e s e c t i o n (APR) is r e s e r v e d for
patients w i t h r e s i d u a l o r r e c u r r e n t c a r c i n o m a .
B e c a u s e s q u a m o u s - c e l l c a r c i n o m a o f the a n a l c a n a l
is relatively rare, it is difficult to a s s e m b l e a larger
series o f p a t i e n t s t r e a t e d b y a single institution so
survival rates, c o l o s t o m y - f r e e survival rates, p a t t e r n s
o f failure, p r o g n o s t i c variables, a c u t e a n d late treat-
m e n t - r e l a t e d toxicity, a n d p o t e n t i a l s a l v a g e p r o c e -
d u r e s c a n b e e v a l u a t e d . This article p r e s e n t s results
after t r e a t m e n t in o n e c e n t e r of 62 patients w i t h car-
c i n o m a o f the anal canal.
MATERIALS AND METHODS
B e t w e e n J a n u a r y 1985 a n d M a y 1996, 65 patients
u n d e r w e n t radical t r e a t m e n t b y c o m b i n e d r a d i a t i o n
a n d c h e m o t h e r a p y (RCT). E x c l u d e d from survival
analysis w e r e t h r e e p a t i e n t s w i t h a c u t e G r a d e 5 tox-
icities. Patient's age, g e n d e r , a n d histologic t y p e o f
t u m o r a r e s h o w n in T a b l e 1. B e f o r e treatment, all
p a t i e n t s h a d clinical e x a m i n a t i o n s i n c l u d i n g s i g m o i d -
o s c o p y a n d b i o p s y . Chest x-ray, l a b o r a t o r y tests, a b -
d o m i n a l u l t r a s o u n d , a n d c o m p u t e d t o m o g r a p h i c (CT)
s c a n s o f t h e a b d o m e n a n d pelvis w e r e p e r f o r m e d
442 GRABENBAUER ETAL Dis Colon Rectum, April 1998

Table 1. an additional boost of external RT and 13 (21 percent)

Patient Characteristics patients by interstitial brachytherapy (BT) with iridi-
No. of patients 62 um-192 low-dose rate. Median time interval between
Median age (range) 62 (26-74) years end of" external RT and BT was 57 days. Indication for
Gender: male/female (%) 9/53 (15/85) the application of BT was either a clinically slow
Histology (WHO 1990) Patients (%) responding tumor or a near total regression in the
Squamous-cell carcinoma (8070/3) 62 (100) biopsy specimen after eight weeks. Table 1 gives the
Large cell, keratinizing (8071/3) 32 (52) dosage of external RT and BT.
Large cell, nonkeratinizing (8072/3) 15 (24)
Basaloid carcinoma (8123/3) 15 (24)
T1/2 35 (56) Chemotherapy
]3/4 26 (42) Sixty-two patients received concomitant chemo-
TO 1 (2)
therapy. 5-Fluorouracil (5-FU) was scheduled as a
NO 53 (86)
N1-3 9 (14) continuous intravenous infusion for 120 hours (1,000
G1 5(8) rag/m2/24 hours) to a maximum of 1,800 mg/24 hours
G2 28 (45) on days 1 to 5 and 29 to 33. Mitomycin C (MMC) was
G3 28 (45) administered on days 1 and 29 as a single bolus
G4 0 intravenous injection with a dosage of 10 mg/m 2. The
GX 1 (2)
External RT second course of chemotherapy was adjusted accord-
<45 Gy 5 (8) ing to the extent of treatment-related hematologic
46-55 Gy 48 (78) toxicity. A summary of the dosage of 5-FU and MMC
5 6 - 6 6 Gy 9 (14) is given in Table 1. Chemotherapy toxicity was graded
Ir- 192 low-dose rate 13 (21) according to the National Cancer Institute's toxicity-
12-15 Gy 9 (15)
criteria, and RT toxicity was graded according to the
16-22 Gy 4 (6)
Radiation Therapy Oncology Group (RTOG) toxicity
WHO = World Health Organization; RT = radiother-
apy; Ir-192 = iridium-192.
criteria. 22

routinely. On the basis of these findings, tumor stages Immunohistochemistry

were assigned according to the International Union
Against Cancer system of 1992. 21 Data on cancers
treated between 1985 and 1987 were revised to con-
form with these criteria. T and N categories are listed
in Table 1.
Radiotherapy
The primary tumor region including perirectal, in-
ternal lilac, and inguinal lymph nodes was irradiated
using parallel o p p o s e d anteroposterio>posteroante-
rior fields in the eariy years of the study (1985-1988)
and later using a 3-field or 4-field box technique.
External radiation therapy (RT) was delivered with
megavoltage equipment (6-10 MV photons) and sin-
gle fractions between 1.8 and 2 (median, 1.9) Gy in an
uninterrupted course up to a median total dose of 50
Gy. Median treatment time was 38 days. The radiation
dose was specified to the isocenter using multiple
field techniques or to the mid plane for parallel op-
posed fields. Otherwise specified doses were retro-
spectively assigned to the reference point according
to the International Commission on Radiological Units
50 guidelines. Eighteen (28 percent) patients received
Routinely processed hematoxylin and eosin-stained
biopsy specimens were classified and graded accord-
ing to World Health Organization criteria. 23 Serial
sections of 4/~m were mounted, dewaxed, and rehy-
drated. Microwave treatment was applied three times
for five minutes in a 10-ram citrate buffer at 750 W.
When performing immunohistochemistry, tissue sec-
tions were incubated overnight with the primary an-
tibodies MIB1 (1:30; Dianova, Hamburg, Germany)
and PC10 (1:100; DAKO Diagnostika GmbH, Ham-
burg, Germany) to demonstrate the antigens Ki-67
and proliferating ceil nuclear antigen (PCNA).
Binding sites of the primary antibodies were de-
tected by use of the alkaline phosphate-anti-alkaline
phosphatase method. Sections were incubated with
the second rabbit anti-mouse antibody (1:10; 30 min-
utes) and, subsequently, with the alkaline phosphate-
anti-alkaline phosphatase complex (both from DAKO
Diagnostika GmbH) at a dilution of 1:50 for 30 min-
utes. These two steps were repeated twice for 10
minutes. Naphthol As-tVLx-phosphate in 0.1 M Tris-
HCl buffer, pH 8.2, containing 0.24 mg/ml 1 M levami-
sole and 10 mg of Fast Red TR (Sigma Chemie GmbH,
Vol. 41, No. 4 PREDICTIVE VALUE OF PCNA AND MIB1 443

Deisenhofen, Germany), was used as the alkaline
phosphatase substrate for 20 minutes. Finally, the
sections were counterstained with hematoxylin for 30
seconds and mounted in Aquatex (Merck KGaA,
Darmstadt, Germany).
Only tumor cells showing distinct nuclear staining
were counted in four to five different areas of the
specimen containing approximately 1,000 ceils. The
mean percentage of positively stained nuclei was de-
termined and given as the labeling index (LI). Table 2
gives the distribution of PCNA and MIB1 LI.
For the cytometric DNA analysis, two sections, 4
/xm thick, were cut from the paraffin-embedded tu-
mor tissues. The first section was hematoxTlin and
eosin-stained, and the second was stained according
to the Feulgen method. DNA measurements were
performed directly on the slides by means of a den-
sitometric devise (Ahrens Image System, Bargteheide/
Hamburg, Germany). Seventy to 100 nuclei per spec-
imen were analyzed, and lymphocytes and/or
granulocytes were used as the standard to establish
the normal diploid 2c value. An u p p e r limit of 2.5c
was set for diploid values. The percentage of tumor
cells greater than the 2.5c limit was taken as the
measure of nondiploidy. Table 2 gives the ploidy
pattern of patients in w h o m paraffin-embedded ma-
terial was available.
biopsies were taken with the patient receiving general
anesthesia. Minimal residual disease (up to 3 foci of
less than i mm) was first treated by interstitial BT and
reassessed after six to eight weeks. All patients with
gross residual or recurrent tumor underwent APR.
Histologically verified lesions in the anal canal were
counted as local disease and positive perirectal, iliac,
or inguinal nodes as regional disease. After negative
biopsies, patients were followed-up at three-month
intervals for two years from treatment and at six-
month intervals thereafter. Median follow-up was 52
(range, 1-125) months. No patients were lost to fol-
low-up. All events before March 1997 were included
in the analysis. For calculating survival rates, only
cancer-related deaths were counted (adjusted survival
rate). Rates of survival, no evidence of disease (NED)
survival, colostomy-free survival rates, and time to
colostomy were determined according to the Kaplan-
Meier method. 24 Differences between patient groups
were assessed by the log-rank test. In case of a con-
tinuous variable (dose, age, treatment time), median
values were chosen as cut-off points. Multivariate
analysis was performed according to the Cox regres-
sion model. 25 The following variables were included
in the analysis: total dose of MMC (continuous vari-
ables), T category (T1/2 v s . T3/4, and N category (NO
v s . N1-3), as the categoric variable.

Follow-Up Assessment RESULTS

Two months after completion of therapy all pa- Actuarial survival (OS), NED survival, and colosto-
tients were reassessed by digital examination, sig- my-free survival rates were 81 +_ 6 percent (Fig. 1),
moidoscopy, and CT scans of the pelvis. In case of 76 + 6 percent, and 86 + 5 percent at five years, Ten
residual mass or suspicious ulcers, multiple (at least 5) (16 percent) patients died of anal cancer and 9 (15
percent) of intercurrent disease. OS and NED survival
rates for patients with T1/2 tumors were 89 -+ 6 and
Table 2.
Proliferation Parameter and Ploidy 87 + 6 percent compared with 70 +_ 10 and 59 ± 11
percent in patients with T3/4 tumors (P = 0.09 and
No. of Patients (%)
Labeling Index 0.03; Fig. 2). Significant prognostic factors for all three
PCNA MIB1 end points are shown in Table 3. N category (NO v s .
<10% 2 (3) 8 (13) N1-3) influenced OS (85 ± 6 v s . 58 ± 19 percent; P =
10-40% 6 (10) 8 (13) 0.002; Fig. 3) and NED survival (80 ± 6 v s . 53 ± 17
41-70% 8 (13) 5 (8) percent; P = 0.02) significantly. The total dose of
>70% 12 (19) 8 (13) MMC was found to be of importance for NED survival
NA 34 (55) 33 (53)
(P = 0.04) in a univariate Cox regression analysis.
Ploidy
Diploid 2 (3) Neither the total dose of external RT nor the treatment
Aneuptoid 24 (39) time had an impact on survival rates.
(Hyper) tetraploid 3(6)
NA 33 (53)
Primary and Regional Tumor Control
PCNA = proliferating cell nuclear antigen; MIB1 =
antibody for detection of Ki-67 antigen; NA = not avail- Two months after completion of therapy, 60 of 62 (97
able. percent) patients had a clinically complete remission,
444 GRABENBAUER E T A L Dis Colon Rectum, April 1998

1.0

81%

62 47 39 29 18

u~ 0.0
o 2o 4o 60 80
Months
Figure 1. Cause specific survival rate for 62 patients.

1.0
NO 85%
I

N 1-3 58 %

p 53 36 p=O.O02
= 9 4
¢n 0.0
0 20 40 60 80
Months
Figure 2. Cause specific survival rate according to N category.

and 2 (3 percent) had a pallial remission. Forty-four Patterns of Failure

patients had biopsies, either performed as local exci-
Thirteen (21 percent) of 62 patients experienced a
sions or multiple needle biopsies. A histologically
tumor recurrence during follow-up. In four cases,
proven total tumor regression was noted in 42 (95 per-
there was an isolated local failure; only two patients
cent) patients and incomplete regression in 2 (5 percent)
had regional failures. Locoregional recurrences were
patients. Significant prognostic factors for the colosto-
noted after a time interval of between 2 and 25 (me-
my-free survival rate are shown in Table 3. Patients with
dian, 8) months. Nine (15 percent) patients experi-
smaller lesions up to a maximum diameter of 5 cm
enced distant metastases between 3 and 34 raonths
(T1/2) had a colostomy-free survival rate of 94 + 4
after completion of therapy. Patterns of failure are
percent compared with patients with larger tumors (T3/
shown in detail in Table 4.
4), in whom a survival rate of 73 -+ 9 percent was
achieved (P = 0.05). A higher proliferative potential as
measured by the MIB1 LI was associated with a better
Salvage Colostomy a n d
colostomy-free survival (MIB1 LI < 10 percent: 50 - 18 Sphincter P r e s e r v a t i o n
vs. 90 + 7 percent for LI ~ 10 percent; P = 0.04). A major objective of the conservative treatment of
Variables with no influence on colostomy-free survival anal carcinoma is the preservation of anorectal func-
were ploidy (diploid vs. aneuptoid), gender, histology, tion. In this trial, the actuarial colostomy rate was
age, grading, total dose of 5-FU and MlVlC, treatment 14 _+ 5 percent. In univariate analysis, patients with
time, and total radiation dose. larger primaries (T3/4) had a colostomy rate of 33
Vol. 41, No. 4 PREDICTIVE VALUE OF PCNA AND MIB1 445

Table 3.
Significant Prognostic Factors for Cause-Specific Survival, NED Survival, and Colostomy-Free Survival at Five Years
(Univariate Analysis)

Specific Survival (%) NED Survival (%) Colostomy-Free

Survival (%)
All patients 81 _+ 6 76 _+ 6 86 _+ 5
T category
T1/2 89 + 6 87 _+ 6 94 +_ 4
T3/4 70 _+ 10 (P = 0.09) 59 + 11 (P = 0.03) 73 _+ 9 (P = 0.05)
N category
NO 85 -+ 6 80 _+ 6 87 _+ 4
N1-3 58 __+19 (P = 0.002) 53 _+ 17 (P = 0.02) 77 _+ 13 (P = 0.4)
PCNA LI
0-40% 45 _+ 19 60 _+ 18
>40% NS 78 + 9 (P = 0.1) 83 +_ 9 (P = 0.2)
MIB1 LI
<10% 50 _+ 18 50 _+ 18
->10% NS 73 + 10 (P = 0.3) 90 _+ 7 (P -- 0.04)
NS = not significant; LI = labeling index; PCNA = proliferating cell nuclear antigen; MIB1 = antibody for detection
of Ki-67 antigen; NED = no evidence of disease.

1,0 [ ~ . .
i Tll2 87 %

T3/4 59%
I

p=O.03

.>
P
35 22 11
12 8
z 0.0 26
I,U

0 20 40 60 80
Months
Figure 3. No evidence of disease (NED) survival rate according to T category.

Table 4. MIB1 LI of less than 10 p e r c e n t (Fig. 5). By contrast,

Patterns of Failure (n = 13/62) tumors of higher proliferation rates w e r e associated
Patients (%) with a l o w e r c o l o s t o m y rate of 10 p e r c e n t
Local alone* 4 (6) ( P = 0.04).
Local, distant* 2 (3) APR was performed in 8 of 62 (13 percent) patients
Local, regional, distant 1 (2)
(in 7 patients after locally recurrent or persisting tu-
Regional, distant 1 (2)
Distant alone 5 (8) mors and in 1 patient on the decision of the attending
APR 8 (12) surgeon). A p e r m a n e n t long-term local control was
Dead of disease 10 (16) achieved in 4 patients having APR for persisting
APR = abdominoperineal resection. (n = 2) or recurrent (n = 2) disease. However, three
* Including two patients with locally persisting disease
patients experienced a second failure, despite salvage
at two months.
APR.
In addition, four patients w e r e scored as being
percent c o m p a r e d with 6 percent for smaller lesions partially incontinent, mainly b e c a u s e of sphincter-
(Fig. 4). A small subgroup of patients with a colos- infiltrating tumors or local excisions either before
t o m y rate as high as 70 percent was identified b y a or following RCT. Thus, a functioning anorectal
446 GRABENBAUERETAL Dis Colon Rectum, April 1998

1,0
26 12 7
35 22 17

p=0.05

T 3/4 33 %
,,I
~._. T 112 6%
m~ml.m=

~0.0
0 20 40 60 80
Months
Figure 4. Time to colostomy according to T category.
ii
1.0
8 4 p=0.04
21 14

MIB1 <t0 % 70 %

t~
n,, 1
E
,9,
°
o¢0
r- MIB1 >=10 % 10 o/,
0
o 0.0
0 20 40 60 80
Months
Figure 5. Time to colostomy according to MIB1 labeling index.

Table 5.
Acute and Late Treatment-Related Toxicity Among 65 Patients Following Radiochemotherapy of
Anal Canal Carcinoma
Grade Dermatitis (%) Diarrhea (%) Anemia (%) Leucopenia (%) Thrombocytopenia (%) Late Toxicity (%)
0 5 (8) 6 (9) 47 (72) t3 (20) 46 (70) 41 (66)
1 7(11) 8(12) 12(19) 12(19) 11 (17) 4(6)
2 22 (34) 23 (35) 6 (9) 23 (35) 4 (6) 14 (23)
3 31 (47) 26 (40) 0 15 (23) 2 (3) 1 (2)
4 0 1 (2) 0 1 (2) 1 (2) 2 (3)
5 0 1 (2) 0 1 (2) 1 (2) 0
National Cancer Institute/Radiation Therapy Oncology Group criteria.

sphincter was preserved in 50 of 62 patients (81
percent) and in 50 of 55 patients (91 percent) in
whom the primary tumor was permanently con-
trolled by RCT.
Toxicity
The various levels of acute and late toxicity are
shown in Table 5. Severe hematologic toxicity (Grade
3/4) occurred in 17 patients (26 percent). Forty-seven
percent and 42 percent of patients experienced a
dermatitis and enteritis Grade 3/4, respectively. Note-
worthy is one episode of coronary vasospasm in a
44-year-old female patient, probably associated with
continuous 5-FU infusion. Three patients died of
treatment-related complications. An 82-yea>old man
refused further treatment after ten days (16 Gy, 1
Vol. 41, No. 4 PREDICTIVE VALUE OF PCNA AND MIB1
course of chemotherapy), developed severe enteritis,
and died of dehydration and acidosis. A 46-year-old
man died of P s e u d o m o n a s and C a n d i d a septicemia
owing to excessive hematologic toxicity. One month
after completion of therapy, a 63-year-old lady died of
C a n d i d a septicemia, possibly secondary to a Hick-
man catheter infection. All fatal toxicities were ob-
served during the first three years of the trial.
Only 3 of 62 patients (5 percent) had late sequelae
of Grade 3/4: one case of rectovaginat fistula after
total regression of a T4 tumor, one patient with a skin
ulceration in the groin area and coexisting sarcoid-
osis, and one patient with small-bowel obstructions
after 50 Gy to the pelvis and salvage APR.
Multivariate Analysis
The only independent and significantly related fac-
tor for survival was the N category ( P = 0.01). A
significant impact on NED survival was noted for the
N category ( P = 0.03) and the total MMC dose
( P = 0.04). With only eight events, no multivariate
analysis was performed for the end point colostomy-
free survival. The final Cox model is given in Table 6.
DISCUSSION
Our results of 62 patients compare favorably with
the literature data on survival, NED survival, and
colostomy-free survival rates at 81, 76, and 86 percent,
respectively. Anal sphincter function was preserved in
50 of 55 (91 percent) patients in w h o m the local tumor
was permanently controlled by RCT. Noteworthy is
the fact that in other series using a moderate total
dose of 45 to 50 Gy with concomitant chemotherapy,
sphincter preservation rate was as high as 70 to 80
percent~, 18, ~9, 2< 27 in comparison with the results
following RT alone, >< 28, 29 for which colostomy-free
Table 6.
Multivariate Analysis on Prognostic Factors for Cancer-
Related Survival and NED Survival (Final Model)
Cancer-related survival
Variable /3 Exp (/3) 95% CI
T category -0.2673 0.7654 0.3622-1.6078
N category -0.9276 0.3995 0.1935-0.8085
MMC dose -0.0920 0.9121 0.8061-1.0320
NED survival
T category 0.9595 2.6105 0.3359-1.1404
N category 1.4215 4.1432 0.2545-0.9482
MMC dose -0.1102 0.8956 0.8079-0.9930
NED = no evidence of disease; MMC = mitomycin C;
Ct = confidence interval.
447
survival rates were 20 to 30 percent lower. External
RT alone or in combination with interstitial BT proved
to be very effective for small lesions of smaller than 4
cm in diameter; local tumor control and sphincter
preservation rates between 76 and 91 percent were
reported.3, 26, 3o For adequate local control of larger
primaries, however, relatively high total doses be-
tween 60 and 65 Gy had to be applied. 3-6 Conse-
quently, late treatment-related toxicity was noted
more frequently, requiring APR for control of distress-
ing symptoms. In a series reported by Touboul e t a l . , 6
the anal conservation rate was 59 percent for T3 and
55 percent for T4 tumors. After 65 to 70 Gy to the anal
region, a colostomy-free survival without major tox-
icity of only 30 to 40 percent can be expected accord-
ing to the recent European Organisation for Research
and Treatment of Cancer Radiotherapy and Gastroin-
testinal Cooperative Groups (EORTC) experience. 28
Two randomized studies have n o w provided data
concerning the issue of whether RCT is superior to RT
alone. In the United Kingdom Co-ordinating Commit-
tee on Cancer Research trial, the main end point was
the local failure rate. After 45 Gy with 5-FU/MMC, 101
of 283 (36 percent) patients had a local failure com-
pared with 164 of 279 (59 percem) in the RT-alone
arm (P < 0.0001). In the EORTC trial, both locore-
gional tumor control and colostomy-free survival rates
increased significantly by 18 and 32 percent at five
years in the concomitant arm, respectively. 28
In an RTOG/Intergroup study, the value of MMC in
addition to 5-FU as part of the concomitant chemo-
therapy was investigated. II As has been pointed out
earlier in a retrospective series by Cummings et al., 9
colostomy-free survival rates were significantly im-
proved by the additional use of MMC (71 vs. 59 per-
cent). With a moderate total dose of 45 to 50 Gy, a
lower colostomy rate was pai~icularly seen in RTOG
T3/4 stages within the treatment arm using MMC. The
advantage of adding MMC to 5-FU is underlined by
the series reported here, with total dose of MMC being
a significant factor for NED survival in the multivariate
analysis.
P In surgical series, histopathologically confirmed in-
0.48 volvement of perirectal, superior hemorrhoidal, pel-
0.01 vic, or inguinal node groups was associated with
0.14 five-year survival rates of approximately- 50 percent,
being 25 percent worse than those of patients without
0.12
0.03 nodal involvement. 3~44 The presence of regional
0.04 lymph node metastases did not correlate with tumor
control in patients managed with RT or RCT protocols
in the early series. 1°' 26, 35 However, we found a strik-
448 GRABENBAUER ETAZ
ing difference in OS and NED survival for patients
without regional metastases being 85 and 80 percent
vs. 58 and 53 percent for patients with positive re-
gional nodes (P = 0.002 and 0.02). It appears that the
application of routine CT scanning of the pelvis for
staging purposes may have detected enlarged nodes
more accurately. Recently, Myerson e t al. 16 reported a
low disease-free survival of 52 percent for T1-3, N1-3
patients compared with that of patients in T1-3,N0
stages, which was as high as 88 percent at ten years
( P = 0.03). This finding is underlined by the indepen-
dent prognostic value of the N category with respect
to OS and NED survival demonstrated in our series.
No data in the literature exists on patients treated
by RT and/or RCT concerning the prognostic value of
tumor DNA content. In one large surgical series of
flow cytometric DNA analysis of paraffin-embedded
tissue, ploidy was found to be strongly predictive for
outcome, patients with diploid tumors having a five-
year survival of 75 percent compared with 55 percent
for patients with aneuploid tumors. 34 However, Gold-
man e t al. 36 could not find any influence of nuclear
DNA content on prognosis. Our investigation identi-
fied the majority of tumor specimens as being aneu-
ploid, only a few- as tetraploid or diploid. Conse-
quently, a statistical evaluation of the predictive or
prognostic value of ploidy did not seem very mean-
ingful.
There are only a few reports concerning the prog-
nostic significance of the expression of proliferation-
associated antigens in squamous-cell carcinoma. After
surgical resection of oral cancer, survival rates of 20 to
28 percent at five years for tumors with a high prolif-
erative index compared with 86 to 92 percent for
patients having low PCNA tumor labeling indexes
( P < 0.001) were r e p o r t e d Y Similar results were
demonstrated after laser resection of early- glottic can-
cer with respect to local tumor control. Patients with a
high proportion of proliferating tumor cells ( > 15 per-
cent MIB1 LI) experienced local failure rates in the
range of 80 percent, whereas the failure rate of pa-
tients with tumors having a low proliferative potential
(-<15 percent ~flB1 LI) was only 20 percent. 3s
The prognostic value of proliferation-associated an-
tigens following RT of squamous-cell carcinoma is
well known but has not been demonstrated for anal
cancer so far. Among 40 patients with oral cancer
treated by preoperative RT, 20 tumors responding
with a histopathologically confirmed complete remis-
sion had a median PCNA LI of 86 percent compared
with 20 patients with no response having a median LI
Dis Colon Rectum, April 1998
of 23 percent. 39 Similar findings were seen in patients
with T1 carcinoma of the glottis. 4°
In our series, a weak expression of proliferation
antigen MIB1 (<10 percent) was associated with a
relatively high colostomy rate of 50 percent compared
with 10 percent for patients with tumors of higher
proliferative potential ( P = 0.04). It should be noted,
however, that this retrospective analysis was only
limited to a subgroup of patients because paraffin-
e m b e d d e d material was not available in all cases. In
addition, colostomy rates in this trial were influenced
by the T category with a colostomy rate of 32 percent
in patients with T3/4 tumors compared with 5 percent
in patients with T1/2 tumors ( P = 0.04). In a similar
attempt to identify patients being at high risk for local
failure after conservative treatment, Touboul e t al. 6
showed a trend toward better survival (42 vs. 40
percent) and local tumor control (82 vs. 60 percent)
for a subgroup of T4 tumors that were submitted to
early APR shortly after RT. In our series, of seven
patients with locally persisting or recurrent tumors,
only four were locally cured by radical surgery,
whereas three had recurrences despite salvage APR. It
may be argued that an earlier surgical intervention
would have been of further benefit.
CONCLUSION
Results from the current study strongly suggest that
with respect to certain prognostic factors, probably a
small subgroup of patients exists demonstrating a
very high risk of local failure. It seems, therefore,
desirable to submit these patients to early APR or at
least to apply a shorter follow-up interval.
REFERENCES
1. Mlal A, Kurtz JM, Pipard G, et aL Radiochemotherapy
versus radiotherapy alone for anal cancer: a retrospec-
tive comparison. Int J Radiat Oncol Biol Phys 1993;27:
59-66.
2. Cantril ST, Green JP, Schall GL, Schaupp WC. Primary
radiation therapy in the treatment of anal carcinoma. Int
J Radiat Oncol Biol Phys 1983;9:1271-8.
3. Eschwege F, Laser P, Cha~eT A, Wibautt P, KacJ, Rougier
Ph. Squamous cell carcinoma of the anal canal: treat-
ment by external beam irradiation. Radiother Oncol
1985;3:145-50.
4. Schlienger M, Krzish C, Pene F, et al. Epidermoid car-
cinoma of the anal canal: treatment results and prog-
nostic variables in a series of 242 cases. Int J Radiat
Oncol Biol Phys 1989;17:1141-51.
5. ToubouI E, Schlienger M, Buffat L, et al. Epidermoid
carcinoma of the anal canal. Cancer 1994;73:1569-79.
Vol. 41, No. 4 PREDICTIVE VALUE OF PCNA AND MIB1
6. Touboul E, Schlienger M, Buffat L, et al. Conservative
versus nonconservative treatment of epidermoid carci-
noma of the anal canal for tumors longer than or equal
to 5 centimeters. Cancer 1995;75:786-93.
7. Wagner JP, Mahe MA, Romestaing P, et al. Radiation
therapy in the conservative treatment of carcinoma of
the anal canal. Int J Radiat Oncol Biol Phys 1994;29:
17-23.
8. Cummings BJ. Anal cancer. IntJ Radiat Oncot Biol Phys
1990;19:1309-15.
9. Cummings BJ, Keane TJ, O'Sullivan B, Wong, CS, Cat-
ton CN. Epidermoid canal cancer: treatment by radia-
tion alone or by radiation and 5-fluorouracil with and
without mitomycin C. Int J Radiat Oncol Biol Phys
1991;21:1115-25.
10. Cummings BJ. Anal canal carcinoma. In: Hermanek P,
Gospodarowicz MK, Henson DE, Hutter RV, Sobin LH,
eds. Prognostic factors in cancer. Berlin: Springe>
Verlag, 1995:81-7.
11. Flam MS, John M, Pajak T, et al. Role of mitomycin in
combination with fluorouracil and radiotherapy, and of
salvage chemoradiation in the definitive nonsurgical
treatment of epidermoid carcinoma of the anal canal:
results of a phase III randomized intergroup study.
J Clin Oncol 1996;14:2527-39.
12. Grabenbauer GG, Schneider IH, Gall F, Sauer R. Epi-
dermoid carcinoma of the anal canal: treatment by com-
bined radiation and chemotherapy. Radiother Oncot
1993;27:59-62.
13. Grabenbauer GG, Panzer M, H/.iltenschmidt B, et al.
Prognostische Faktoren nach simultaner Radiochemo-
therapie des Analkanalkarzinoms in einer multizen-
trischen Serie yon 139 Patienten. Swahlenther Onkol
1994;170:391-9.
14. Schneider IH, Grabenbauer GG, Reck T, K6ckerling F,
Saner R, Gall FP. Combined radiation and chemother-
apy for epidermoid carcinoma of the anal canal. Int J
ColorectaI Dis 1992;7:192-6.
15. Martenson JA, Lipsitz SR, Lefkopoulou M, et al. Results
of combined modality therapy for patients with anal
cancer. Cancer 1995;76:1731-6.
16. Myerson RJ, Shapiro SJ, Lacey D, et al. Carcinoma of the
anal canal. Am J Clin Oncol 1995;18:32-9.
17. Nigro ND, Vaitkevicius VK, Considine B Jr. Combined
therapy for cancer of the anal canal: a preliminary
report. Dis Colon Rectum 1974;17:354-6,
18. Sischy B. The use of radiation therapy combined with
chemotherapy in the management of squamous cell
carcinoma of the anus. Int J Radiat Oncol Biol Phys
1985;11:1587-93.
19. Sischy B, Doggett RL, Krall JM, et al. Definitive irradia-
tion and chemotherapy for radiosensitisation in man-
agement of anal carcinoma: interim report on RTOG
study no. 8314. J Natl Cancer Inst 1989;81:850-6.
20. UKCCCR Anal Canal Cancer Trial Working Party. Epi-
449
dermoid anat cancer: results from the UKCCCR random-
ised trial of radiotherapy alone versus radiotherapy,
5-fluorouracil, and mitomycin, Lancet 1996;348:
1049-54.
21. Hermanek P, Sobin LH, eds. UICC TNM classification
of malignant tumors. 4th ed (2nd revision). Berlin:
Springer-Verlag, 1992.
22. John MJ. Grading of chemoradiation toxicity. In: John
MJ, Flare MS, Legha SS, et al., eds. Chemoradiation: an
integrated approach to cancer treatment. Philadelphia:
Lea & Fiebiger, 1993:601-6.
23. WItO. International classification of diseases for oncol-
ogy~ 2nd ed. Geneva, 1990.
24. Kaplan EL, Meier P. Nonparametric estimation from
incomplete observations. J Am Stat Assoc 1958;53:
457-81.
25. Cox DR. Regression models and life tableas. J R Stat Soc
1972;B34:187-202.
26. Papillon J, Montbaron JF, Gerard JP, Chassard JL, Ardiet
JM, Touraine-Romestaing P. Role of combined radiation
and chemotherapy: the Lyon experience. In: Sauer R,
ed. Interventional radiation therapy. Berlin: Springer-
Vertag, 1991.
27. Pipard, G. Combined therapy of anal canal cancer: a
report on external irradiation with or without chemo-
therapy followed by interstitial Ir-192. In: Saner R, ed.
Interventional radiation therapy. Berlin: Springer-
Verlag, 1991.
28. Bartelink H, Roelofsen F, Eschwege F, et al. Concomi-
tant radiotherapy and chemotherapy is superior to ra-
diotherapy alone in the treatment of locally advanced
anal cancer: results of a phase III-randomized trial of
the European Organisation for Research and Treatment
of Cancer Radiotherapy and Gastrointestinal Coopera-
tive Groups. J Clin Oncol 1997;15:2040-9.
29. Ng YK, Pigneux J, Auvray H, Brunet R, Thomas L,
Denepoux R. Our experience of conservative treatment
of anal canal carcinoma combining external irradia-
tion and interstitial implant: 32 cases treated b e t w e e n
1973 and 1982. Int J Radiat Oncol Biol Phys 1988;14:
253-9.
30. Papillon J, Montbarbon JF. Epidermoid carcinoma of
the anal canal: a series of 276 cases. Dis Colon Rectum
1987;30:324-33.
31. Boman BM, Moertel CG, O'Connel MJ, et al. Carcinoma
of the anal canal--a clinical and pathologic study of 188
cases. Cancer 1984;54:114-25.
32. Frost DB, Richards PC, Montague ED, Giacco GG, Mar-
tin RG. Epidermoid cancer of the anorectum. Cancer
1984;53:1285-93.
33. Pintor MP, Northover JM, Nicolts RJ. Squamous cell
carcinoma of the anus 1948-1984. Br J Surg 1989;76:
806-10.
34. Shephard NA, Scholefield JH, Love SB, England J,
450 GRABENBAUER ETAL Dis Colon Rectum, April 1998

Northover JM. Prognostic factors in anal squamous cell
carcinoma: a multivariate analysis of clinical flow c}~o-
metric and pathologic factors in 235 cases. Histopathol-
ogy 1990;16:545-55.
35. Panzer M, Sutter T, Wendt T, Jauch KW. Radiochemo-
therapie mit und ohne Radikaloperation bei Analkarzi-
nom: GroIghademer Langzeitergebnisse. Tumordiagn
Ther 1993;14:167-74.
36. Goldman S, Svensson C, Bronnergard M, Glimelius B,
Wallin G. Prognostic significance of serum concen-
tration of squamous cell carcinoma antigen in anal
epidermoid carcinoma. Int J Colorectal Dis 1993;8:
98-102.
37. St6rkel S, Reichert T, Reiffen KA, Wagner W. EGFR
and PCNA expression in oral squamous cell carcino-
m a - - a vatuabte toot in estimating the patient prog-
nosis. Eur J Cancer 1993;29B:273-7.
38. Hake R, Echel E, Pritzbuer E, Volling P, Thiele J. Wer-
tigkeit monoklonaler Antik6rper (PC10, MIB1, p53 und
Leu M1) ffflr die Absch~ttzung der Prognose yon Pati-
enten mit Plattenepithelkarzinomen des Larynx nach
Laserresektion. Pathologe 1995;16:197-203.
39. Gtinzl HJ, Horn H, Schnficke R, Donath K. Prognostic
value of PCNA and cytokeratins for radiation therapy of
oral squamous cell carcinoma. Eur J Cancer 1993;29B:
141-5.
40. Munck-WiMand E, Fember J, Kuylenstierna R, Lind-
holm J, Auer G. PCNA expression and nuclear DNA
content in predicting recurrence after radiotherapy of
early glottic cancer. Eur J Cancer 1993;29B:75-9.

XVIIth Biennial Congress

of the
International Society of University
Colon and Rectal Surgeons
Malmo, Sweden
June 7-11, 1998
Website: ~ . k i r . m a s . l u . se/isucrs