ORIGINAL ARTICLE – COLORECTAL CANCER
A Phase II Trial of Neoadjuvant Chemoradiation and Local
Excision for T2N0 Rectal Cancer: Preliminary Results
of the ACOSOG Z6041 Trial
Julio Garcia-Aguilar, MD, PhD1, Qian Shi, PhD2, Charles R. Thomas Jr. , MD3, Emily Chan, MD, PhD4,
Peter Cataldo, MD5, Jorge Marcet, MD6, David Medich, MD7, Alessio Pigazzi, MD1, Samuel Oommen, MD8,
and Mitchell C. Posner, MD9
1Department of Surgery, City of Hope, Duarte;2Division of Biomedical Statistics and Informatics, Mayo Clinic,
Rochester;3Knight Cancer Institute, Oregon Health and Science University, Portland;4Vanderbilt University Medical
Center, Nashville;5Department of Surgery, University of Vermont, Burlington;6Tampa General Hospital, Tampa;
7Allegheny Cancer Center, Pittsburgh;8John Muir Hospital, Concord;9University of Chicago Medical Center, Chicago
Purpose. We designed American College of Surgeons
Oncology Group (ACOSOG) Z6041, a prospective, mul-
ticenter, single-arm, phase II trial to assess the efficacy and
safety of neoadjuvant chemoradiation (CRT) and local
excision (LE) for T2N0 rectal cancer. Here, we report
tumor response, CRT-related toxicity, and perioperative
Methods. Clinically staged T2N0 rectal cancer patients
were treated with capecitabine and oxaliplatin during
radiation followed by LE. Because of toxicity, capecitabine
and radiation doses were reduced. LE was performed
6 weeks after CRT. Patients were evaluated for clinical and
pathologic response. CRT-related complications and PCs
Results. Ninety patients were accrued; 6 received non-
protocol treatment. The remaining 84 were 65% male;
median age 63 years; 83% Eastern Cooperative Oncology
Group performance score 0; 92% white; mean tumor size
2.9 cm; and average distance from anal verge 5.1 cm. Five
patients were considered ineligible. Therapy was com-
pleted per protocol in 79 patients, but two patients did not
undergo LE. Among 77 eligible patients who underwent
LE, 34 patients achieved a pathologic complete response
(44%) and 49 (64%) tumors were downstaged (ypT0–1),
but 4 patients (5%) had ypT3 tumors. Five LE specimens
contained lymph nodes; one T3 tumor had a positive node.
All but one patient had negative margins. Thirty-three
(39%) of 84 patients developed CRT-related grade C3
complications. Rectal pain was the most common PC.
Conclusions. CRT before LE for T2N0 tumors results in a
high pathologic complete response rate and negative
resection margins. However, complications during CRT
and after LE are high. The true efficacy of this approach
will ultimately be assessed by the long-term oncologic
The mainstay of treatment for rectal cancer is total mes-
orectal excision (TME). For most rectal cancers, TME is
TME results in a permanent colostomy. Most patients with
early rectal cancer who undergo TME experience high cure
recurrence rates lower than 7%.1–4However, TME is asso-
ciated with mortality (1–6%) and morbidity.5–8Local
excision (LE) is an alternative to TME for early stage rectal
cancer because it is associated with lower morbidity and
mortality, and it alleviates the need for a colostomy or the
distressing sequelae of a low colorectal anastomosis. How-
ever, LE alone often results in high local recurrence rates
that, although occasionally salvageable by TME, could
ultimately reduce long-term survival.9Consequently, LE as
gain widespread acceptance.
The oncologic benefits of neoadjuvant chemoradiation
(CRT) in patients with locally advanced rectal cancer
? Society of Surgical Oncology 2011
First Received: 3 January 2011
J. Garcia-Aguilar, MD, PhD
Ann Surg Oncol
treated with TME have increased interest in investigating
whether CRT could also reduce recurrence after LE in
patients with early rectal cancer.10–13Several retrospective
case series and a small prospective study suggest that CRT
before LE reduces recurrence to a level comparable with
TME.14–21However, these studies are collectively limited
by their small size, variable clinical staging criteria and
imaging modalities, heterogeneous tumor populations, and
use of varying CRT regimens. Thus, prospective data from
larger multicenter trials are needed.
To address this, the American College of Surgeons
Oncology Group (ACOSOG) designed a prospective phase
II trial that used neoadjuvant CRT followed by LE in
patients with ultrasound or magnetic resonance imaging
(MRI)-staged T2N0 rectal cancer (Z6041 trial). We report
tumor response, CRT-related toxicity, and complications
Study Design and Patients
The study was a single-arm, multicenter phase II trial
(Fig. 1a). A central institutional review board and the
institutional review board at each participating institution
approved the study. All patients provided written informed
consent before entering the trial. Before enrollment,
patients underwent a complete colonoscopy, rigid proc-
toscopy, either an endorectal ultrasound (ERUS) or
endorectal coil MRI, abdominal and pelvic computed
tomography (CT), and chest X-ray or chest CT. Central
review of all staging ERUS or endorectal coil MRI images
was performed for quality assurance.
All patients had an Eastern Cooperative Oncology
Group performance status of B2 and invasive rectal
FIG. 1 a ACOSOG Z6041 trial
protocol schema. b Patient disposition.
QARC Quality Assurance Review
Center, OD original dose group, RD
revised dose group, ANC absolute
J. Garcia-Aguilar et al.
adenocarcinoma with the distal margin located within 8 cm
of the anal verge, determined by rigid proctoscopy. TN
stage was T2N0 in all cases, established by either ERUS or
endorectal coil MRI. Greatest tumor diameter was B4 cm
and B40% of the rectum circumference, determined by
ERUS or endorectal coil MRI. Patients with tumors fixed to
adjacent structures, as established by digital rectal exami-
nation, were ineligible.
ICRU-50 prescription methods and nomenclature were
used. External beam radiotherapy (EBRT) with megavolt-
age linear accelerators (C6 MV) was delivered to a 3–4-
field pelvis arrangement after CT-based simulation and
computer-assisted treatment planning. Intensity-modulated
radiotherapy was allowed after a protocol modification,
primarily to increase accrual. Patients were treated 5 days/
week at 1.8 Gy/day for 5 weeks to a dose of 45 Gy to
planning target volume (PTV) 1, followed by a boost to
PTV2 (defined as gross tumor volume plus 2 cm) for a total
dose of 54 Gy. After an unfavorable toxicity profile, total
EBRT dose was reduced from 54 to 50.4 Gy. All fields
were treated daily. The radiotherapy treatment portals of
PTV1 were constructed such that the final cephalad border
of the field was at least at or above S2 and no higher than
mid L5. The caudad border excluded the perianal skin
when feasible. Posterior borders of the lateral fields were at
least 1.5 cm posterior to the sacral hollow and coccyx. The
anterior border included the internal iliac nodal drainage.
After 45 Gy, fields were reduced to include a 2-cm margin
around the tumor volume.
Patients received capecitabine (825 mg/m2days 1–14
and 22–35) and oxaliplatin (50 mg/m2weeks 1, 2, 4, and 5)
during radiation. As a result of higher-than-expected tox-
icity, capecitabine dosage was reduced to 725 mg/m2twice
a day, 5 days a week, for 5 weeks. Oxaliplatin dose was
not modified. Modifications in total EBRT dose and
capecitabine dose were introduced simultaneously.
Surgery and Pathology
Surgery was performed within 4–8 weeks after com-
pleting CRT (surgeon’s choice). LE was performed by
conventional transanal excision or transanal endoscopic
microsurgery. Full-thickness excision of the tumor area
with a 1-cm surrounding margin of normal rectal wall was
required. All surgeons were required to have performed at
least three transanal rectal tumor excisions with negative
margins and completed a surgeon skill verification pro-
gram. Before starting the tumor excision, surgeons assessed
clinical response to CRT. A clinical complete response
(cCR) was defined as the complete disappearance of tumor
on proctoscopic examination.
Tumors were staged according to American Joint
Committee on Cancer criteria.22Patients with ypT0–T2 N0
tumors and negative margins were followed as described
below. Patients with ypT3 tumors, positive nodes, or
positive margins were treated at the discretion of the
supervising physician, and alternative surgical options,
including TME, were considered.
Patients received a postsurgical examination 1 month
after surgery, then every 4 months for 3 years, and then
every 6 months for the next 2 years. Follow-up proctos-
copy and ERUS were conducted as clinically indicated or
at the physician’s discretion. In addition, patients under-
went colonoscopy 3 years after surgery. Other diagnostic
tests to detect or confirm tumor recurrence or distal
metastasis were performed if clinically indicated.
Study End Points and Statistical Analysis
The primary end point is 3-year disease-free survival.
To date, all patients have finished treatment, pathologic
data are complete, and patient follow-up is continuing.
Secondaryend points include
response (pCR) rate, accuracy of pCR prediction, negative
margin rate, morbidity and mortality after CRT and LE,
and assessment of quality of life.
The original accrual goal was 83 patients. Sixty-two
patients were accrued onto the original dose. After the
EBRT and capecitabine dosage reductions, the protocol
was amended to accrue 40 additional patients onto the
revised dose group, for a total accrual goal of 102 patients.
A toxicity threshold of 30% was set for the revised dose
group such that if the proportion of patients with grade C3
adverse events (AEs) reached 30%, accrual would be
Analysis pertaining to the pCR rate included all eligible
patients who completed CRT and LE. The pCR rates are
reported as percentages with 95% confidence intervals,
overall and by dose group.
Safety assessment involved monitoring and reporting
AEs and perioperative complications (PCs) occurring
within 60 days of surgery. AEs were evaluated according
to the National Cancer Institute Common Terminology
Criteria for Adverse Events, version 3.0. The ACOSOG
Data Monitoring Committee reviewed AEs to evaluate
ongoing safety and efficacy. Safety analysis pertaining to
CRT was performed in all patients who received at least
one dose of CRT. PCs were assessed in all eligible patients
who completed both CRT and LE. AEs related to CRT and
Neoadjuvant CRT and LE for Rectal Cancer
LE are descriptive in nature. The Wilcoxon rank sum test
and Fisher’s exact test were used to compare continuous
and categorical variables between dose groups. All P val-
ues were based on two-sided tests with a significance level
Ninety patients, 62 receiving the original dose and 28
receiving the revised dose, were enrolled onto the study
from May 2006 to October 2009 at 30 institutions. Six of
the 90 patients consented but did not begin protocol
treatment and were deemed unevaluable (Fig. 1b). Table 1
summarizes patient demographics, Eastern Cooperative
Oncology Group performance status, and pretreatment
tumor characteristics for the 84 eligible patients. All
received at least one dose of CRT and were therefore
included in analysis of CRT-related AEs, representing the
full analysis set. Of these 84 patients, 5 were later con-
sidered ineligible (Fig. 1b). The remaining 79 patients
received CRT per protocol and represent the per-protocol
set. Two of these patients did not have LE (Fig. 1b).
Analysis pertaining to tumor response (pCR) and PCs
includes the 77 patients who successfully completed both
CRT and LE.
Chemotherapy and radiotherapy information for all full
analysis set patients and by dose group is shown in Table 2.
Overall, 62 patients (72%) completed both chemotherapy
and radiotherapy per protocol. More patients completed
radiotherapy per protocol than chemotherapy. The propor-
tion of patients who completed chemotherapy per protocol
was lower for the revised dose group compared to the ori-
ginal dose group. The opposite was observed with
radiotherapy; all patients in the revised dose group com-
pleted treatment per protocol comparedto 47 patients (83%)
in the original dose group. Time from beginning and end of
CRT to surgery was not different between dosage groups.
Ten patients received intensity-modulated radiotherapy.
Overall, 33 patients (39%), 25 (44%) in the original dose
group and 8 (30%) in the revised dose group, developed
grade C3 AEs potentially attributable to treatment. The
most common grade C3 AEs by body system are presented
in Table 3. There were no deaths on treatment. The toxicity
threshold rate set for the revised dose group was reached
when 8 (30%) of the first 27 patients accrued developed
grade C3 AEs possibly related to treatment, and the study
was closed to accrual.
Surgical and Pathologic Data
Surgical information and pathologic tumor characteris-
tics for the 77 patients who had LE are shown in Table 4.
At surgery tumors were smaller compared to baseline, and
over half were considered to have a cCR to CRT. Resection
margins were negative in all but one patient. Overall, 49
patients (64%) had tumors down-staged to ypT0–1, 23
(30%) were ypT2, and 4 (5%) were ypT3. Only 5 LE
specimens contained lymph nodes; one patient with a T3
tumor had a positive node. This patient later underwent
TME and had no tumor left in either the rectal wall or
perirectal lymph nodes.
Thirty-four patients experienced pCR (44%; 95% con-
fidence interval 32–55), 25 patients (48%) in the original
dose group and 9 patients (36%) in the revised dose group.
TABLE 1 Baseline patient demographics and disease characteristics
(n = 84)
(n = 57)
(n = 27)
Age, years, median (range) 63 (30–83)63 (30–80) 64 (45–83)
Male 55 (65)35 (61)20 (74)
Female29 (35) 22 (39)7 (26)
White 77 (92) 51 (90)26 (96)
Black2 (2)2 (4) 0 (0)
Native Hawaiian/ Pacific
1 (1) 1 (2)0 (0)
Asian 2 (2) 1 (2)1 (4)
American Indian1 (1) 1 (2) 0 (0)
Unknown 1 (1)1 (2)0 (0)
ECOG PS (%)
0 70 (83) 49 (86)21 (78)
1 13 (16) 7 (12) 6 (22)
21 (1)1 (2) 0 (0)
Tumor size, cm,
mean ± SD
2.9 ± 0.82.8 ± 0.82.9 ± 0.7
Tumor location (%)
Anterior16 (19)11 (19) 5 (19)
Posterior43 (51)32 (56)11 (41)
Left lateral 18 (21)11 (19)7 (26)
Right lateral 7 (8)3 (5)4 (15)
Distance from anal verge
(distal), cm, mean ± SD
5.1 ± 2 4.9 ± 1.9 5.4 ± 2.1
ECOG PS Eastern Cooperative Oncology Group performance status
J. Garcia-Aguilar et al.
No pretreatment tumor characteristic or treatment-related
variable was associated with pCR. A cCR correlated with
pCR in 29 of 34 patients: sensitivity 85%, specificity 67%,
21 of 25 patients in the original dose group; sensitivity
84%, specificity 67%, and 8 of 9 patients in the revised
dose group; and sensitivity 89%, specificity 69%.
PC data were collected for the 77 eligible patients who
underwent surgery (original dose group, n = 52; revised
dose group, n = 25). Overall, 28 patients (54%) in the
original dose group and 17 patients (68%) in the revised
dose group developed PCs. One patient in the original dose
group developed grade 4 bleeding after LE. The most
common grade 3 complications are listed in Table 5.
This study shows that radiotherapy concurrent with
capecitabine- and oxaliplatin-based chemotherapy fol-
lowed by LE for T2N0 rectal cancer results in a pCR in
close to half the treated patients. In addition, nearly all
eligible patients who received per-protocol CRT underwent
LE with negative margins. However, despite a dose
reduction during the trial, CRT-related toxicity was high,
and PCs after LE were not uncommon.
In recent years, tumor response to CRT has emerged as
an important predictor of tumor control and patient survival
and has become an important end point in clinical trials of
rectal cancer treated by CRT.23–25Although the pCR rate
to CRT in locally advanced rectal cancer is well known,
data on pCR rates in patients with early rectal cancer are
limited. Mohiuddin et al. was first to report a 38% pCR rate
in patients with T1–T3 distal rectal cancers treated with
radiation and LE.12–14Since then, several investigators
have reported pCR rates ranging 30–73% for T2 and T3
TABLE 2 Chemotherapy and
CRT chemoradiation therapy
Patients did not receive any
doses of capecitabine or
Patients began treatment but
did not undergo surgery;
therefore, days from start and
end of CRT to surgery are
(n = 84)
(n = 57)
(n = 27)
Capecitabine total dose, mg/m2, mean ± SD
No. of patients missinga
Oxaliplatin total dose, mg/m2, mean ± SD
No of patients missinga
755 ± 199.6 824.9 ± 182615.3 ± 157
36.1 ± 8.8 35.9 ± 7.936.5 ± 10.7
Radiotherapy total dose, Gy, mean ± SD 51.8 ± 5.7 52.2 ± 6.8 51 ± 1.4
Chemotherapy completed per protocol, n (%)
Yes 68 (81)48 (84) 20 (74)
No16 (19)9 (16) 7 (26)
Chemotherapy delayed or modified, n (%)
Yes41 (49)26 (46) 15 (56)
No 43 (51)31 (54)12 (44)
Radiotherapy completed per protocol, n (%)
Yes74 (88) 47 (83) 27 (100)
No 10 (12)10 (18) 0 (0)
Radiotherapy interrupted, n (%)
Yes35 (42)27 (47) 8 (30)
No49 (58) 30 (53)19 (70)
Days from start of CRT to surgery
No. of patients missingb
88.5 ± 16 89.2 ± 13.187.2 ± 21.3
Days from end of CRT to surgery
No. of patients missingb
47.5 ± 14.347.4 ± 11.3 47.6 ± 19.6
TABLE 3 Most common AEs occurring during CRT
(n = 84)
(n = 57)
(n = 27)
Gastrointestinal 19 (23) 1 (1) 16 (28) 1 (2)3 (11) 0 (0)
Dermatologic8 (10)0 (0)6 (11) 0 (0) 2 (7)0 (0)
Hematologic 9 (11)1 (1) 4 (7)1 (2)5 (19) 0 (0)
Pain6 (7) 1 (1) 4 (7)1 (2)2 (7) 0 (0)
Metabolic 5 (6)2 (2) 3 (5)1 (2) 2 (7) 1 (4)
CRT chemoradiation therapy
AE at least possibly attributed to CRT for CRT visits 3 to 8. No grade
5 fatal toxicity was observed
Neoadjuvant CRT and LE for Rectal Cancer
tumors treated with CRT and LE.15–21However, these
single-institution studies are limited by their small size,
varying CRT regimens, and heterogonous patient popula-
tions. Lezoche et al.21reported a 30% pCR rate in T2N0
rectal cancer patients treated with 5-fluorouracil (5-FU)-
based CRT, and either LE or TME. The higher pCR rate
observed in our study could be attributable to the difference
in sensitizing chemotherapy; the patients of Lezoche et al.
received only 5-FU, whereas in our trial, patients received
capecitabine and oxaliplatin. However, it is important to
note that in non-LE trials, a pCR requires both the primary
site and lymph nodes to be free of tumor, and in our trial,
lymph nodes were not examined in most cases, so this
could also account for our higher pCR rate. It is noteworthy
that after treatment a small number of patients (5%) had
ypT3 tumors. This underscores the relatively low accuracy
of ERUS and endorectal coil MRI for staging rectal cancer
and suggests that some patients were undertreated while
others may have been overtreated.
The CRT regimen chosen for our study was based on a
regimen used by Rodel et al.26With a regimen of cape-
citabine, oxaliplatin, and radiation before TME, they
reported a grade C3 AE rate of 8%. We encountered a
much higher treatment-related toxicity in our patients, with
25 (44%) of the first 57 patients entered onto our trial
experiencing a grade 3 or 4 AE. Failure to proactively
address grades 1–2 toxicities along with discordance
between physician and patient assessment of severity of
treatment-related symptoms may have contributed in part
to the unfavorable toxicity profile from CRT in our study.
Dose reductions in capecitabine and radiation did reduce
toxicity, but it still remained higher than the number
reported by Rodel et al. Potential explanations for these
discrepancies include differences in criteria for dose
modification, regional differences in capecitabine tolera-
bility, and quickness to recognize and interrupt dosing.
The STAR-01 and ACCORD 12/0405—Prodige 2 trials
have assessed the effect of adding oxaliplatin to a regimen
of preoperative 5-FU-based CRT in patients with locally
advanced rectal cancer.27,28
patients receiving oxaliplatin reported higher toxicity
compared to patients who did not, with no marked differ-
ence in tumor response. In our study, dose reductions in
capecitabine and radiation not only decreased toxicity, but
also reduced the pCR rate from 48% (original dose group)
to 36% (revised dose group), although this may be con-
founded by the smaller numbers in the revised dose group.
Nonetheless, on the basis of the results of the STAR-01 and
ACCORD 12/0405—Prodige 2 trials, it is possible to
speculate that a reduction in oxaliplatin instead of cape-
citabine and radiation may have had a more beneficial
effect on CRT safety without compromising pCR rate, thus
contributing to a more favorable therapeutic ratio.
The presence of tumor at the resection margins after LE
is not uncommon and often requires immediate TME.29,30
In our series, only one patient had positive margins. This
patient underwent abdominoperineal resection and had no
residual tumor. In the CALGB 8984 trial, the largest pro-
spective study on LE, patients with clinical stage I rectal
cancer were registered before surgery.31,32A second reg-
istration occurred after surgery; patients with T1 tumors
were observed while patients with T2 tumors received
CRT. Patients with positive margins and stage[T2 or\T1
were eliminated. Twenty (11%) of 180 patients registered
on the trial were excluded because of positive or ques-
tionable resection margins. Our data suggest that by
Both studies found that
TABLE 4 Pathologic tumor characteristics
(n = 77)
(n = 52)
(n = 25)
Resected tumor margins free of tumor
Yes76 (99)52 (100) 24 (96)
No 1 (1)0 (0)1 (4)
Pathologic tumor size, cm,
mean ± SD
0.9 ± 1.1 0.9 ± 1.1 0.9 ± 1
No. of patients missing 220
Tumor T stage
T034 (44)25 (48)9 (36)
Tis 5 (7)3 (6) 2 (8)
T110 (13) 7 (13)3 (12)
T223 (30)14 (27) 9 (36)
4 (5) 2 (4)2 (8)
1 (1) 1 (2)0 (0)
Clinical complete response
Yes43 (56) 30 (58)13 (52)
No34 (44) 22 (42)12 (48)
Disease was not T0 because the presence of residual cancer cells
TABLE 5 Most common grade 3 AEs occurring within 60 days of
(n = 77) (%)
(n = 52) (%)
(n = 25) (%)
Rectal pain 6 (8)5 (10)1 (4)
Hemorrhage2 (3)1 (2)1 (4)
Infection 2 (3)1 (2)1 (4)
Urinary retention 2 (3)1 (2) 1 (4)
1 (1) 1 (2) 0 (0)
12 (16) 7 (13)5 (20)
Number of patients who experienced any grade 3 complication
J. Garcia-Aguilar et al.
reducing the risk of positive resection margins, neoadju-
vant CRT may increase the proportion of patients with
early rectal cancer who would be candidates for LE.
Complications after LE were common in our patients.
Perianal pain was the most common AE, experienced by
8% of patients. The source of the pain is unclear, but it was
more common among patients in the original dose group
(10%) than in the revised dose group (4%), and it subsided
in most patients within 3 months of LE, indicating that the
postoperative pain may be related to delayed healing of the
LE wound in a heavily radiated tissue. The anal canal was
not routinely included in the radiation field. Nonetheless,
by virtue of the distal location of these tumors, the anal
canal and perianal area were included in the radiation field
in some patients. Marks et al.33reported that CRT before
LE does increase the rate of wound-related complications
(26%) compared to LE alone (0%). However, most com-
plications reported in their series were classified as minor
(82%), and many (91%) were treated without any addi-
tional surgery or intervention. In their series, the mean dose
of radiation (51.7 Gy) was similar to ours (51.8 Gy), but
their patients only received sensitizing 5-FU. Taken toge-
ther, these data suggest that postoperative morbidity may
be a limiting factor with respect to intensity of the neo-
adjuvant regimen. Further, it is important to note that
although CRT before LE is advantageous because it results
in a low positive margin rate, it has the disadvantage of
possibly causing postoperative pain.
Accurate pCR diagnosis before surgery is critical for
implementation of an organ-preservation approach in
selected patients with rectal cancer. Neither clinical
examination nor commonly used imaging methods have
been able to diagnose pCR with a reasonable degree of
accuracy in patients with locally advanced rectal can-
cer.34–36Hiotis et al.37investigated the accuracy of digital
rectal examination and proctoscopy in predicting pCR after
CRT in patients with locally advanced rectal cancer treated
with TME. Although 19% of patients had a cCR, only 25%
of these had a pCR. In their series, the sensitivity of cCR as
a predictor of pCR was 77%, but the specificity was only
16%. In our series, cCR predicted pCR with 85% sensi-
tivity and 67% specificity—a better predictor than
previously reported. These discrepant results may be
attributable to pCR rate differences, 10% in the series of
Hiotis et al. versus 44% in ours, as well as methodological
differences between studies; their study was retrospective
and ours was prospective.
In conclusion, our prospective multicenter trial demon-
strates that CRT and LE for T2N0 rectal cancer results in a
pCR in almost half the treated patients, with a negative
margin rate close to 100%. However, CRT-related toxicity
was high and PCs after LE were common, suggesting that
although this approach is promising, it still requires further
modification to improve the therapeutic ratio. A successor
trial is planned to decrease CRT toxicity while optimizing
for assistance in writing and editing the article. This work was sup-
ported by funding from the US National Cancer Institute (NCI) to the
American College of Surgeons Oncology Group (ACOSOG); grant
U10 CA76001; and Sanofi-Aventis.
The authors thank Nicola Solomon, PhD,
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