Current Management of
Anal Canal Cancer
Brian G. Czito, MD, and Christopher G. Willett, MD
Corresponding author
Brian G. Czito, MD
Department of Radiation Oncology, Box 3085, Duke University
Medical Center, Durham, NC 27710, USA.
E-mail: czito001@mc.duke.edu
Current Oncology Reports 2009, 11:186–192
Current Medicine Group LLC ISSN 1523-3790
Copyright © 2009 by Current Medicine Group LLC
Squamous cell carcinoma of the anal canal his-
torically has been treated with abdominoperineal
resection, resulting in high rates of morbidity and
local recurrence. Pioneering work led to the fi nding
that radiation therapy (RT) combined with 5-fluo-
rouracil (5-FU) and mitomycin results in high rates
of local control and disease-free and colostomy-free
survival without surgery. Prospective randomized
trials from Europe and the United States have shown
the superiority of RT, 5-FU, and mitomycin over 1)
RT alone, 2) RT with 5-FU, and 3) neoadjuvant cis-
platin/5-FU with concurrent radiation, cisplatin, and
5-FU. At present, RT with 5-FU and mitomycin is
the standard of care for anal cancer patients. Recent
advances include the integration of positron emis-
sion tomography into staging, radiation treatment
planning and monitoring, and the use of intensity
modulated RT. European randomized trials are fur-
ther evaluating the role of cisplatin in the neoadjuvant,
concurrent, and adjuvant settings, as well as radiation
dose escalation. Other studies are evaluating the use
of capecitabine, oxaliplatin, and the anti–epidermal
growth factor receptor agent cetuximab with RT in
this malignancy.
Introduction
The anal canal is the distal end of the alimentary tract
extending from the anorectal ring (the palpable muscle
bundle formed by the junction of the puborectalis, distal
longitudinal bowel, upper internal sphincter, and deep
external sphincter musculature) inferiorly to the anal
verge (the mucocutaneous junction). The skin extend-
ing 5 cm from the anal verge often is referred to as the
anal margin. Although the canal spans only 4 to 5 cm in
most people, it is a heterogeneous structure, arbitrarily
divided by the dentate line near its mid-aspect. The den-
tate line is not a true “line” but an endoscopically visible
zone of epithelial transition where the anal glands drain
into the anal lumen. Proximal to the dentate line, the epi-
thelium “transitions” into the glandular rectal mucosa.
This transitional epithelium gives rise to nonkeratinizing
squamous cell carcinomas. Historically, these histologic
variants have been classified as transitional, cloacogenic,
or basaloid tumors. Clinically, patients with these histo-
logic variants have a similar prognosis and are treated
the same as patients with keratinizing squamous cell
carcinoma. Tumors distal to the dentate line are usually
keratinizing squamous cell carcinoma. Anatomically,
lymphatic and vascular drainage above the dentate line
flows to the superior and middle rectal veins and lymphat-
ics, ultimately into the periaortic/portal system, whereas
the distal canal flows to inguinofemoral vasculature and
nodal basins, ultimately systemically. Although these are
generalizations, there are extensive interconnections of
lymphatics, resulting in “cross-drainage.” In contrast to
squamous cell carcinoma, anal canal adenocarcinomas
have a distinct clinical biology, and patients with this
histology usually are managed surgically.
Anal Canal Squamous Cell Carcinoma: The Past
In the past, the treatment of localized squamous cell car-
cinoma of the anal canal was abdominoperineal resection
(APR), leading to removal of the anorectum. APR results
in permanent colostomy with high rates of urinary/sexual
dysfunction, wound morbidity, and perioperative mortal-
ity. Surgical studies report 5-year survival rates of 30% to
71%, with local regional recurrence rates of 19% to 45%.
A large series from the Mayo Clinic showed local recur-
rence rates of approximately 30% following APR [1].
Because of these inferior results, Nigro et al. [2] from
Wayne State University treated three patients with preop-
erative low-dose radiation therapy (RT) with concurrent
infusional 5-fluorouracil (5-FU)–based chemotherapy
followed by APR. The surgical specimens of two patients
showed no evidence of residual disease, whereas a third
patient refused surgery and remained disease-free. Fur-
ther experience from this group and other investigators
 Current Management of Anal Canal Cancer
reported similar high rates of clinical and pathologic
response using preoperative chemoradiotherapy and sur-
gery [3–7]. These results led to multiple phase 2 trials
evaluating RT alone or combined chemoradiotherapy as
“defi nitive” therapy. These studies demonstrated that
most patients treated by these approaches were long-term
disease-free survivors.
Anal Canal Squamous Cell Carcinoma:
The Present
The foundation for the contemporary treatment of anal
cancer is based on the results of four randomized trials.
Because relatively high rates of local control and disease-
free survival could be achieved by RT alone, the role of
concurrent chemotherapy in the “defi nitive” management
of this disease was ambiguous. To clarify this, the UK
Coordinating Committee on Cancer Research (UKCCCR)
Anal Canal Trial Working Party randomly assigned 585
patients with anal cancer to receive 45 Gy of RT alone
or the same regimen with concurrent chemotherapy (con-
tinuous-infusion 5-FU in weeks 1 and 5 and mitomycin in
week 1). Patients with a good clinical response received
a “boost” dose of RT, whereas poor responders under-
went salvage surgery [8]. Local control was significantly
enhanced in the combined modality therapy group (64%
vs 41%, P < 0.0001), with a significant improvement in
anal cancer–related mortality (28% vs 39%, P = 0.02) in
the combined modality–treated patients. However, 3-year
overall survival was not different between the arms (65%
vs 58%, P = 0.25). The authors concluded that patients
with squamous cell carcinoma of the anal canal can be
treated with RT, 5-FU, and mitomycin, with surgery
reserved for salvage.
Similarly, a study by the European Organisation for
Research and Treatment of Cancer (EORTC) randomly
assigned 110 patients to receive RT alone (45 Gy) followed
by a boost radiation dose (dose depending on response)
versus the same regimen plus 5-FU in weeks 1 and 5 and
mitomycin in week 1. As in the UKCCCR study, patients
undergoing combined modality therapy had a significant
improvement in local control and colostomy-free and
progression-free survival rates. No significant survival
difference was seen between the groups (3-year survival,
72% vs 65%, P = 0.17) [9].
A third randomized trial from the United States
conducted by the Radiation Therapy Oncology Group
(RTOG) and Eastern Cooperative Oncology Group
(ECOG) evaluated the role of mitomycin in this treatment
regimen. Mitomycin has significant toxicities, includ-
ing thrombocytopenia, leukopenia, pulmonary toxicity,
nephrotoxicity, and hemolytic–uremic syndrome. In this
study, 310 patients were randomly assigned to receive RT
(45–54.4 Gy) with infusional 5-FU in week 1 or the same
regimen with an infusion of mitomycin in weeks 1 and 5.
I Czito and Willett
I 187
Patients with biopsy-proven residual disease following com-
bined therapy were eligible to receive additional pelvic RT
(9 Gy) with 5-FU and cisplatin chemotherapy. Four-year
colostomy-free and disease-free survival rates were signifi-
cantly higher in patients receiving mitomycin versus those
receiving 5-FU alone. No difference in overall survival was
observed between the treatment arms. However, grade 4/5
toxicities (primarily related to neutropenia and sepsis) were
significantly higher in patients receiving mitomycin. Of
24 patients with positive posttreatment biopsy, half were
rendered disease-free by “salvage” chemoradiotherapy
[10]. The role of salvage RT and chemotherapy is not clear,
however, given the very long regression periods in some
patients after chemoradiotherapy (up to 1 year) and reports
demonstrating that many patients with biopsy-positive dis-
ease following combined modality therapy will experience
long-term disease-free survival with no additional therapy.
Nonetheless, all three randomized trials demonstrated
that combined modality therapy with radiation, 5-FU,
and mitomycin results in long-term disease-free survival
and sphincter preservation in most patients with anal
cancer and superior outcomes relative to RT alone or RT
combined with 5-FU alone, albeit at the expense of higher
treatment-related morbidity.
Because of the significant toxicities of mitomycin
and the efficacy of cisplatin-based chemoradiotherapy in
squamous cell carcinoma of other sites (head and neck,
esophageal, and cervical cancers), there has been interest
in substituting cisplatin for mitomycin in the combined
modality treatment of anal cancer. Phase 2 trials from the
United States and Europe using this strategy have demon-
strated high rates of local control and disease-free survival,
with acceptable toxicity. Based on these data, the RTOG
initiated the 98-11 trial, randomly assigning 682 patients
to receive RT (45–59 Gy) with continuous-infusion 5-FU
and bolus mitomycin in weeks 1 and 5 or a regimen of
continuous-infusion 5-FU and bolus cisplatin in weeks 1,
5, 9, and 13, with radiation (45–59 Gy) starting in week
9 (ie, a “neoadjuvant” chemotherapy-alone approach).
The rate of significant hematologic toxicity was higher in
patients receiving mitomycin (61% vs 42%, P < 0.001).
No significant difference was seen in 5-year disease-free
survival (60% vs 54%, P = 0.17), overall survival (75% vs
70%, P = 0.10), or local-regional relapse (25% vs 33%,
P = 0.07) rates. However, the 5-year colostomy rate was
10% in patients receiving mitomycin, versus 19% in the
cisplatin arm (P = 0.02) [11••,12,13]. The influence of the
use of neoadjuvant chemotherapy on this study’s outcome
remains uncertain (as discussed later).
In summary, the results of these four randomized trials
show that the standard of care for anal cancer remains RT
combined with 5-FU and mitomycin. Recent technologic
advances in RT, as well as interest in examining less toxic
yet more active chemotherapy regimens, are directing future
treatment approaches to this disease.
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I Gastrointestinal Cancers
Anal Canal Squamous Cell Carcinoma:
The Future
Imaging
Positron emission tomography (PET) and combined PET/
CT have advanced the staging and treatment of patients
with anal cancer. Recent studies have demonstrated that
PET-detected nodal metastases occur in 17% to 24% of
patients judged to have clinically uninvolved lymph nodes
by CT [14,15]. In the absence of PET, these sites usually
would receive “subclinical” doses of RT (as compared
with higher doses used to treat gross disease), thus lead-
ing to underdosage and potentially predisposing patients
to pelvic failure. To emphasize this point, one recent series
reported on 23 patients with anorectal cancer receiv-
ing chemoradiotherapy. All patients underwent PET/CT
fusion–based radiation planning. In one fourth of patients,
PET detected distant metastases and changed overall
patient management, as well as altering the radiation
oncologist’s target volumes and radiation treatment plan in
a similar number of patients [16]. Preliminary studies also
have suggested that patients achieving less than a complete
metabolic response following combined modality therapy
may experience significantly decreased progression-free
and cause-specific survival [17]. The role of PET in this
disease is an active area of investigation.
Chemotherapy
The results of the RTOG 98-11 trial have not supported the
use of “induction” chemotherapy in the treatment of this
malignancy. In many cancers, the overall treatment course
duration (namely, duration of radiation treatment) influences
clinical outcomes. In anal cancer, a phase 2 dose-escalation
trial by the RTOG mandating a 2-week treatment break
showed inferior outcomes compared with historical con-
trols. The authors hypothesized that the mandated treatment
break negated any benefits of dose escalation [18]. Similarly,
a recent experience from Memorial Sloan-Kettering reported
that patients with prolonged treatment breaks/protracted
duration of therapy were more likely to suffer disease failure,
a phenomenon confirmed in other institutional series [19].
In this respect, the role of neoadjuvant chemotherapy pre-
ceding (and delaying) “definitive” RT remains unanswered.
Many investigators have disputed the use of neoadjuvant
chemotherapy before RT, pointing out that this approach
has failed to improve disease-free and overall survival
when delivered before RT in most tumor sites, and empha-
sizing that this approach may prolong overall treatment
time and adversely affect radiation compliance. In lung
cancer, a recent meta-analysis of limited-stage small cell
lung cancer randomized trials demonstrated that overall
(ie, prolonged) treatment time associated with the use of
neoadjuvant chemotherapy was the strongest predictor of
ultimate outcomes. This may be a result of the develop-
ment of “accelerated repopulation” of tumor clonogens.
Additionally, the role of neoadjuvant chemotherapy in
upregulating pathways that confer radioresistance remains
unknown [20–22].
Given this controversy as well as the potentially more
favorable toxicity profi le of cisplatin, further randomized
trials assessing the role of cisplatin in both the neoadju-
vant and concurrent settings are in progress. A second
randomized phase 3 study from the UKCCCR has been
completed (the Anal Cancer Trial [ACT] II). This study
is comparing cisplatin, 5-FU, and RT with mitomycin,
5-FU, and RT [23]. Patients were randomly assigned to
one of four arms: 1) concurrent 5-FU/mitomycin/RT, 2)
concurrent 5-FU/mitomycin/RT followed by adjuvant
5-FU/cisplatin, 3) concurrent 5-FU/cisplatin/RT, and 4)
concurrent 5-FU/cisplatin/RT followed by adjuvant 5-
FU/cisplatin. Patients in each arm received 50.4 Gy over
5.5 weeks without a planned treatment break. All patients
also received continuous 5-FU in weeks 1 and 5. In arms
1 and 2, mitomycin was delivered on day 1; in arms 3 and
4, cisplatin was delivered on days 1 and 29 (Table 1). This
trial will permit a defi nitive comparison of cisplatin and
mitomycin in the concurrent treatment of anal cancer.
Results are pending.
The EORTC is conducting a randomized phase 2/3
trial (EORTC 22001/400014) comparing mitomycin plus
weekly cisplatin given concurrently with RT versus mito-
mycin and continuous-infusion 5-FU given concurrently
with RT. The initial radiation course is 36 Gy delivered
over 4 weeks, followed by a 2-week break, followed by an
additional 23.4 Gy given over 2.5 weeks, with concurrent
chemotherapy delivered during both radiation sessions.
The French Federation Nationale des Centres de
Lutte Contre le Cancer is conducting the ACCORD 03
trial. In this study, patients with stage II/III anal cancer
are randomly assigned to one of four treatment arms: 1)
neoadjuvant 5-FU/cisplatin alone followed by 5-FU/cis-
platin/RT (45 Gy), followed by a break and low-dose
RT “boost” (15 Gy); 2) the same as arm 1, except with
a high-dose RT boost (20–25 Gy); 3) the same as arm
1, but without neoadjuvant chemotherapy; 4) the same
as arm 2, but without neoadjuvant chemotherapy. In all
the arms, the initial radiation course is delivered over 5
weeks, with concurrent 5-FU/cisplatin in weeks 1 and 5.
Patients then have a mandated 3-week break and receive
boost radiation treatments. The boost dose depends on
the randomization arm and response to initial treatment,
and is delivered using external beam radiation or brachy-
therapy techniques.
The AIDS Associated Malignancies Clinical Trials
Consortium is conducting a phase 2 trial combining cis-
platin, 5-FU, and the antiepidermal growth factor receptor
monoclonal antibody cetuximab with RT in HIV-positive
patients with stage I to III anal cancer. The ECOG also
is conducting a phase 2 trial using a similar regimen in
non-HIV patients with stage I to III disease. Addition-
ally, investigators from the M.D. Anderson Cancer Center
 Current Management of Anal Canal Cancer
Table 1. Ongoing/pending randomized trials in anal cancer
Organization Accrual goal, n
UKCCCR 600
EORTC 678 (phase 2/3)
French National (ACCORD 03) 350
5-FU—5-fluorouracil; EORTC—European Organisation for Research and Treatment of Cancer; RT—radiation therapy; UKCCCR—UK
Coordinating Committee on Cancer Research.
are conducting a phase 2 study of the oral 5-FU prodrug
capecitabine and oxaliplatin combined with RT in patients
with stage II to III anal cancer. The results of these studies
may help further refi ne the optimal chemotherapy regi-
men and sequencing in the treatment of this disease.
Radiation therapy
Although chemotherapy enhances the acute toxicity of RT
in the treatment of anal cancer, RT accounts for most acute
and chronic therapy-related toxicities. Randomized trials
have used two-dimensional (2-D)–based RT planning, in
which known anatomic (bony) landmarks are used to guide
field design through the use of orthogonal radiographic
images. Since the late 1980s, conformal (CT-guided or
three-dimensional [3-D]) RT–based treatments have been
implemented in the clinic, allowing the radiation oncolo-
gist to identify normal as well as target structures on axial
CT images, facilitating improved treatment accuracy and
delivery. Both techniques, however, use “uniform” fields
for RT delivery. Beginning in the late 1990s, intensity
modulated RT (IMRT) has been implemented in the clinic.
Like 3-D conformal RT, IMRT involves the 3-D identifica-
tion of normal pelvic organs as well as target structures,
including the primary disease and draining lymph nodes.
In contrast to 3-D–based planning, in which the physician
designs treatment fields based on a “beams-eye view” of
the target volumes and normal structures, IMRT-based
planning entails setting strict radiation dose constraints
to normal organs, a prescription dose to varying target
volumes, and the use of computer software “inverse plan-
ning” algorithms to design unconventional treatment fields
that would not be possible with standard planning meth-
ods. Importantly, IMRT involves partitioning of a given
radiation field into multiple smaller fields, which may
occur in the form of dynamic IMRT (in which collimating
leaves move “across” an active radiation field using highly
I Czito and Willett
I 189
Randomization
Arm 1: RT (50.4 Gy)/5-FU/mitomycin
Arm 2: arm 1 + adjuvant cisplatin/5-FU
Arm 3: RT (50.4 Gy)/5-FU/cisplatin
Arm 4: arm 3 + adjuvant chemotherapy as in arm 2
Arm 1: RT (59.4 Gy, split course)/5-FU/mitomycin
Arm 2: RT (59.4 Gy, split course)/mitomycin/cisplatin
Arm 1: neoadjuvant 5-FU/cisplatin → 5-FU /cisplatin/RT
(45 Gy) → break → low-dose RT boost (15 Gy)
Arm 2: as in arm 1, except high-dose RT boost (20–25 Gy)
Arm 3: as in arm 1, except no neoadjuvant chemotherapy
Arm 4: as in arm 2, except no neoadjuvant chemotherapy
specific leaf sequences) or a “step-and-shoot” IMRT (in
which leaves sculpt the field shape while the beam is off).
The end result is that the intensity of the radiation beam
per field varies. Ultimately, the cumulative effect of all
treatment fields results in a radiation dose distribution that
closely conforms the prescription radiation dose around
the target volumes while significantly reducing the dose to
surrounding normal tissues, which could not be achieved
through conventional planning methods. Figure 1 shows
an example of IMRT-based treatment in a case of anal
cancer. The advantage of IMRT techniques is the reduction
of acute and chronic radiation-related toxicities relative to
2-D and 3-D approaches, which often are significant using
conventional radiation techniques. Additionally, IMRT
may permit safe radiation dose escalation in this disease.
Several retrospective series have suggested that increas-
ing radiation dose in the treatment of anal cancer may
enhance local control and disease-free survival. The role
of dose escalation is being evaluated in the randomized
French National study described earlier.
Dosimetric studies have shown the superiority of
IMRT in sparing normal tissues in the pelvis, including
small bowel, femoral heads, and bladder (Fig. 1). Recent
clinical series of IMRT-based therapy of anal cancer have
reported reduced acute treatment-related toxicity (primar-
ily bowel and skin related) and similar disease-related
outcomes versus historical controls using 2-D and 3-D
planning. For example, a multi-institutional study from
Salama et al. [24•] analyzing 53 patients with anal cancer
treated with IMRT-based chemoradiotherapy showed 18-
month colostomy-free survival, overall survival, and local
control rates of 84%, 93%, and 84%, respectively, with a
complete response rate of 93%. These results are similar
to outcomes from earlier trials using non-IMRT tech-
niques, with improvement in rates of high-grade toxicities,
supporting the authors’ conclusion that anal cancers can
190
I Gastrointestinal Cancers

Figure 1. Intensity modulated radiation therapy for anal cancer. A, Axial CT view of a 46-year-old HIV-positive man with early-stage anal
canal squamous cell carcinoma treated using intensity modulated radiation therapy. The colored isodose lines represent varying doses of
radiation therapy. Note the conformality of the 3060- and 4500-cGy lines to the target volume (the PTV, or planning target volume, which
is shaded) and “bending” of isodose lines around nearby normal organs. (Note: Please see full text online version for full-color image.) B,
Dose–volume histogram displaying varying radiation doses to the pelvic organs and PTV. Note the relative sparing of organs adjacent to the
PTV, which receives a full radiation dose. (Courtesy of Sua Yoo, PhD.)
 Current Management of Anal Canal Cancer
be treated successfully with IMRT, with improvements in
toxicity without compromising clinical outcomes. In addi-
tion, the RTOG recently completed a prospective phase
2 study combining 5-FU, mitomycin, and IMRT-based
therapy. The primary goal of this study was to determine
the feasibility of this approach in a cooperative group set-
ting, as well as to determine treatment-related toxicity and
preliminary disease-related outcomes in these patients. In
sum, although early results with IMRT (in the context
of reduced acute toxicity and favorable treatment-related
outcomes) appear promising, larger experiences with
long-term follow-up are necessary.
Conclusions
Although historically managed by surgery, anal cancer is
now treated with RT combined with mitomycin and 5-
FU; surgery is reserved for salvage. This regimen results
in long-term local control and colostomy-free and overall
survival in most patients. Randomized trials have shown
this regimen’s superiority to 1) RT alone, 2) RT plus 5-FU,
and 3) neoadjuvant cisplatin/5-FU followed by concurrent
RT, cisplatin, and 5-FU. Recent advances in anal cancer
therapy include the integration of PET into staging, treat-
ment planning, and treatment response evaluation, as
well as the use of IMRT, with its potential to reduce acute
and chronic radiation-related toxicities and radiation
dose escalation. Randomized trials are further evaluating
the role of cisplatin in the neoadjuvant, concurrent, and
adjuvant setting, as well as the role of radiation dose esca-
lation. Additional phase 2 trials are evaluating the roles
of capecitabine, oxaliplatin, and cetuximab delivered con-
currently with RT.
Disclosure
No potential confl icts of interest relevant to this article
were reported.
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This article describes a multi-institutional experience showing
improvement in acute toxicity rates and similar disease-related
outcomes relative to historic controls in patients treated with
IMRT-based chemoradiotherapy.