Tumor Site Predicts Outcome After
Radiochemotherapy in Squamous-Cell
Carcinoma of the Anal Region:
Long-Term Results of 101 Patients
Gerhard G. Grabenbauer, M.D.,1 Hermann Kessler, M.D.,2 Klaus E. Matzel, M.D.,2
Rolf Sauer, M.D.,1 Werner Hohenberger, M.D.,2 Ignaz H. F. Schneider, M.D.2
1
Department of Radiation Oncology, University Hospital of Erlangen, Erlangen, Germany
2
Department of Surgery, University Hospitals of Erlangen, Erlangen, Germany
PURPOSE: This study was designed to assess the long-term
results following radiochemotherapy in patients with anal
squamous-cell carcinoma and to evaluate the impact of tu-
mor location on response, survival, and colostomy-free sur-
vival. PATIENTS AND METHODS: Between 1985 and 2001,
a total of 101 patients with anal carcinoma were registered
for curative treatment, of whom 77 had involvement of the
anal canal alone, 10 cases had extension into the perianal
skin, and 14 patients had pure anal margin tumors. Small
tumors of the anal margin were not included since they
were treated by surgical excision only. Among the 101 pa-
tients were 74 women and 27 men with a median age of 62
(range, 26–84) years. T categories (International Union
against Cancer) were T1 (15), T2 (36), T3 (34), and T4 (16).
Seventy-one patients had no evidence of nodal disease,
whereas 30 presented with involved regional nodes. Radia-
tion treatment was directed to the primary tumor region
and to the inguinal, perirectal, and internal iliac nodes using
a three-field to four-field box technique with 10MV photons
up to a total dose of 5040 cGy. Lesions greater than 5 cm
received an additional boost by interstitial or external radia-
Supported by Grant No. D 15 from the Interdisciplinary Center
for Clinical Research of the Medical Faculty of the University of
Erlangen-Nuremberg.
Presented at the meeting of the American Society for Therapeutic
Radiology and Oncology, Denver, Colorado, October 16 to 20,
2005.
Correspondence to: Gerhard G. Grabenbauer, M.D., Department
of Radiation Oncology, University of Erlangen, Universitätsstraße
27, 91054 Erlangen, Germany, e-mail: gg@strahlen.imed.uni-
erlangen.de
Dis Colon Rectum 2005; 48: 1742–1751
DOI: 10.1007/s10350-005-0098-5
© The American Society of Colon and Rectal Surgeons
Published online: 29 June 2005
1742
tion depending on circumferential extension of the residual
tumor. All patients were scheduled for simultaneous che-
motherapy with two cycles of 5-fluorouracil at a dose of
1000 mg/m2/day as 120 hours of continuous intravenous
infusion on Days 1 to 5 and 29 to 33 and mitomycin C at 10
mg/m2/day on Days 1 and 29. Median follow-up time was
was 7.5 (range, 1–16) years. RESULTS: Overall survival and
colostomy-free survival rates for patients with anal canal
cancer were 75 percent and 87 percent at five years, re-
spectively. Patients with anal margin cancer had a less fa-
vorable outcome with five-year-overall and colostomy-free
survival rates of 54 percent and 69 percent, respectively.
After correction for imbalance between anal canal and anal
margin tumors, i.e., exclusion of T1 tumors of the anal ca-
nal, difference in overall survival remained significant (73
percent vs. 54 percent, P = 0.01). Following multivariate
analysis, tumor location (anal canal vs. anal margin, P =
0.02), age (P = 0.003), and dose intensity of chemotherapy
(ⱕ75 percent vs. >75 percent, P = 0.03) remained indepen-
dent significant factors for overall survival. Initial tumor re-
sponse at six weeks (P = 0.03) was predictive for colos-
tomy-free survival. CONCLUSIONS: With colostomy-free
survival rates around 85 percent, long-term treatment re-
sults for anal canal carcinoma have reached a satisfactory
level. However, patients with larger lesions of the perianal
skin are at high risk for locoregional recurrence and pos-
sible treatment intensification in this subgroup seems desir-
able. [Key words: Anal carcinoma; Anal margin; Radioche-
motherapy]
W ith the advent of simultaneous radiochemo-
therapy, no other solid tumor has experienced
such a profound shift from radical surgery to sphinc-
ter-saving combined modality treatment like anal ca-
nal carcinoma. This occurred despite the absence of
Vol. 48, No. 9 ANAL CANCER: TUMOR SITE PREDICTS OUTCOME 1743

Table 1. to combined radiochemotherapy, both for primary

Patients’ and Treatment Characteristics advanced disease13 and for tumors of all stages.14,15
Patients However, significant acute and especially late mor-
(N) (%) bidity has been associated with radiation treatment as
All Patients 101 (100) delivered in these trials. The reason may have been
Gender Male 27 (26.7) the relatively high total dose of 45 Gy together with a
Female 74 (73.3)
local boost of 15 to 20 Gy.13 The data reported here
Age (yr) 26–40 10 (10)
41–50 12 (12) summarize treatment results and long-term outcome
51–60 25 (25) in our center following treatment by a consistent
61–70 30 (30) policy of radical radiochemotherapy. While all pa-
71–80 20 (20)
81–84 4 (4) tients with anal canal tumors were included in the
Tumor extent Anal canal 77 (77) analysis, only larger primaries of the anal margin were
Anal margin 14 (14) treated by radiochemotherapy, because T1 tumors
AC with AM 10 (10)
could be excised without scarifying the function of
involvement
Histology Squamous-cell 84 (83) the anal sphincter. This is a reason for a potential
Cloacogenic 17 (17) imbalance of T categories. In this analysis, special em-
Grading G1–G2 61 (60) phasis is put on the evaluation of a possible impact of
G3 40 (40)
External dose 45 Gy 15 (15) tumor location (anal canal vs. anal margin) on prog-
pelvis nosis.
46–50 Gy 47 (47)
50.4–54 Gy 39 (39)
External boost None 67 (66)
PATIENTS AND METHODS
5.4 Gy 17 (17)
9 Gy 17 (17) Between 1985 and 2001, a total of 112 patients with
Interstitial boost None 81 (80) anal carcinoma were admitted to this University Hos-
12–18 Gy 15 (15) pital for treatment by combined radiochemotherapy.
21–36 Gy 5 (5)
Dose intensity >75% 62 (61) Eleven patients were excluded from further analysis:
5-FU + MMC ⱕ75% 39 (39) five with metastatic disease, four with recurrent dis-
Remission CR 85 (85) ease at the primary, and two with recurrent regional
PR 14 (13)
NAa 2 (2)
lymphnodes had palliative treatment only. Seventy-
seven patients presented with anal canal tumors, ten
AC = anal canal, AM = anal margin, CR = complete
remission, PR = partial remission, NA = not assessable, had additional involvement of the perianal skin, and
5-FU = 5-fluorouracil, MMC = mitomycin C. 14 had anal margin tumors. According to the Interna-
a
Patients died during or shortly after treatment. tional Union against Cancer, anal canal is defined as
the region extending from the anal verge to the ano-
prospective randomized trials, mainly because long- rectal line, and perianal skin is defined as the region
term results after radiation alone were available from around the anal verge with a diameter of 5 cm.16 Clini-
different centers.1–7 In the early 1970s, Papillon and cal patient characteristics are presented in Table 1.
colleagues3,4 reported on the use of cobalt 60 (Co-60) Among the 101 patients reported were 74 women and
sources with remarkable treatment techniques and 27 men with a median age of 62 (range, 26–84) years.
fractionation schedules for anal canal carcinoma. Tu-
mor control and sphincter preservation rates have Staging Procedures and Workup
been as high as 80 percent and 66 percent, respec- Following clinical and rectal examination, a biopsy
tively, with Grade 3 proctitis being in the range of 10 was taken under general anesthesia. All patients had
to 15 percent. The introduction of simultaneous ra- rectoscopy including endorectal ultrasound when-
diochemotherapy by Nigro et al.8 with refinements in ever feasible. Staging was completed by computed
fractionation schedules and treatment techniques and tomography scans of the abdomen and pelvis, chest
the combination with 5-fluorouracil (5-FU) and mito- X-rays and liver ultrasound. Histopathologic diagno-
mycin C provided further improvement of tumor re- sis was established according to World Health Orga-
sponse and colostomy-free survival rates.8–12 As of nization criteria17 with 84 patients with squamous-cell
today this approach has been confirmed by two ran- carcinoma and 17 patients with cloacogenic carci-
domized prospective trials comparing radiation alone noma. T categories (International Union against Can-
1744 GRABENBAUER ET AL Dis Colon Rectum, September 2005

Table 2. nique with 10-MV photons. Anterior–posterior

T and N Categories According to Tumor Site opposed fields were intended to cover pelvic, peri-
(UICC 1987)
rectal, and inguinal nodes and the primary tumor,
N Category whereas lateral beams were directed to the primary,
Tumor Extension T Category N0 N1 N2 N3 perirectal, and iliac/presacral nodes. Inguinal regions
Anal canal (AC) T1 12 1 1 0
were supplemented by an anterior electron beam of
alone (n = 77) T2 26 1 1 1 appropriate energy. Dose prescription followed the
T3 19 4 3 1 International Commission on Radiation Units report
T4 4 1 2 0 No. 50 guidelines with single fractions of 180 cGy and
All patients 61 7 7 2
Anal margin (AM) T2 3 1 a total dose of 5040 cGy. An additional local boost
alone (n = 14) T3 2 2 was to be applied to larger (>4 cm) primaries either by
T4 1 4 external multiple-field techniques (540–900 cGy) or
All patients 6 7
1 patient was by interstitial radiation using iridium 192 (Ir-92) low-
T2 NX dose rate or pulsed-dose rate (1200–1600 cGy) de-
AC with AM T1 1 0 0 0 pending on circumferential extension of the disease.
involvement T2 1 0 0 1 In case of involvement of less than 180° of the anal
(n = 10) T3 2 0 1 0
T4 0 0 1 1 canal, brachytherapy was preferred, whereas larger
All patients 4 0 2 2 primaries were treated by an external radiation boost.
2 patients were Dose specification of brachytherapy was performed
T4 NX
according to the Paris system (85 percent isodose)
UICC = International Union Against Cancer. and according to the International Commission on Ra-
TNM staging (anal canal): T1: <2 cm, T2: 2–5 cm, T3:
>5 cm, T4: infiltration of other organs, N1: perirectal
diation Units report No. 58. Inguinal nodes larger than
nodes, N2: inguinal or internal iliac nodes (unilateral), N3: 2 cm received an external boost using an anterior
perirectal and inguinal and/or internal iliac bilateral and/or electron beam of appropriate energy with 900 cGy in
bilateral inguinal nodes. fractions of 180 cGy. External boost was intended to
TNM staging (anal margin): T1: <2 cm, T2: 2–5 cm, T3: be delivered without a gap following larger-volume
>5 cm, T4: infiltration of other organs, N1: nodes (not
treatment; interstitial boost was given after cessation
specified).
of radiation proctitis, mostly after a rest period of four
cer 1987) were T1 (15), T2 (36), T3 (34), and T4 (16). to six weeks.
No patients with small perianal lesions (<2 cm) after All patients were scheduled for simultaneous che-
complete excision were included in this protocol. motherapy with two cycles of 5-FU at a dose of 1000
Seventy-one patients had no evidence of nodal dis- mg/m2/day as 120 hours of continuous intravenous
ease, whereas 27 initially had clinically involved re- infusion on days 1 to 5 and 29 to 33 and mitomycin C
gional nodes and three patients had undetermined (MMC) at 10 mg/m2/day on days 1 and 29 as a single
nodal status. Among the 77 patients with anal canal intravenous bolus injection. Dose adjustments were to
tumors, 16 (21 percent) had nodal involvement; in the be applied in case of Grade IV hematologic toxicity
group of patients with involvement of the perianal following course 1 (to 75 percent dose intensity) and
skin, 11 of 24 (46 percent) had clinically positive re- incomplete recovery before the second course de-
gional nodes. Nodes with the largest diameter of 1.5 pending on most recent white blood cell (WBC) and
cm or more were judged positive and biopsy and platelet counts (to 0 percent dose intensity in case of
histopathologic confirmation was attempted in un- WBC < 3.0 × 109/l or platelets < 75 × 109/l, to 50
clear cases only. For comparison of tumor site (anal percent dose intensity with WBC 3.0 - 3.5 x109/l or
canal vs. anal margin), a subgroup of patients with T2 platelets 75 to 100 × 109/l). No other reasons (e.g.,
to T4 lesions only was generated. The T and N cat- age) for dose reduction were to be considered.
egories of patients according to tumor site are given in
Table 2. Response Evaluation and Further Treatment
Treatment Protocol Six weeks after radiochemotherapy tumor response
Radiation treatment was directed to the primary tu- was evaluated clinically and by means of proctos-
mor region and to the inguinal, perirectal, and inter- copy, endorectal ultrasound and computed tomogra-
nal iliac/presacral nodes using a four-field box tech- phy scans of the pelvis. Figure 1 displays a complete
Vol. 48, No. 9 ANAL CANCER: TUMOR SITE PREDICTS OUTCOME
regression of a large perianal carcinoma six weeks
after completion of radiochemotherapy. Only in case
of persisent suspicious findings such as ulcerative le-
sions, palpable mass, or fistula, multiple tru-cut
needle biopsies were taken under general anesthesia.
Decision on further treatment was based on patho-
logic findings and abdominoperineal excision was
recommended only for viable tumor cells in more
than three biopsies.18 In case of persistent inguinal
nodes, excisional biopsy was recommended. All other
patients had regular follow-up in three-month inter-
vals during the first two years and in six-month inter-
vals thereafter. Acute treatment-related toxicity was
graded according to the World Health Organization
classification,19 late morbidity following the Late Ef-
fects on Normal Tissue–Subjective Objective Manage-
ment Analytic system criteria.20
Statistical Methods
Overall survival, disease-free survival, and colos-
tomy-free survival rates were calculated according to
Kaplan–Meier21 and results were given as percentage
± standard deviation. The log-rank test22 was used to
compare survival rates. Multivariate analysis was per-
formed by the use of the Cox regression model.23 All
variables with P values <0.1 were evaluated by mul-
tivariate analysis. Because of the small number of
events, only three variables were included in one
model simultaneously. Follow-up time was calculated
1745
Figure 1. Regression of a
large perianal carcinoma six
weeks after completion of
radiochemotherapy.
as the interval between end of chemoradiation and
last follow-up or death. The following events were
defined as end points: death (overall survival), death
of anal tumor (cause-specific survival), abdomino-
perineal excision (colostomy-free survival), and the
appearance of local, nodal, or distant recurrence (no
evidence of disease survival).
RESULTS
Median follow-up time was 7.5 (range, 1–16) years.
All events observed until November 2003 were in-
cluded in the analysis. Overall survival and colos-
tomy-free survival rates for all 101 evaluable patients
were 72 percent and 86 percent at five years. No dif-
ference was seen between patients with anal canal
carcinoma with and without perianal skin infiltration
having colostomy-free rates of 87 percent and 89 per-
cent at five years. However, patients with anal margin
cancer arising from the perianal skin alone had a less
favorable outcome with five-year-overall and colos-
tomy-free survival rates of 54 percent and 69 percent,
respectively (Table 3).
Prognostic Factors
Prognostic factors for overall and colostomy-free
survival are displayed in Table 4. In univariate analy-
sis, tumor site (P = 0.003, Figs. 2A and B) and intensity
of both chemotherapeutic agents (P = 0.03, Fig. 3) and
T category (P = 0.04, Fig. 4), N category (P = 0.02),
and age (P = 0.01) were significantly associated with
1746 GRABENBAUER ET AL Dis Colon Rectum, September 2005

Table 3.
Five-Year Survival Rates According to Tumor Extent
Site Overall Survival Cause-Specific Survival Colostomy-Free Survival NED Survival
All patients (N = 101) 72 ± 5% 82 ± 4% 86 ± 4% 81 ± 4%
Anal canal (N = 87) 75 ± 5% 85 ± 4% 87 ± 4% 82 ± 5%
Anal margin alone (N = 14) 54 ± 14% 69 ± 13% 69 ± 21% 68 ± 17%
NED = no evidence of disease.

Table 4.
Association of Risk Factors With Overall Survival and Colostomy-Free Survival
Overall Survival (5 yr) Colostomy-Free Survival (5 yr)
P Value P Value
Factors % * ** % * **
T category
T1 / T2 (N = 51 82 ± 6 — 98 ± 2
T3 / T4 (N = 50) 60 ± 8 0.04 72 ± 7 0.003 0.1
N category
N0, X (N = 74) 76 ± 5 86 ± 4 —
N+ (N = 27) 62 ± 10 0.02 0.07 84 ± 9 0.9
Grading
G1/2 (N = 66) 72 ± 6 — 83 ± 5 —
G3/4 (N = 35) 62 ± 10 0.7 91 ± 5 0.2
Remission
CR (N = 85) 75 ± 5 — 91 ± 3
PR (N = 14) 70 ± 15 0.09 56 ± 15 0.0003 0.03
External dose
>50 Gy (N = 51) 80 ± 6 — 80 ± 6 —
ⱕ50 Gy (N = 50) 66 ± 7 0.42 92 ± 4 0.3
5-FU+MMC
>75% (N = 62) 82 ± 5 92 ± 4
ⱕ75% (N = 39) 57 ± 9 0.03 0.03 76 ± 8 0.2 0.3
Tumor site
Anal canal (N = 87) 75 ± 5 87 ± 4 —
Margin (N = 14) 54 ± 14 0.003 0.02 69 ± 20 0.7
Age
>62,4 (N = 46) 59 ± 8 87 ± 6 —
ⱕ62,4 (N = 55) 82 ± 5 0.01 0.003 86 ± 5 0.8
Gender
Male (N = 27) 58 ± 10 — 83 ± 8 —
Female (N = 74) 76 ± 5 0.1 87 ± 4 0.3
* = univariate analysis, ** = multivariate analysis, 5-FU = 5-fluorouracil, MMC = mitomycin C, CR = complete response,
PR = partial response, NC = no change.

overall survival. Even after correction for imbalance
between anal canal and anal margin tumors, i.e., ex-
clusion of T1 tumors of the anal canal, difference in
overall survival remained significant (73 percent vs. 54
percent, P = 0.01, Fig. 2B). Only T category (P =
0.003) and initial response at six weeks (P = 0.0003)
significantly impacted colostomy-free survival. Fol-
lowing multivariate analysis, tumor site (P = 0.02), age
(P = 0.003), and dose intensity of chemotherapy (P =
0.03) remained independently significant for overall
survival, and initial tumor response at six weeks (P =
0.03) remained independently significant for colos-
tomy-free survival.
Patterns of Recurrence and the Use of
Salvage Abdominoperineal Resection (APR)
Initial response at six weeks and patterns of recur-
rent disease at any time during follow-up according to
tumor site are displayed in Table 5. It is noteworthy
that complete remission rates at six weeks after radio-
chemotherapy differed greatly between tumors aris-
ing from the anal canal and anal margin tumors (92
percent vs. 50 percent). During follow-up, in addition,
local recurrence rates were also doubled in the pa-
tients with anal margin tumors compared with pa-
tients with anal canal cancer (21 percent vs. 8 per-
Vol. 48, No. 9 ANAL CANCER: TUMOR SITE PREDICTS OUTCOME
Figure 2. A. Influence of tumor site on overall survival.
Upper curve represents patients with anal canal carci-
noma; lower curve represents those with anal margin tu-
mors. B. Influence of tumor site on overall survival. Upper
curve represents only T2 to T4 patients with anal canal
carcinoma; lower curve represents those with anal margin
tumors.
cent). An APR for recurrent disease was performed in
14 patients after a time interval between 4 and 107
months (median, 10 months). During long-term fol-
low-up a total of six patients with isolated locally re-
current or persistent disease and salvage APR re-
mained disease-free. Comparing the group of anal
canal vs. anal margin tumors, local events necessitat-
ing surgical salvage treatment differed with 11 of 87
patients for anal canal tumors vs. 9 out of 14 patients
with anal margin tumors (Table 5).
Toxicity
The extent of acute treatment-related toxicity is dis-
played in Table 6. Grade 4 side effects were uncom-
mon (range, 1–4 percent). One 80-year-old patient
died of severe dehydration because of prolonged en-
1747
Figure 3. Influence of intensity of both chemotherapeutic
agents on overall survival. Upper curve represents pa-
tients with full-dose chemotherapy (at least 75 percent of
prescribed dose); lower curve represents patients with re-
duced chemotherapy (below 75 percent).
Figure 4. Influence of T category on overall survival. Up-
per curve represents patients with tumors of the T1 and
T2 category; lower curve represents those with T3 and T4
tumors.
teritis, which was initially managed on an outpatient
basis. Late toxicity of Grades 3 and 4 was noted oc-
casionally (0–2 percent). In this series we have ob-
served three cases with Grade 4 toxicity including one
case with rectovaginal fistula (following regression of
a large infiltrating tumor mass), one patient with small
bowel obstruction, and one case with anal stenosis;
all cases needed surgery. No patients with radiation
proctitis requiring APR were observed.
DISCUSSION
This analysis on a large monoinstitutional series
provides further evidence of excellent long-term re-
1748 GRABENBAUER ET AL Dis Colon Rectum, September 2005

Table 5.
Response at Six Weeks and Failure Pattern
Anal Canal (n = 77) Anal Margin (n = 14) AC with AM Involvement (n = 10)
Response at six weeks
CR 71 (92%) 7 (50%) 7 (70%)
PR 6 (8%) 6 (43%) 2 (20%)
NA — 1 1
Failures at any time
local 6 (8%) 3 (21%) 1 (10%)
regional 3 (4%) 0 0
distant 8 (10%) 1 0
Local excision 2 3 1
Abdominoperineal excision 6 (8%) 6 (43%) 2
AN = anal canal, AM = anal margin, CR = complete response, PR = partial response, NA = not available.

Table 6. nodal involvement (P = 0.0003), ulceration but not

Acute Toxicity (CTC) infiltration of the perianal skin (P = 0.006), and male
Type of Toxicity III IV Va gender (P = 0.01) as shown by the EORTC trial.13
Dermatitis 44 (44%) 1 (1%) 0 (0%) Gerard et al.26 identified “response at eight weeks” as
Diarrhea 32 (32%) 1 (1%) 1 (1%) the only independent factor (P < 0.001) for overall
Leukopenia 22 (22%) 4 (4%) 0 (0%) survival. Cause-specific survival was influenced by tu-
Anemia 2 (2%) 0 (0%) 0 (0%)
Thrombocytopenia 4 (4%) 3 (3%) 0 (0%) mor size, nodal disease, and response.25 In our series,
tumor site (anal canal with or without involvement of
CTC = Common Toxicity Criteria.
a
Died during treatment. the perianal skin vs. perianal skin, P = 0.02), age (P =
0.003), and dose intensity of chemotherapy (P = 0.03)
sults following radical radiochemotherapy of anal remained independently significant for overall sur-
squamous-cell carcinoma. Overall survival and colos- vival, and initial tumor response at six weeks (P =
tomy-free survival rates of 72 percent and 86 percent, 0.03) remained independently significant for colos-
respectively, at five years are in line with data from tomy-free survival. Recent data from the University of
the literature. Several phase II and phase III trials that Geneva suggest that an age younger than 65 years (P
used a minimal total dose of 45 to 50 Gy together with = 0.01) and a four-week treatment interruption after
a simultaneous 5-FU/MMC9–12,15,24 or 5-FU/cisplatin 40 Gy (P = 0.02) both were associated with a pro-
regimen25–27 achieved colostomy-free survival rates in found negative impact on local tumor control. Par-
the range of 66 to 87 percent. In the same trials overall ticularly in younger individuals a decrease in local
survival rates ranged between 61 and 84 percent. Ran- control from 74 percent to 50 percent without a gap
domized studies conducted by the European Organi- with treatment interruption was found.28
zation for Research and Treatment of Cancer (EORTC)
and United Kingdom Coordinating Committee on Impact of Tumor Location on Survival and
Cancer Research that compared radiation alone to si- Local Control
multaneous radiochemotherapy clearly demonstrated One interesting aspect of our series is the fact that
a benefit for local tumor control and colostomy-free a total of 101 consecutive patients, including those
survival following combined modality treatment.13,14 with involvment of the anal margin and with tumors
Further improvements with a significantly lower local of the perianal skin alone, were treated quite consis-
relapse rate (36 percent vs. 17 percent, P < 0.001) tently by a prospective protocol using radical radio-
were identified for the combination of radiation with chemotherapy. Both overall survival and colostomy-
5-FU/MMC compared with radiation with 5-FU alone free survival were negatively affected by tumor
by the Radiation Therapy Oncology Group (RTOG)/ location outside the anal canal with a five-year sur-
Intergroup study.15 vival rate of only 54 percent for patients with tumors
arising from the perianal skin. This may be simply a
Prognostic Factors consquence of an overrepresentation of larger lesions
Prognostic factors as reported from the literature (>5 cm: 9/14 patients (64 percent)) and tumors with
that have a negative impact on survival were regional positive inguinal nodes at diagnosis (7/14 patients (50
Vol. 48, No. 9 ANAL CANCER: TUMOR SITE PREDICTS OUTCOME
percent)) in the group of patients with carcinoma of
the perianal region. Clearly, smaller lesions that are
suitable for complete surgery will undergo primary
excision with or without postoperative radiation ac-
cording to their locoregional extent and did not qual-
ify for radiochemotherapy in this series. It has been
argued that the difference between anal canal tumors
and anal margin tumors in our series may simply be
the results of a major sampling error with an overrep-
resentation of larger lesions in the latter group. How-
ever, even after exclusion of all T1 lesions of the anal
canal, the difference in overall survival remained sig-
nificant (P = 0.01). This observation strengthens the
long-standing hypothesis that perianal tumors repre-
sent a distinct biologic entity characterized by an in-
ferior response toward chemoradiation compared
with anal canal tumors.
For anal margin tumors a very similiar differentiated
therapeutic approach was advocated by Papillon and
Chassard29 who reported a crude five-year survival
rate of 59 percent in a series of 57 patients. Two other
smaller series using radiation alone or radiation with
and without concomitant chemotherapy in anal mar-
gin tumors revealed sphincter preservation in 9 of 21
(43 percent) patients who had radiation alone30 and
in 16 of 24 (67 percent) patients who had the com-
bined modality.31 Given that in our series the rate of
salvage APR following chemoradiation in the group of
patients with involvement of the perianal skin was
fourfold higher (8/24 (33 percent)) compared with
patients with anal canal involvement alone (6/77 (8
percent)), it remains to be elucidated whether this
inferior response is because of intrinsic biologic fac-
tors such as individual patterns of proliferation and/or
apoptosis as recently shown by our group.32
Long-Term Toxicity and
Quality-of-Life Issues
Extent and severity of late morbidity following che-
moradiation as reported by the literature were clearly
related to the applied treatment techniques, fraction-
ation schedules, and single dose and total dose of
radiation treatment. Radiotherapy by a pair of simple
anterior–posterior fields and the use of a minimum
total dose of approximately 60 to 65 Gy (45 Gy to
larger portals and 15–20 Gy for local boost) were as-
sociated with severe late effects in the range of 30 to
40 percent, which is unacceptable by today’s perspec-
tive.13,14 As a result of the RTOG/Intergroup trial, by
applying a much lower dose of only 45 Gy plus 5.4
1749
to 9 Gy, the rate of late Grade 4/5 toxicity (RTOG) was
only 2 percent.15 In a recently published phase II trial
by the EORTC, by using a total dose of 59.4 Gy the
severe toxicity-free survival rate was 84 percent at
three years.33 In our series we observed three cases
with Grade 4 toxicity, including rectovaginal fistula
(following regression of a large infiltrating tumor
mass), small bowel obstruction, and anal stenosis, all
requiring surgery. In addition, according to literature
data, late morbidity, namely, chronic proctitis, may be
the result of altered fractionation schemes using a
single fraction size greater than 200 cGy.6,9 The rate of
local painful ulcerations was reported to be in the
range of 15 percent with a regimen of 3,000 cGy ap-
plied in 300-cGy fractions followed by an interstitial
Ir-192 low-dose-rate implant with 2,000 cGy.24 Inter-
estingly, only limited data exist on quality-of-life is-
sues and sphincter function during long-term follow-
up. According to Allal et al.,34 who evaluated a total of
41 patients with a minimum follow-up time of three
years, there was an acceptable level of quality of life
except for problems with chronic diarrhea and sexual
function. Vordermark et al.35 presented data on ano-
rectal manometry in a small group of patients, in
which 60 percent had normal manometry and the re-
mainder had significantly decreased pressure data
and sphincter length. In our study, among the 42 pa-
tients surviving for more than five years without APR,
complete continence was reported in 33 patients (79
percent). The remaining patients who were affected
by partial incontinence had either local tumor exci-
sion before chemoradiation or large sphincter-
infiltrating masses with preexisting decreased sphinc-
ter tonus.
CONCLUSIONS AND FUTURE DIRECTIONS
With colostomy-free survival rates around 85 per-
cent in an unselected patient population, results of
anal carcinoma treatment have reached a satisfactory
level and are not likely to improve. Late treatment-
related morbidity, including a reduction in quality of
life, may call for newer treatment techniques such as
intensity-modulated radiotherapy. A minority of 15 to
20 percent of the patients will relapse despite com-
bined modality treatment and still need salvage sur-
gery.36,37 Patients with larger lesions of the perianal
skin are at a very high risk of recurrence and this
subgroup clearly qualifies for treatment intensification
including refinements of surgery.38
1750 GRABENBAUER ET AL
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