Preoperative Radiation Therapy for Upper Rectal CancerT3,T4/Nx: Selectivity Essential Sarah Popek,

Preoperative Radiation Therapy for Upper Rectal
CancerT3,T4/Nx: Selectivity Essential
Sarah Popek,
1
Vassiliki Liana Tsikitis,
1
Lisa Hazard,
2
Alfred M. Cohen
1
Abstract
This review explores the current available literature regarding the role of neoadjuvant therapy for upper locally
advanced rectal cancers (ⱖ10cm-15cm). Although there is a paucity of data evaluating the outcomes of preoperative
chemoradiation for upper rectal cancers the authors suggest that T3N0 tumors will not likely benefit from radiation
and that treatment of T4N0 should be individualized.
Clinical Colorectal Cancer, Vol. xx, No. x, xxx © 2011 Published by Elsevier Inc.
Keywords: Neoadjuvant therapy, Rectal cancer, T3, T4Nx
Introduction
The past two decades have seen major advances in surgical treat-
ment and combined modality therapy of patients who have rectal
cancer. For patients who have mid and lower rectal cancer (ⱕ10 to
12 cm) the standard of surgical care now includes total mesorectal
excision (TME), which has been shown to significantly decrease local
recurrence rates.
1
Locoregional recurrence is further reduced with
the combination of optimal surgery and chemoradiation therapy.
Clinical trials now support the use of preoperative (neoadjuvant)
sequencing as the preferred strategy for transmural and/or clinical
node positive tumors. It remains controversial as to the selective
application of this paradigm when the cancer is above the peritoneal
reflection.
2
In the 7
th
edition of the American Joint Committee on
Cancer (AJCC) Cancer Staging Manual, upper rectal tumors are
defined as partially peritonalized, versus tumors of the mid and lower
rectum, which are not peritonalized (Figure 1). The significance of
this difference translates into a different T stage for transmural upper
and lower rectal tumors. For example, for a mid-low rectum, a trans-
mural tumor is always a T3 lesion, whereas a transmural upper rectal
tumor is classified as a T4 lesion when located anteriorly, but as a T3
lesion when located posteriorly (Figure 1). Anterior T4 lesions, node
negative, frequently receive adjuvant postoperative chemotherapy
only. Patients with T3N0 lesions have a better prognosis compared
to patients with other types of locally advanced rectal cancer, as
reflected by the modifications made in the 7
th
edition of the AJCC
cancer staging manual.
It has been well-demonstrated that neoadjuvant radiotherapy
(RT) improves local recurrence rates in locally advanced rectal cancer
for which the circumferential radial margin (CRM) is the most im-
portant prognostic marker of recurrence.
2-4
For upper rectal tumors
located above the peritoneal reflection (ⱖ10 to 12 cm), one could
argue that circumferential margin is free from the anatomically re-
strictive pelvis and clear radial margins more feasible to obtain. In
addition, it remains unclear if neoadjuvant RT has the same efficacy
and results with upper rectal lesions. Although, when cancer-specific
survival was examined, upper rectal cancers behaved more like mid
and lower rectal than sigmoid cancers. Local recurrence was not
investigated.
5
This review article examines the current available literature con-
cerning the treatment paradigms and treatment outcomes for T3T4
Nx upper rectal cancers.
In the last decade, neoadjuvant RT has emerged as the pre-
eminent mode of treatment for locally advanced rectal cancer in
terms of local recurrence rates and toxicity. In 2004, the German
Rectal Cancer Study Group compared local recurrence and over-
all survival rates for rectal cancer patients treated with neoadju-
vant versus adjuvant chemoradiation therapy (CMT) and found
significantly improved rates of local recurrence in the neoadjuvant
arm (6% versus 13%, P⫽.006), yet no difference in overall
survival.
6
A few years later, the MRC CR07/NCIC CTG C016
7
study confirmed the superiority of neoadjuvant RT compared to
selective adjuvant RT, the latter of which delivered radiation only
in patients with close circumferential margin. This study demon-
strated a 61% relative risk reduction in local recurrence in the
neoadjuvant arm (P⬍.0001). A second critical benefit of neoad-
juvant RT is the decrease in rates of acute and chronic toxicity,
1
Department of Surgery, Section of Surgical Oncology
2
Department of Radiation Oncology, University Medical Center, University of
Arizona, Tucson AZ 85734
Submitted: Apr 8, 2011; Accepted: Jun 14, 2011
Address for correspondence: Alfred Cohen, MD, FACS, FASCRS, 1501 N Campbell
Ave, Tucson, Arizona 85724-5131
Tel: [phone]; Fax: [phone]; e-mail contact: acohen@surgery.
arizona.edu
Review
Clinical Colorectal Cancer Month 2011 1
1533-0028/$ - see frontmatter © 2011 Published by Elsevier Inc.
doi: 10.1016/j.clcc.2011.06.009

translating into more patients completing treatment with less
postoperative anorectal dysfunction.
8-11
Imaging for Staging of Rectal
Cancer
The assumption behind asking the question, “Do upper rectal
cancer patients benefit from neoadjuvant radiotherapy?” is that these
patients can be accurately identified preoperatively. In fact, one of
the main obstacles in answering this question is the ambiguity of
preoperative clinical staging. Currently in the United States, preop-
erative staging consists of a combination of imaging modalities in-
cluding computed tomography (CT), endorectal ultrasound
(ERUS), and magnetic resonance imaging (MRI). The decision of
which modality to pursue is often based on local expertise and avail-
ability. In contrast, in Europe, preoperative staging uses high-reso-
lution MRI to estimate the CRM. Whereas in the United States,
currently all T3N0 patients are offered neoadjuvant CMT and ad-
juvant chemotherapy. In Europe, the estimated CRM determines
which patients will receive neoadjuvant RT.
12
The Magnetic Resonance Imaging and Rectal Cancer European
Equivalence Study (MERCURY) trial, published in 2006, set the
standard for preoperative assessment of CRM with a specificity of
92% using high-resolution MRI.
13
In this trial, the authors used
high-resolution MRI to estimate the CRM in 408 consecutive rectal
cancer patients. These estimates were then contrasted to the actual
pathologic findings. Although distance from the anal verge is one of
the variables studied, the authors do not discuss variation in accuracy
based on tumor location. One important limitation discussed is the
inaccuracy of lymph node identification. MRI is able to identify
lymph nodes greater than 1 cm in size. However, although sugges-
tive, size is not pathognomic of malignancy. Several smaller studies
have evaluated and compared the efficacy of CT scanning to MRI
with mixed results. Studies have shown that multidetector-row CT
14
has a poor accuracy rate in evaluating CRM in low rectal cancers and
moderate accuracy in mid to high rectal cancers, but is not superior
to MRI.
14,15
ERUS was first used to stage rectal cancer in 1985,
15
and use of
this modality has increased. ERUS has established itself as a key
component of preoperative staging for rectal cancer,
16
however, ex-
actly where in the paradigm of preoperative imaging it lies has yet to
be refined. A small study published in 2008
17
comparing ERUS and
MRI in preoperative staging for rectal cancer found that accuracy of
T staging was slightly higher with MRI than ERUS (85% versus
89%), whereas both modalities had poor identification of lymph
node involvement (76% versus 74%). A recent meta-analysis evalu-
ating the sensitivity of ERUS for identification of lymph node in-
volvement in 2732 patients demonstrated a pooled sensitivity of
73.2% (95% confidence interval [95% CI] 70.6-75.6) and specific-
ity of 75.8% (95% CI 73.5-78).
18
Enthusiasm for ERUS has waned
recently, reflecting the recent trend toward lower rates of accuracy
published in the literature, which has prompted concerns about pub-
lication bias
19,20
or increased use by inexperienced physicians.
19
There has been suggestion that the addition of fine-needle aspiration
to ERUS would add a significant diagnostic benefit, however, the
data so far has not borne this out.
21
A meta-analysis from the Netherlands
22
compared the sensitivity
and specificity of all three imaging techniques (ERUS, CT, and
MRI) in preoperative staging for rectal cancer. ERUS and MRI had
comparable sensitivity in estimating invasion of the muscularis pro-
pria (94%, 95% CI 90-97 versus 94%, 95% CI 89-97), but ERUS
was significantly more specific than MRI (86%, 95% CI 80-90 ver-
sus 69%, 95% CI 52-82, P⫽.02). No data was available for CT. In
assessing perirectal tissue invasion, ERUS was significantly more sen-
sitive than either CT or MRI (90%, 95% CI 88-92 versus 79%, 95%
CI 74-84, versus 82%, 95% CI 74-87, P⫽.003), although the
specificities were similar (75%, 95% CI 69-81 versus 78%, 95% CI
73-83 versus 76%, 95% CI 65-84). Lastly, there was no significant
difference found between the three modalities in diagnosing adjacent
organ or lymph node involvement. The authors conclude that ERUS
is the most accurate modality for preoperative staging of locally ad-
vanced rectal cancer, however, they note the continued inaccuracy of
identification of lymph node involvement is a significant limitation
of all three imaging modalities. Upper rectal tumors are even more
difficult to study and accurately differentiate between a T3 and T4
Nx lesion with a rigid ERUS. Currently ERUS and MRI are the
standard modalities used in the United States for staging of rectal
cancer.
Local Recurrence
There are three major trials evaluating local recurrence in rectal
cancer with neoadjuvant and adjuvant therapy that include data
based on tumor location (Table 1). The first trial, the Swedish Rectal
Cancer Trial
23
published in 1997, was a landmark article demon-
strating significant improvements in local control and overall survival
for patients undergoing neoadjuvant short-course RT. The study
population was composed of stage I to III patients diagnosed using
Figure 1 Upper Rectal Tumors are Defined as Partially
Peritonalized, Versus Tumors of the Mid and Lower
Rectum, Which are not Peritonalized
Sacrum
T4
T3
T3
Non-transmural
Transmural
Transmural
UPPER
T3
Transmural
DISTAL
Preoperative RT for Upper Rectal Cancer
2Clinical Colorectal Cancer Month 2011

barium enema and rigid proctoscope, 27% of whom had upper rectal
lesions (⬎11 cm from anal verge). The authors found that neoad-
juvant treatment with short-course RT had a significant effect on
decreasing rates of local recurrence for mid and low rectal tumors
(P⬍.001, P⫽.003), however, the effect on upper rectal tumors was
not significant (P⫽.3) on long-term follow-up.
24
The Dutch TME trial,
25
the first trial to standardize surgical ther-
apy, also found a significant correlation between local recurrence
rates and tumor location within the rectum. Of the 1805 patients
included in the trial, 30% had upper rectal tumors (10.1 to 15 cm
from anal verge), 40% were mid-rectal (5.1 to 10 cm), and 30% were
lower rectal (⬍5 cm) tumors as determined by flexible endoscopy.
The patient population was also included all stages of disease, the
majority of whom were stage I-III. The data at 2-year follow-up
shows that both mid-rectal tumors and lower rectal tumors had a
significantly higher risk of developing local recurrence compared to
upper rectal tumors (hazard ratio [HR] 2.13, 95% CI 1.13-4.01, P⫽
.02; HR 2.78, 95% CI 1.22-6.31, P⫽.02). However, on univariate
subgroup analysis, patients with upper rectal tumors who were ad-
ministered neoadjuvant RT were found to have no improvement in
local recurrence rates (P⫽.17) compared to the surgery-alone cohort
at 2-year follow-up; these results were confirmed at 5-year follow-up
(P⫽.122).
26
The third trial, the German CAO/ARO/AIO trial,
6
is limited to
patients with T3/4 tumors who were staged with ERUS and CT
scans, 15% of whom had upper rectal lesions (⬎10 cm from anal
verge). The authors do not include the data from their subset analy-
sis, only the conclusion that there was no difference in local recur-
rence outcomes between upper and lower rectal tumors.
27
None of the aforementioned trials were designed or powered to
evaluate the benefit of radiation in the subset of patients with T3/
4N0 disease. Nonetheless, the Swedish and Dutch studies suggest
that the absolute benefit of RT in this subset is, if present, a small one.
Gunderson et al
28
combined data from five randomized studies to
examine the relationship between survival and relapse and T and N
stage, as well as treatment modalities. They evaluated data from a
total of 3791 patients and used these data to create a risk classification
comprised of four categories (low, intermediate, moderately high,
high) based on local recurrence and survival rates. Higher T stage
lesions are categorized as intermediate-risk based on the overall
5-year survival rate of 75% and local recurrence rate of 9%. The
authors note that patients in subgroups who received neoadjuvant
RT had lower recurrence rates (5% to 10%) compared to patients
who were treated with surgery alone (11%). Unfortunately, they did
not have data concerning tumor location within the rectum; there-
fore, although the authors extrapolate that trimodality treatment of
intermediate-risk tumors may be excessive and unnecessary, no de-
finitive recommendations can be made at this juncture. Several smaller
studies concerning patients with only T3N0 rectal cancer treated with
surgery alone have reported 5-year local recurrence, systemic recurrence,
and survival rates comparable to cohorts of patients treated with neoad-
juvant or adjuvant CMT.
29-31
However, these studies do not differen-
tiate tumor location within the rectum and have small patient popula-
tions, therefore suggesting the further need into investigating if and
when it is safe to treat T3N0 patients with surgery alone.
Predictors of Local Recurrence
It has been well-established that CRM has important prognostic
value concerning local and distal recurrence in rectal cancer. What
has not been well-established is the relevance of CRM in upper rectal
cancer. In contrast to low and middle tumors constrained by a nar-
row pelvis, upper rectal tumors are not bound by similar physical
limitations. Thus, it has been hypothesized that CRM has less im-
portance as a prognostic indicator in upper rectal tumors. One study
2
comparing the 5-year local and systemic recurrence rates between
patients with positive CRM (n ⫽460) and patients with negative
CRM (n ⫽44) found that 5-year local recurrence was 35% in pa-
tients with a positive CRM compared to 11% in the negative-CRM
group (P⫽.010); 5-year systemic recurrence was 60% in the posi-
tive-CRM and 25% in the negative-CRM group (P⬍.001). Upper
rectal tumors comprised 24% of the negative-CRM group and 23%
of the positive-CRM group; however, there was no significant corre-
lation between tumor location and rate of CRM positivity or nega-
tivity (P⫽.466). Bernstein et al
4
also studied the predictive impact
of CRM after surgery to identify the ideal CRM. The authors looked
at a much larger study group (n ⫽3196) than the aforementioned
study and found that patients with CRM of 0 to 2 mm had a local
recurrence of 23.7% compared to 8.9% in patients with wider mar-
Table 1 Local Recurrence in Rectal Cancer With Neoadjuvant and Adjuvant Therapy
Trial (Year Results
Published)
Study
Design
No. of
Patients
No. of Patients
in Upper
Rectal Subset
Tumor Distance
From Anal
Verge (cm)
Follow-up
(Months) Treatment Outcome (%): Local Recurrence
Swedish Rectal Cancer
Trial (1997) RCT 1168 ⬎11 60 Neoadjuvant short-course RT vs surgery alone
11% vs 27%
(P⬍.001)
Dutch TME Trial (2001) RCT 1861 10.1-15 24
Neoadjuvant short-course
RT (standard TME ) vs
surgery alone
2.4% vs 8.2%
(P⬍.001)
German Rectal Cancer
Study Group (2004) RCT 799 ⬎10 60
Neoadjuvant long-course
RT ⫹chemotherapy vs.
adjuvant long-course
RT ⫹chemotherapy
6% vs 13%
(P⫽.006)
MSKCC (2008) Prospective 188
Abbreviations: MSKCC ⫽Memorial Sloan-Kettering Cancer Center; RCT ⫽randomized controlled trial; RT ⫽radiation therapy; TME ⫽total mesorectal excision.
Sarah Popek et al
Clinical Colorectal Cancer Month 2011 3

gins. Overall survival was 44.5% in the CRM 0-2-mm group and
66.7% in patients with wider margins. In the setting of TME surgery
without RT, the authors found that patients with mid-rectal tumors
are 38% more likely to have local recurrence than upper rectal tu-
mors, and low rectal tumors are 72% more likely to have a local
recurrence (HR 1.38, CI 1.01, 1.89; HR 1.72, CI 1.06, 2.79; P⫽
.047). They also found a significant correlation between local recur-
rence and CRM status in upper rectal lesions. They report that a
CRM of 0 to 2 mm nearly doubles the risk of having a local recur-
rence compared to CRM ⬎3 mm (HR 1.97, 95% CI 1.03, 3.77,
P⫽.044), suggesting that CRM is relevant in upper rectal tumors.
To conclude, CRM margins and, in particular, CRM margins more
than 2 mm, are critical for all heights of rectal tumors. The MRC
CR07
7
trial attempted to determine if RT could be delivered selec-
tively to only those patients with close CRM by randomizing patients to
neoadjuvant RT versus adjuvant RT only if CRM was ⬍1 mm. Approx-
imately 12% of patients in the selective adjuvant radiation arm had close
margins and received RT. Local recurrence rates were decreased with
neoadjuvant RT compared to selective adjuvant RT. Although this
study suggests that local recurrences are lowest with preoperative radia-
tion, it raises the question of whether clinical predictors of CRM mar-
gins, such as an MRI scan, could allow physicians to be able to more
intelligently select patients requiring preoperative therapy.
Another approach to the question of which higher T stage patients
benefit from neoadjuvant RT is to evaluate predictors of recurrence.
In a series of 100 consecutive pT2/T3 N0 patients
32
studied over a
period of 6.5 years, lymphovascular invasion, preoperative carcino-
embryonic antigen levels ⬎5 ng/mL, and patients older than 70
years were factors predictive of poor outcome. The authors of this
study did not include data concerning tumor location within the
rectum, however, they report local and distal recurrence rates of
4.1% and 28.6, respectively, for locally advanced tumors treated with
surgery alone. The authors state that treatment for uT3N0 rectal
cancer is radical surgery with TME and postulate that preoperative
identification of high-risk patients allows refinement of the popula-
tion of T3N0 patients who receive neoadjuvant RT to those who
truly benefit from it. A study
33
published in 2008 designed to address
the questions surrounding optimal management of T3N0 tumors
regardless of tumor height further obfuscates the issue. One hundred
eighty-eight uT3N0 patients were treated with neoadjuvant CMT
followed by surgery. The preoperative stage was compared to the
postoperative pathologic stage. Positive lymph nodes were identified
in 22% of patients. The incidence of involved lymph nodes corre-
sponded to pathologic T stage (ypT0 3%, ypT1 7%, ypT2 20%,
ypT3-4 36%, P⫽.001); suggesting that significant preoperative
understaging of rectal cancer occurs in at least 22% of patients. Dis-
tance from the anal verge was included as a tumor variable and the
incidence of lymph node positivity was not related to distance from
the anal verge (P⫽.58). The authors conclude that the risk of
overtreatment is lower than the risk of undertreatment and recom-
mend that locally aggressive tumors (T3 N0), independent of height
from the anal verge, should be treated with neoadjuvant CMT. Con-
versely, we could argue that if the pathologic examination has shown
that the upper rectal tumor with adequate CRM was significantly
understaged, or that surgery alone was not optimal, those patients
could receive adjuvant therapy. The potential drawback to this ap-
proach is a small decrease in local control with adjuvant versus neo-
adjuvant RT and increase in toxicity as demonstrated in the German
Rectal Cancer Study Group.
Summary
There is a paucity of data evaluating the outcomes of locally ad-
vanced upper rectal cancer treated with and without neoadjuvant
RT. Although several surrogate markers have been proposed for use
in determining which patients would benefit from neoadjuvant RT,
adequate CRM is the only variable shown in large population studies
to correlate with local recurrence rates in upper rectal cancer.
4
Syn-
thesizing the available data suggests that a subset of upper locally
advanced rectal cancers will not experience local recurrence, and in
this subset of patients, neoadjuvant RT only increases toxicity rates,
both acute and chronic.
34
Accurate preoperative staging is key to
making informed decisions regarding patient treatment because ad-
juvant CMT is less effective and more toxic than neoadjuvant CMT.
Careful physical examination combined with rigid proctoscopy can
facilitate defining the clinical location. Looking at the CT scan from
the perspective of tumor location provides additional relevant infor-
mation, such as, is the patient male or female? And, if the latter, did
she have a prior hysterectomy? Because of the risk of local recurrence
and the associated diminution of quality of life, the importance of
appropriately and selectively treating locally advanced rectal cancer
with neoadjuvant therapy intensifies. We propose that most patients
with T3N0 upper rectal tumors will not benefit from RT, and future
randomized trials should be considered in this subgroup of patients.
Treatment of T4N0 should be individualized. RT is likely of limited
benefit for patients with T4 disease by virtue of anterior extension
through the peritoneal surface, and these patients may be considered
for adjuvant single- modality chemotherapy. Extensive nodal metas-
tases or adherence of a transmural tumor to the pelvic sidewall may
be an indication for postoperative chemoradiation. Local recurrence
genetic signatures, independent of tumor distance from the anal
verge, may represent the next major breakthrough in the manage-
ment paradigm of locally advanced rectal cancer.
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