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Int. J. Radiation Oncology Biol. Phys., Vol. 69, No. 4, pp. 1167–1172, 2007Copyright � 2007 Elsevier Inc.
Printed in the USA. All rights reserved0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2007.04.047
CLINICAL INVESTIGATION Rectum
CLINICAL PARAMETERS PREDICTING PATHOLOGIC TUMOR RESPONSE AFTERPREOPERATIVE CHEMORADIOTHERAPY FOR RECTAL CANCER
SANG MIN YOON, M.D., DAE YONG KIM, M.D., TAE HYUN KIM, M.D., KYUNG HAE JUNG, M.D.,HEE JIN CHANG, M.D., WOONG SUB KOOM, M.D., SEOK-BYUNG LIM, M.D., HYO SEONG CHOI, M.D.,
SEUNG-YONG JEONG, M.D., AND JAE-GAHB PARK, M.D.
Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
Purpose: To identify pretreatment clinical parameters that could predict pathologic tumor response to preopera-tive chemoradiotherapy (CRT) for rectal cancer.Methods and Materials: The study involved 351 patients who underwent preoperative CRT followed by surgerybetween October 2001 and July 2006. Tumor responses to preoperative CRT were assessed in terms of tumordownstaging and tumor regression. Statistical analyses were performed to identify clinical factors associatedwith pathologic tumor response.Results: Tumor downstaging (defined as ypT2 or less) was observed in 167 patients (47.6%), whereas tumor regres-sion (defined as Dworak’s Regression Grades 3 or 4) was observed in 103 patients (29.3%) and complete regressionin 51 patients (14.5%). Multivariate analysis found that predictors of downstaging were pretreatment hemoglobinlevel (p = 0.045), cN0 classification (p < 0.001), and serum carcinoembryonic antigen (CEA) level (p < 0.001), thatpredictors of tumor regression were cN0 classification (p = 0.044) and CEA level (p < 0.001), and that the predictorof complete regression was CEA level (p = 0.004).Conclusions: The data suggest that pretreatment CEA level is the most important clinical predictor of pathologictumor response. It may be of benefit in the selection of treatment options as well as the assessment of individualprognosis. � 2007 Elsevier Inc.
Rectal cancer, Preoperative chemoradiotherapy, Downstaging, Tumor regression.
INTRODUCTION
Postoperative chemoradiotherapy (CRT) improves local
control and survival in locally advanced rectal cancer (1).
In the past, radical surgery followed by postoperative CRT
was considered standard treatment. However, preoperative
CRT for advanced rectal cancer has been increasingly used
in recent years and has now become a standard treatment,
and a recent prospective, randomized trial confirmed the su-
periority of preoperative over postoperative CRT in terms of
local control and toxicity (2).
In contrast to the postoperative setting, preoperative CRT
allows a relatively short-term evaluation because it offers
alternative endpoints based on pathologic tumor response.
The most commonly used endpoint is tumor downstaging.
Numerous studies have reported that tumor downstaging
after preoperative radiotherapy with or without chemother-
apy followed by surgical resection is associated with
11
decreased recurrence and improved survival (3–9). Another
endpoint for assessing pathologic tumor response is tumor
regression grade after preoperative CRT. A variety of defini-
tions and techniques for identifying and scoring the residual
cancer exist, and several studies have reported correlations
between tumor regression grade and long-term clinical out-
comes (8, 10–12). On the basis of these reports, the ability
to predict the pathologic tumor response before treatment
would be of clinical advantage in that it may provide addi-
tional information for permitting tailored treatment options
as well as for assessing the individual prognosis.
Using specific molecular markers or gene expression pro-
filing, many translational studies have sought to identify the
biologic properties of tumors that might predict therapeutic
response (13–19). Although those studies identified a number
of potentially important predictors, the results have not yet
had clinical impact owing to variable findings between stud-
ies and because the techniques used are complex and time
Reprint requests to: Dae Yong Kim, M.D., Center for ColorectalCancer, National Cancer Center, 809 Madu-1-dong, Ilsandong-gu,Goyang-si, Gyeonggi-do 410-769, Republic of Korea. Tel: (+82)31-920-1721; Fax: (+82) 31-920-0149; E-mail: radiopia@ncc.re.kr
Supported by the Korea Health 21 R&D Project, Ministry of
6
Health and Welfare, Republic of Korea (Grant No. 0412-CR01-0704-0001).
Conflict of interest: none.Received Feb 1, 2007, and in revised form April 24, 2007.
Accepted for publication April 26, 2007.
7
1168 I. J. Radiation Oncology d Biology d Physics Volume 69, Number 4, 2007
consuming in terms of clinical application. Thus, despite nu-
merous studies, neither molecular marker nor gene expres-
sion profiling data have identified definitive predictors of
tumor response. In contrast, there has been no systematic
investigation of clinical parameters that may predict preoper-
ative CRT tumor response.
With this background, the present study sought to identify
pretreatment clinical parameters that may predict pathologic
tumor response to preoperative CRT.
METHODS AND MATERIALS
PatientsBetween October 2001 and July 2006, 388 patients with primary
rectal cancer underwent preoperative CRT at the National Cancer
Center, Republic of Korea. Medical records were reviewed to ana-
lyze clinical prognostic parameters and to identify the following in-
clusion criteria: (1) histologically confirmed rectal adenocarcinoma,
(2) tumor located within 8 cm of the anal verge, (3) locally advanced
(cT3-4 classification) and curatively resectable tumor evaluated with
magnetic resonance imaging (MRI) with or without transrectal ultra-
sonography, (4) adequate bone marrow, hepatic, and renal function,
and (5) no evidence of distant metastasis.
TreatmentPreoperative radiotherapy was delivered to the whole pelvis at
a dose of 45 Gy in 25 fractions, followed by a boost of 5.4 Gy in
3 fractions to the primary tumor within 6 weeks. All patients under-
went computed tomography (CT) simulation for three-dimensional
conformal radiotherapy planning, and a three-field treatment plan
was used involving a 6-MV photon posterior–anterior field and
15-MV photon opposed lateral beams. The beam weights of the
plan were optimized to minimize the maximal dose within the target
volume. The initial radiation field encompassed a volume that
included the gross tumor, mesorectum, presacral space, whole of
the sacral hollow, and regional lymphatics. The superior border
was placed at L5/S1 and the inferior border at 3 cm or more caudal
to the gross tumor. The boost field included the gross tumor volume
and mesorectum with $2-cm margins in all directions.
Preoperative chemotherapy was initiated on the first day of
pelvic radiotherapy and was delivered concurrently with radiother-
apy. Three different chemotherapy regimens were used. The 5-
fluorouracil and leucovorin group received two cycles of an i.v.
bolus injection of 5-fluorouracil (400 mg/m2/day) and leucovorin
(20 mg/m2/day) for 3 days in the first and fifth weeks of radiotherapy
(from October 2001 to July 2006). The capecitabine group received
825 mg/m2 capecitabine orally twice daily during radiotherapy with-
out weekend breaks (from April 2003 to July 2006). The capecita-
bine and irinotecan group received 825 mg/m2 capecitabine twice
daily during radiotherapy with weekend breaks and 40 mg/m2 irino-
tecan weekly for 5 weeks (from July 2004 to July 2006).
After the completion of preoperative CRT, all patients underwent
a radical proctectomy, including high ligation of the inferior mesen-
teric vessels and total mesorectal excision. Low anterior resection
was performed in 292 patients (83.2%) and abdominoperineal resec-
tion in 59 patients (16.8%). Lateral node dissection was not
performed routinely in the surgical procedure. The median interval
between CRT and surgery was 6 weeks (range, 4–8 weeks).
EvaluationBefore preoperative CRT, patients underwent preoperative diag-
nostic and staging workups, including digital rectal examination,
full blood counts and a biochemical profile, serum carcino-
embryonic antigen (CEA) level measurement, colonoscopy with
biopsy, chest radiography, abdominopelvic CT, pelvic MRI, and/
or transrectal ultrasonography. The MRI protocol has been described
in our previous report (20). The cross-sectional areas of the primary
tumors were measured using axial T2-weighted images by tracing
the lesion boundary. On T2-weighted images, the cross-sectional
lesion areas were defined as intermediate signal intensity areas
that had a different signal intensity and contour from the normal
rectal wall. The lesion volumes were displayed automatically in
a three-dimensional format and were calculated by summing each
of the cross-sectional volumes of the entire lesion. Positive lymph
node involvement was defined as a lymph node $5 mm in the small-
est diameter observed on CT or MRI (21).
After radical surgery, tumor specimens were reviewed and the
post-CRT pathologic stage (yp) was determined according to the
TNM classification system recommended by the American Joint
Committee on Cancer (22). Tumor downstaging was determined
by comparing pretreatment clinical and postoperative pathologic
T classifications, and downstaging was defined as ypT2 or lower.
Tumors were also assessed using Dworak’s tumor regression grading
system for semiquantitative evaluation of histopathologic tumor
regression (23). Regression was graded as follows: Grade 0, no re-
gression; Grade 1, dominant tumor mass with obvious fibrosis and/
or vasculopathy (minimal regression); Grade 2, dominant fibrotic
changes with few tumor cells or groups (moderate regression); Grade
3, very few tumor cells in fibrotic tissue with or without mucous sub-
stance; Grade 4, no tumor cells, only fibrotic mass or acellular mucin
pools (complete regression). The regression grade concerned both
primary tumor and regional lymph nodes. The study defined Grades
3 and 4 as tumor regression for the purpose of statistical analysis.
StatisticsThe study was designed to identify clinical variables that could
predict pathologic stage and tumor regression. Logistic regression
analysis was used to identify correlations between pathologic re-
sponses and continuous variables. Chi-square or Fisher’s exact tests
were used to determine the significance of associations between
pathologic findings and categoric variables. The multivariate analy-
sis used to identify correlations between pathologic findings and all
potential parameters involved a backward likelihood ratio using a
logistic regression model. A receiver operating characteristic curve
was used to define the cutoff point for the various continuous
variables that were relative to the predicting tumor response. Prob-
ability (p) values of <0.05 were considered to indicate a significant
difference.
RESULTS
Patient characteristicsOf the 388 patients, 20 refused surgery, 7 were treated with
transanal excision because of comorbidities or strong refusal
of anal ablation, and 10 were transferred to other hospitals
closer to their residence. Therefore, 351 patients who met
the inclusion criteria were analyzed in this study. Table 1
shows detailed patient characteristics. The study population
was mostly male (66.7%) and had a median age of 57
years (range, 31–83 years). Almost all patients had a cT3
Clinical parameters predicting response d S. M. YOON et al. 1169
classification of their primary tumor (96.9%), and the major
type was adenocarcinoma (96.9%). Elevated serum CEA
levels were observed in 33.6% of patients at diagnosis (the
upper limit of normal was defined as 5 ng/mL).
Pathologic tumor response after preoperative CRTPathologic examination of resected specimens revealed
ypT0 in 54 patients (15.4%) (including ypT0N1 in 3 pa-
tients), ypTis in 3 patients (0.9%), ypT1 in 20 patients
(5.7%), ypT2 in 90 patients (25.6%), ypT3 in 168 patients
(47.9%), and ypT4 in 16 patients (4.5%). Downstaging to
ypT2 or less was observed in 167 patients (47.6%). Dworak’s
tumor regression grades after preoperative CRT were Grade 1
in 57 patients (16.3%), Grade 2 in 191 patients (54.4%),
Grade 3 in 52 patients (14.8%), and Grade 4 in 51 patients
(14.5%). Thus, 103 patients (29.3%) showed tumor regres-
sion (i.e., Grade 3 or 4) as defined in the present study.
Clinical parameters predicting pathologic tumor responseUnivariate predictors of downstaging (ypT0-2) were
found to be a pretreatment hemoglobin level $12.5 g/dL
Table 1. Patient characteristics
GenderMale 234 (66.7)Female 117 (33.3)
Age (y)Median 57Range 31–83
Pretreatment hemoglobin level#12.5 g/dL 142 (40.5)>12.5 g/dL 209 (59.5)
Distance from anal verge (cm)Median 5Range 0–8
Clinical T classificationcT3 340 (96.9)cT4 11 (3.1)
Clinical N classificationcN0 55 (15.7)cN+ 296 (84.3)
Histologic typeAdenocarcinoma 340 (96.9)Mucinous 9 (2.6)Signet ring cell 2 (0.5)
Histologic gradeLow grade 330 (94.0)High grade 21 (6.0)
Pretreatment tumor volume (cm3)Mean � SD 19.1 � 21.5Median 13.8Range 0.8–235.8
Pretreatment CEA level#5 ng/mL 233 (66.4)>5 ng/mL 118 (33.6)
Chemotherapy regimenFL group 146 (41.6)Capecitabine group 134 (38.2)IX group 71 (20.2)
Abbreviations: SD = standard deviation; CEA = carcinoem-bryonic antigen; FL = 5-fluorouracil and leucovorin; IX = irinotecanand capecitabine.
Values are number (percentage) unless otherwise noted.
(p = 0.016), cT3 classification (p = 0.047), cN0 classification
(p < 0.001), pretreatment tumor volume #13 cm3 (p <
0.001), and CEA levels #5 ng/mL (p < 0.001). Univariate
predictors of tumor regression were found to be a cN0 class-
ification (p = 0.011), pretreatment tumor volume #13 cm3
(p = 0.018), and CEA levels #5 ng/mL (p < 0.001). Univar-
iate predictors of complete regression were found to be
a cN0 classification (p = 0.037) and CEA levels #5 ng/mL
(p < 0.001) (Table 2).
Multivariate analysis revealed that pretreatment hemoglo-
bin levels $12.5 g/dL (p = 0.045), cN0 classification (p <
0.001), and CEA levels #5 ng/mL (p < 0.001) were predic-
tors of downstaging, that cN0 classification (p = 0.044) and
CEA levels #5 ng/mL (p < 0.001) were predictors of tumor
regression, and that CEA levels #5 ng/mL (p = 0.004) was
a predictor of complete regression (Table 3).
DISCUSSION
A wide spectrum of tumor responses has been reported
after preoperative CRT for locally advanced rectal cancer, and
the clinical meaning of such responses in terms of prognosis
has been the subject of many investigations. Tumor response
prediction before surgery may be of benefit to effective man-
agement. The prognostic factors for predicting long-term
clinical outcomes have mostly been based on histopathologic
parameters after curative resection in preoperative setting
studies (3–12, 24). The potential advantage of using these
pathologic parameters includes their availability in the rela-
tively short-term and that they are objectively measurable
(25). However, a significant proportion of patients are un-
likely to respond to standard preoperative CRT. Consider-
ation of more intensive and individualized CRT regimens
may be indicated for these patients. Conversely, less aggres-
sive surgical procedures may be an alternative to sphincter-
ablating surgery in highly selected patients with distal rectal
cancers who had marked regression after preoperative CRT.
Thus, there is an obvious need for new markers to predict path-
ologic response before preoperative CRT with a perspective of
tailored treatment. Histologic tumor response is associated
with several factors, including patient-, tumor-, and treat-
ment-related factors. In the present study, treatment-related
factors, such as radiation dose schedules and concomitant
administration of chemotherapy, were relatively homogeneous
for all patients, and, thus, any differences in downstaging and
tumor regression were likely to be due to factors relating to
individual patients and particular tumor characteristics.
In the present study, multivariate analysis found that
pretreatment CEA level was the common predictor of down-
staging, tumor regression, and complete regression. Carcino-
embryonic antigen levels have long been known to provide
potential benefit for predicting outcomes. Furthermore, the
preoperative CEA level is considered a Category I prognostic
indicator in the College of American Pathologists Consensus
Statement 1999 (26). However, few studies have validated
the predictive value of the CEA level as a marker for tumor
response after preoperative CRT. In a recent study, Park
1170 I. J. Radiation Oncology d Biology d Physics Volume 69, Number 4, 2007
Table 2. Univariate analysis to identify predictors of downstaging, tumor regression, and complete regresion
Downstaging Tumor regression grade (1–2 vs. 3–4) Tumor regression grade (1–3 vs. 4)
Variable No (n = 184) Yes (n = 167) 1–2 (n = 248) 3–4 (n = 103) 1–3 (n = 300) 4 (n = 51)
GenderMale 124 (53.0) 110 (47.0) 167 (71.4) 67 (28.6) 199 (85.0) 35 (15.0)Female 60 (51.3) 57 (48.7) 81 (69.2) 36 (30.8) 101 (86.3) 16 (13.7)p* 0.762 0.679 0.748
Age (y)#57 94 (52.5) 85 (47.5) 122 (68.2) 57 (31.8) 147 (82.1) 32 (17.9)>57 90 (52.3) 82 (47.7) 126 (73.3) 46 (26.7) 153 (89.0) 19 (11.0)p 0.972 0.294 0.069
PretreatmentHb level (g/dL)
#12.5 85 (60.3) 56 (39.7) 105 (74.5) 36 (25.5) 122 (86.5) 19 (13.5)>12.5 99 (47.1) 111 (52.9) 143 (68.1) 67 (31.9) 178 (84.8) 32 (15.2)p 0.016 0.199 0.646
Distance fromanal verge (cm)
<5 74 (50.3) 73 (49.7) 105 (71.4) 42 (28.6) 125 (85.0) 22 (15.0)$5 110 (53.9) 94 (46.1) 143 (70.1) 61 (29.9) 175 (85.8) 29 (14.2)p 0.507 0.787 0.844
T classificationcT3 175 (51.5) 165 (48.5) 239 (70.3) 101 (29.7) 291 (85.6) 49 (14.4)cT4 9 (81.8) 2 (18.2) 9 (81.8) 2 (18.2) 9 (81.8) 2 (18.2)p 0.047 0.519 0.665
N classificationcN (�) 15 (27.3) 40 (72.7) 31 (56.4) 24 (43.6) 42 (76.4) 13 (23.6)cN (+) 169 (57.1) 127 (42.9) 217 (73.3) 79 (26.7) 258 (87.2) 38 (12.8)p <0.001 0.011 0.037
Histologic gradeLow grade 171 (51.8) 159 (48.2) 232 (70.3) 98 (29.7) 282 (85.5) 48 (14.5)High grade 13 (61.9) 8 (38.1) 16 (76.2) 5 (23.8) 18 (85.7) 3 (14.3)p 0.369 0.566 0.974
Pretreatment tumorvolume (cm3)
#13 67 (41.9) 93 (58.1) 103 (64.4) 57 (35.6) 133 (83.1) 27 (16.9)>13 117 (61.3) 74 (38.7) 145 (75.9) 46 (24.1) 167 (87.4) 24 (12.6)p <0.001 0.018 0.254
Pretreatment CEAlevel (ng/mL)
#5 98 (42.1) 135 (57.9) 148 (63.5) 85 (36.5) 189 (81.1) 44 (18.9)>5 86 (72.9) 32 (27.1) 100 (84.7) 18 (15.3) 111 (94.1) 7 (5.9)p <0.001 <0.001 <0.001
CRT–Op interval (wk)#6 109 (54.5) 91 (45.5) 147 (73.5) 53 (26.5) 172 (86.0) 28 (14.0)>6 75 (49.7) 76 (50.3) 101 (66.9) 50 (33.1) 128 (84.8) 23 (15.2)p 0.370 0.178 0.746
ChemotherapyFL 82 (56.2) 64 (43.8) 110 (75.3) 36 (24.7) 131 (89.7) 15 (10.3)Capecitabine 68 (50.7) 66 (49.3) 94 (70.1) 40 (29.9) 112 (83.6) 22 (16.4)IX 34 (47.9) 37 (52.1) 44 (62.0) 27 (38.0) 57 (80.3) 14 (19.7)p 0.459 0.126 0.132
Abbreviations: Hb = hemoglobin; CEA = carcinoembryonic antigen; CRT = chemoradiotherapy; Op = operation; FL = 5-fluorouracil andleucovorin; IX = irinotecan and capecitabine.
Values are number (percentage).* Determined by chi-square or Fisher exact test.
et al. (27) reported that an elevated pre-CRT serum CEA
level predicted a poor tumor response to preoperative CRT
in rectal cancer patients, independent of other clinicopatho-
logic features in their analysis. Those data are consistent
with the present study results. Another recent study, by Das
et al. (28), demonstrated that circumferential extent of tumor,
CEA level, and distance from the anal verge predicted for
the pathologic response to preoperative CRT for patients
with rectal cancer. These findings indicate that further studies
are warranted to confirm the apparent association between
serum CEA level and tumor response after preoperative
CRT.
Table 3. Multivariate analysis to identify predictors of downstaging, tumor regression, and complete regression
Downstaging Tumor regression grade (1–2 vs. 3–4) Tumor regression grade (1–3 vs. 4)
Odds ratio 95% CI p* Odds ratio 95% CI p Odds ratio 95% CI p
Pretreatment Hb level 1.595 1.002-2.532 0.045 — — NS — — NSN classification 3.303 1.691-6.452 <0.001 1.863 1.016-3.415 0.044 — — NSPretreatment CEA level 3.444 2.097-5.654 <0.001 3.023 1.705-5.358 <0.001 3.376 1.460-7.808 0.004
Abbreviations: CI = confidence interval; Hb = hemoglobin; CEA = carcinoembryonic antigen.* Determined by logistic regression analysis.
Clinical parameters predicting response d S. M. YOON et al. 1171
Interestingly, the present study found that pretreatment
hemoglobin level was a predictor for tumor downstaging.
Anemia is present in many cancer patients at the time of
diagnosis and has been hypothesized to lead to tumor hypoxia,
angiogenesis, and resistance to chemotherapy and radiother-
apy. Many cervical cancer and head-and-neck cancer studies
have shown a correlation between low hemoglobin levels
and poorer prognosis, despite the use of different definitions
of anemia (varying from 10 to 14.5 g/dL) (29). However,
few studies have evaluated the prognostic value of the hemo-
globin level in rectal cancer, and none has investigated its
potential as a predictor of tumor response. One recent study
revealed that the hazard ratio of death was 0.35 (95% confi-
dence interval 0.19–0.65, p = 0.001) in patients without preop-
erative anemia, which indicates a threefold higher mortality
risk for anemic patients with rectal cancer treated with total
mesorectal excision (30). Although no studies report investi-
gating whether pretreatment hemoglobin levels can predict
preoperative CRT response, the current findings indicate that
a prospective trial involving rectal cancer patients is warranted.
The present study found that pretreatment nodal classifica-
tion was a predictor of pathologic downstaging and tumor
regression. Pathologic tumor or nodal classification were the
most important prognostic factors for rectal cancer in either
neoadjuvant or adjuvant settings. However, questions sur-
round pre-CRT clinical staging and its prognostic significance,
owing to the low accuracy of exact staging, especially in lymph
node evaluation (31). Previous studies found that pretreatment
nodal status did not influence levels of tumor regression by the
pretreatment characteristics analysis in the same manner (11,
24, 27). Therefore, the present correlation between cN classifi-
cations and downstaging or tumor regression should be inter-
preted cautiously until more accurate methods of lymph
node evaluation are developed.
The present study also identified a range of clinical factors
that were not associated with histologic response, and such
a lack of association with these factors has been reported in
other tumor response studies (5–7, 11, 27). Pretreatment tu-
mor volume was associated with the degree of both down-
staging and tumor regression in univariate analysis, but this
was not an independent prognostic factor in further multivar-
iate analysis. Theoretically, the response to radiotherapy is
related to the number of cells to be killed according to the ra-
diobiologic principle, and the correlation between tumor size
and treatment response was revealed in other reports (24, 32).
However, this result was not confirmed in our study. This
finding might be related to an individual tumor gene profile
being more important than the number of tumor cells in a re-
sponse to CRT, and hopefully future studies will clarify this
genetic characteristic. The duration of the interval between
CRT and surgery did not have an influence on pathologic tu-
mor response. Because the interval between CRT and surgery
ranged from 4 to 8 weeks in the present study, we could
assume that the difference of pathologic tumor response is
not significant within these intervals, although it may have
an influence on downstaging for rectal cancer (33).
This study had some limitations. First, the analysis end-
points were limited to the pathologic response and not
extended to long-term clinical outcomes. It would be very
useful to analyze the present population in terms of early re-
sponse and survival data, such as disease-free and overall sur-
vival. Second, overstaging a tumor remains a possibility in
staging analysis. Thus, to enhance the accuracy, only the T
classification was used in downstaging analysis in the present
study. Transrectal ultrasonography and MRI are more reli-
able methods for determining T classification than evaluation
of lymph node status. However, staging failures still occur,
owing to difficulties in accurate discrimination between T2
and T3 lesions, which are caused by perirectal fat desmoplas-
tic reactions on MRI (34). These inaccuracies may challenge
the validity of using downstaging parameters to predict treat-
ment response. Third, there was a discrepancy between the
factors predicting downstaging and those predicting tumor
regressions. Although CRT-induced tumor shrinkage may
lead to complete or partial pathologic regression, in many
cases the pathologic stage does not change even if the tumor
cell density decreases. The differing criteria for defining
tumor response, and the different number of patients in
each group, may contribute to such a discrepancy. However,
it should be noted that each endpoint had a clinical meaning
in previous reports, and the results should be interpreted
separately concerning clinical outcomes.
In summary, the present data suggest that pretreatment
CEA level is the most important clinical predictor of patho-
logic tumor response. It may be of benefit for selecting treat-
ment options and for assessing individual prognosis. These
findings using retrospective data indicate the need for a larger,
prospective clinical trial. Furthermore, a comprehensive
comparison between these surrogate endpoints and long-
term survival data should be undertaken to determine the
prognostic significance of the present endpoints in a random-
ized preoperative setting.
1172 I. J. Radiation Oncology d Biology d Physics Volume 69, Number 4, 2007
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