Introduction
Magnetic resonance imaging (MRI) is the most commonly
used diagnostic method for radiologically imaging
rectal cancer. MRI has advantages in the evaluation
of locally advanced stage rectal cancer (LARC). With
rectal MRI, it is possible to determine many tumor lesion
features, including size, morphology, and borders,
which are useful in treatment planning.[,] MRI is
used both before and after neoadjuvant chemoradiotherapy
(nCRT). Significant progress has been made in
controlling the local disease using nCRT in cases with
LARC detected by MRI. At present, the most preferred
imaging method for local staging of rectal cancer is
rectal MRI.[,] Due to the increasing prominence of
nCRT in recent years, the importance of imaging techniques
has been studied, for both staging and accurately
evaluating radiological response. Tumor volume
reduction and fibrotic transformation are the two primary
response markers that can be appreciated on morphological
(T2 weighted) MRI and can help guide the
treatment strategy after nCRT. However, research has
indicated that morphological MRI is unable to differentiate
between sterile fibrosis and fibrosis-containing
tumor tissue, which is a significant clinical limitation.
Researchers have concluded that it would be appropriate
to add diffusion-weighted imaging to the MRI protocol,
stating that diffusion-weighted MRI successfully
distinguishes between tumor and fibrosis.[]
Pathological tumor regression grade (pTRG) is a
system used in the histological evaluation of tumor response
to nCRT that was initially used in other cancers
of the gastrointestinal system, bladder, head, and neck.
[-] Overtime, studies were carried out on the use of
pTRG in determining the prognosis of LARC.[,]
The most well-known pTRG systems are Mandard,
Rödel, Dworak, and the American Joint Committee on
Cancer (AJCC) scoring systems.[,-] Recently, a
pTRG-like MRI tumor regression grade (mrTRG) system
was developed.[,] The basic principle of both
the mrTRG and pTRG systems is related to tumor fibrosis
rate following nCRT. Radiological interpretation
requires the comparison of high-resolution oblique images
with basal scans to determine the proportions of
the tumor with fibrotic low signal intensity and residual
medium signal intensity. There has been a lack of
consensus in previous studies on the compatibility of
mrTRG and pTRG in patients with LARC. In the study
by Sclafani et al.,[] agreement between mrTRG and
pTRG was found to be poor, and mrTRG was seen as
a complementary prognostic tool for surgical decision-making and pTRG. In contrast, Rengo et al.[] found
the compatibility between mrTRG and pTRG to be
excellent. Ko et al.[] recommended combining MRI
and endoscopic biopsy to detect complete remission.
The histopathological definition of extramural vascular
invasion (EMVI) is tumor cells invading vessels
beyond the muscularis propria, which indicates a poor
prognosis in patients with rectal cancer.[] MRI can
provide accurate guidance in detecting EMVI (mr-
EMVI).[] Several studies have shown that mr-EMVI
is one of the risk factors for distant metastasis in rectal
cancer.[,] Particularly in patients with a baseline T3
stage, defining EMVI may be important in predicting patients"
response to nCRT and long-term results.[]
In this study, changes in T and N stages and the
positivity of EMVI were investigated. In addition, the
compatibility of mrTRG and pTRG was examined to
investigate the reliability of MRI in the diagnosis and
treatment of rectal cancer.
Methods
Patient Selection
A total of 72 patients with a diagnosis of rectal cancer
who received nCRT in the radiation oncology clinic
of our hospital between June 2014 and July 2019 were
evaluated. Patient interview information, patient files,
and electronic system data were used for data collection.
The patients" demographic status, primary diagnosis,
disease stage, tumor localization, distance to the
anal sphincter, MRI examination, treatment method,
treatment response, and final status were noted.
Patients older than 18 years of age with pathological
evidence of rectum adenocarcinoma, Eastern Cooperative
Oncology Group 1-2, locally advanced stage
according to AJCC eighth edition, complete imaging
and treatment information, and nCRT treatment were
included in the study. Ten patients with missing files,
follow-up information, or MRI imaging were excluded
from the study. In addition, 21 patients who were prescribed
nCRT but were not operated on for any reason
were excluded from the study. The remaining 41 patients
were included in the study.
Imaging and Treatment Details
Before treatment, all patients were evaluated by the
multidisciplinary treatment council including general
surgery, medical oncology, and radiation oncology.
Digital examination of the rectum, colonoscopy, multislice
triphasic thorax, abdominal, and pelvic computed tomography, endorectal ultrasonography (USG),
and pelvic MRI was ordered in the initial evaluation.
Pelvic MRIs were obtained with pelvic phased-array
coils and 1.5 T MRI. Pelvic MRI consisted of sagittal
fast spin-echo T2-weighted images, coronal short-au
inversion recovery, axial fast spin-echo T2-weighted
images, axial T2-weighted images with fat saturation,
axial T1-weighted images, axial T1-weighted images
with gadolinium, and sagittal T1-weighted images with
gadolinium. Table 1 shows the parameters for pelvic
MRI sequences.
Table 1: Technical information on pre-nCRT and post-nCRT MRIs
First, sagittal T2-weighted images were obtained,
and after a segment containing tumor tissue was detected,
this segment was scanned transversely. EMVI
was evaluated with axial T2-weighted images and axial
T1-weighted images with gadolinium. On MRI, EMVI
is characterized by focal enlargement of the vessel, wall
irregularity, and loss of flow void. Diffusion-weighted
MRI was not obtained. Fibrosis was evaluated with T2-
weighted and post-contrast T1-weighted images.
The nCRT treatment was performed with Varian
DHX and IX devices at Kayseri Training and Research
Hospital and Kayseri City Hospital. A total dose of 45
Gy with a fraction dose of 180 cGy was administered
5 days a week for 5 weeks. For the radiotherapy (RT)
technique, 3-field 3-dimensional conformal RT (3DCRT),
double-arc volumetric arc therapy, and 7-field
intensity-modulated RT were used. No additional dose
was administered to the mesorectum due to the feedback
regarding the difficulties experienced in surgical
operations due to RT. RT was applied to the rectum and
mesorectum as well as to the internal iliac, obturator,
and presacral lymph nodes. Capecitabine was administered
as a chemotherapy (ChT) agent at a dose of 825
mg/m2 twice a day, 5 days a week concurrent with RT.
Patients underwent surgical operation an average of 68
days (range, 33-385 days) after nCRT. Total mesorectal excision (TME) was performed on all patients.
Capecitabine plus oxaliplatin, oxaliplatin plus leucovorin
plus 5-FU, and capecitabine were administered to
the patients as adjuvant ChT. The patients were evaluated
before treatment, 1 and 2 months after the end of
nCRT, and every 3 months after the operation. During
the evaluation, blood tests were performed and the tumor
markers carcinoembryonic antigen and carbohydrate
antigen 19-9 were evaluated. Abdominal USG and
pelvic MRIs were performed for all patients.
Primary and Secondary Endpoints
The primary endpoint of the study was to evaluate
the relationship between mrTRG and pTRG after
treatment. In accordance with the literature, tumor
response grade was divided into five groups for both
pathological and MRI methods.[13,15,16] The grading
paradigms for the Dworak pTRG system and the
mrTRG system are presented in Table 2. Patel et al.[]
demonstrated the prognostic significance of reassessing
rectal cancers using high-resolution T2-weighted
MRI after completing nCRT.[] In our study, based
on the previous studies, the MRI response was divided
into two groups: Good response (GR; mrTRG1-2) and
poor response (PR; mrTRG3-5).
Table 2: The classification system for mrTRG and pTRG
Similarly, the pathological response was dichotomized
as GR (pTRG3-4) and PR (pTRG0-2).
[,] MRI sensitivity and specificity were evaluated
by comparing the MRI-based response assessment
with pathological results after neoadjuvant therapy.
The secondary endpoint of the study was to evaluate
the variables that affect mrTRG and pTRG.
Statistical Analysis
Descriptive statistics for continuous (quantitative) variables
were expressed as mean, standard deviation, minimum-
maximum, and median values, while categorical variables were expressed as number (n) and ratio
(%). Cohen's Kappa analysis was used for mrTRG and
pTRG compatibility (κ<0.20: poor agreement; κ=0.21-
0.40: fair agreement; κ=0.41-0.60: moderate agreement;
κ=0.61-0.80: good agreement; and κ=0.81-1.00:
very good agreement). Non-parametric tests were used
in the study, the Mann-Whitney U-test for statistical
analysis of two independent groups and the Kruskal-
Wallis test for analysis of three or more independent
groups. Significance was evaluated with post hoc analysis
after Bonferroni correction. Chi-square and Fisher's
exact tests were used to calculate the categorical demographic
characteristics of the patients. Analyses were
performed with IBM SPSS Package Program version
24.0 (IBM Corporation, Armonk, NY, USA). Statistical
significance was determined as p<0.05.
Results
The results of 41 patients diagnosed with LARC who received
curative treatment in our clinic were evaluated.
The patients" median age was 61 years (range, 26-79
years), and 18 (43.9%) were female. All patients had prenCRT
and pre-operative comparative functional MRI results.
Only 2 patients (4.9%) had high rectal localization,
while 19 (46.3%) patients had midrectal localization and
20 (48.8%) patients had low rectal localization. Radiologically,
EMVI was positive in 16 (39%) patients on MRI
before nCRT, and pathological lymph node (pLN) was positive in 34 (82.9%) patients. A majority of patients underwent
3D-CRT (56.1%, n=23). Patient characteristics
and treatment details are summarized in Table 3.
Table 3: Patient characteristics and treatment details
Radiological Effect of nCRT on EMVI
While 16 patients (39%) had EMVI positivity on prenCRT
MRI, the number of EMVI-positive patients
decreased to 7 (17.1%) on post-nCRT MRI. Although
the number of EMVI-positive patients decreased after
nCRT, the difference was not statistically significant
(p>0.05).
Evaluation of mrTRG and Dworak pTRG Relationship
The relationship between mrTRG and Dworak pTRG
was assessed using the Cohen kappa fit analysis test. A
low level but significant (κ=0.319, p=0.002) compatibility
was observed between pTRG and mrTRG (Table 4).
Table 4: Detailed analysis of the relationship between mrTRG and pTRG
GR was observed in 21 (51.2%) patients and PR was
observed in 20 (48.8%) patients according to basal images
in the post-nCRT MRI. GR was observed in 20
(48.8%) patients and PR was observed in 21 (51.2%)
patients based on the pathological evaluation.
When the accuracy of mrTRG in treatment response
evaluation was compared with pTRG, mrTRG
was determined to have a sensitivity of 90% (18/20),
specificity of 14.3% (3/21), positive predictive value of
85.7% (18/21), and negative predictive value of 90%
(18/20) (Table 5).
Table 5: MRI pathological response relationship after neoadjuvant therapy
Analysis of Variables and pTRG
No significant relationships were found between pTRG
and gender, tumor localization, pre-nCRT EMVI,
post-nCRT EMVI, pre-nCRT pLN, post-nCRT pLN, pre-nCRT T stage, post-nCRT T stage, pre-nCRT N
stage, post-nCRT N stage, pre-nCRT tumor length,
post-nCRT tumor length, pre-nCRT tumor diameter,
post-nCRT tumor diameter, RT technique, pathological subtype, and time between the end of RT and the
operation (p>0.05).
The median age of patients with GR based on pTRG
was 57 years (range, 26-73 years), and the median
age of patients with PR based on pTRG was 64 years
(range, 41-79 years). As age increased, a significantly
higher rate of PR was observed (p=0.037) (Fig. 1).
Fig 1: Age and pathological tumor regression grade relationship.
pTRG: Pathological tumor regression grade; GR: Good response;
PR: Poor response.
Analysis of Variables and mrTRG
No significant relationships were found between
mrTRG and age, gender, tumor location, pre-nCRT
EMVI, post-nCRT EMVI, pre-nCRT pLN, post-nCRT
pLN, pre-nCRT T stage, post-nCRT T stage, prenCRT
N stage, pre-nCRT tumor length, post-nCRT
tumor length, pre-nCRT tumor diameter, post-nCRT tumor diameter, RT technique, pathological subtype,
and time between the end of RT and MRI (p>0.05).
The relationship between response based on mrTRG
and post-nCRT N stage was significant (p=0.048); as
the N stage progressed, the ratio of patients with PR
increased significantly (Table 6).
Table 6: mrTRG and post-nCRT nodal stage analysis
Discussion
The stage of the disease and surgical margins largely
determines the prognosis of patients with rectal cancer.[] In addition, venous invasion, perineural invasion,
and tumor grade impact prognosis.[] EMVI is
defined histologically as the involvement of veins other
than the muscularis propria.[] The presence of EMVI
is an independent predictor of local or distant recurrence,
nodal disease, and lower overall survival. Comparing
pre-treatment and post-treatment scans, it has
been shown that MRI has a high sensitivity even when
advanced histopathological techniques are used to define
EMVI.[] MRI is currently the standard method
for post-nCRT local staging of rectal cancer and has
demonstrated good accuracy in identifying EMVI.[]
In our study, the prognostic value of EMVI was not examined,
but the effect of nCRT on EMVI was examined
to emphasize the importance of EMVI presence. The
number of EMVI-positive patients decreased when prenCRT
and post-nCRT MRIs were compared. The number
of patients with positive EMVI on MRI decreased
from 16 (39%) pre-nCRT to 7 (17.1%) post-nCRT.
In recent years, compatibility between mrTRG and
pTRG has been the subject of multiple studies. Particularly in rectal cancer, the watch-and-wait approach has
increased the importance of mrTRG. However, mrTRG
is not a routinely offered service in every center. In addition,
mrTRG findings have not been as consistent as
pTRG findings, and studies have produced conflicting
results regarding compatibility.
In the study by Siddiqui et al.,[] mrTRG evaluation
of the images of 12 patients by 35 radiologists was compared. Eight radiologists showed very good
to near-perfect agreement (? >0.8), 6 showed good
agreement (0.8≥ κ>0.6), and 12 showed moderate
agreement (0.6≥κ> 0.4). The radiologists identified
good responders in 65.9% of cases and poor responders
in 90% of cases. Although there was a trend toward
good agreement among the radiologists, it is clear that
there were still differing assessments. Since our study
was retrospective, mrTRG evaluation by a single radiologist
was specifically requested. Evaluation of all 41
cases by the same radiologist was deemed appropriate
for the stability of the study. The conclusion of the previous
study emphasized that radiologists can be taught
mrTRG measurement and that good agreement can be
achieved between radiologists.
Similar to the differences seen between studies in
the evaluation of mrTRG, different results have been
obtained regarding the agreement between mrTRG
and pTRG. In research investigating the correlation between
mrTRG and pTRG, 191 patients were evaluated
and mrTRG and pTRG findings were compared in two
Phase-II studies (EXPERT and EXPERT-C).[] Patients
were given 4 cycles of induction capecitabine and
oxaliplatin (CAPOX) ChT first, and then, capecitabinebased
concurrent nCRT (54 Gy in EXPERT; 50.4 Gy
in EXPERT-C) was administered. TME was administered
4-6 weeks after the end of nCRT and 4 cycles
of adjuvant ChT (capecitabine in EXPERT; CAPOX
in EXPERT-C) were given. High-resolution MRI was
taken at the end of induction ChT and 4 weeks after
concurrent nCRT. The compatibility between mrTRG
and pTRG was evaluated by the weighted kappa test.
Fair agreement was found between mrTRG and pTRG
when the regression was classified according to standard
5-tier systems (κ=0.24) or modified 3-tier systems
(κ = 0.25). The sensitivity and specificity of mrTRG1-2
(complete/good radiological regression) for the prediction
of pathological complete response (pCR) were
74.4% (95% confidence interval [CI]: 58.8-86.5) and
62.8% (95% CI: 54.5-70.6), respectively. The study concluded that the compatibility between mrTRG and
pTRG was low and that mrTRG could not be used
as a proxy for pTRG. It was emphasized that mrTRG
can provide complementary prognostic information
to pTRG for improved post-operative risk stratification
and identify complete pathological responders for
adopting non-operative management strategies, with
the need for further studies on this topic highlighted.
In another study, the MRIs of 65 patients were evaluated
to quantitatively assess the percentage of fibrosis
developing in LARC after nCRT.[] The patients
were followed for 30 months. Fibrosis percentage was
measured on T2-weighted images, and mrTRG classes
were determined and compared with histopathological
pTRG. The compatibility between pTRG and mrTRG
was determined to be perfect (κ=0.923). The automated
measurement of fibrosis detected by MRI has thus
been recorded as feasible and reproducible. Significant
agreement was found in our study between mrTRG
and pTRG (p=0.002), though the agreement was low
(κ=0.319). When compared to Sclafani et al.,[] the
number of patients in our study was markedly less. In
addition, in our study, RT dose was 45 Gy, capecitabine
was used as the standard ChT, and only standard 5-tier
systems were used. Despite differences in methodology,
our study results were similar to those of Sclafani
et al.[] in terms of the low agreement measured
between mrTRG and pTRG. Our sample size of 41
was more similar to the sample size of 65 in Rengo et
al.,[] though very different results were obtained in
the compatibility of mrTRG and pTRG grades. Rengo
et al.[] measured the percentage of fibrosis on T2-
weighted images using the automated k-means clustering
algorithm. In our study, the percentage of fibrosis
was measured visually on T2-weighted MRIs by the
radiologist. The reason for the differences between the
two studies may be due to the differences in methodology
for measuring the percentage of fibrosis.
A different approach has been employed by Ko et
al.[] In their study, 102 patients who underwent an
endoscopy and MRI 2-4 weeks after nCRT were examined
retrospectively.[] A confidence interval (1-4)
was established for endoscopy and MRI evaluations.
Accuracy, sensitivity, and specificity were analyzed
based on the findings of endoscopy, MRI, and a combination
method. Patients simultaneously received a
total of 50.4 Gy RT from 3 to 4 fields (45 Gy pelvic and
5.4 Gy boost) and capecitabine, and pCR was achieved
in 17 (16.7%) of 102 patients. The accuracy, sensitivity,
and specificity of pCR prediction from biopsy and
endoscopy were 85.3%, 52.9%, and 91.8%, respectively, while from MRI, they were 91.2%, 70.6%, and 95.3%,
respectively. With combined endoscopy and MRI, accuracy,
sensitivity, and specificity were 89.2%, 52.9%,
and 96.5%, respectively. No significant differences were
found in the sensitivity and specificity of each method.
The pCR prediction rate using the combination method
was 92.6% after the final probability test. The study
showed that the combination of endoscopic biopsy and
MRI could positively predict pCR in patients with rectal
cancer after nCRT.
No consensus has thus far been reached on the utility
of mrTRG. In fact, mrTRG is not routinely evaluated
in all centers. Therefore, more training and further
studies are needed. In our study, we retrospectively
investigated the compatibility of mrTRG and pTRG
with a small patient group. Although compatibility was
found to be low, these results are not decisive, as differing
results have been obtained in other studies. At this
stage, mrTRG cannot replace pTRG, but has prognostic
value in the watch-and-wait patient group whose
operations are delayed.
Limitations of the Study
The limitations of our study are the small number of
patients and the single-center and retrospective study
design. However, the evaluation of mrTRG by a single
radiologist and the evaluation of pTRG by a single
pathologist, as well as the consistent ChT agent and
dosage used were considered strengths of the study in
terms of data balance.
Conclusion
As age increased, pTRG was negatively affected; as the
post-nCRT N stage increased, mrTRG was negatively
affected. There was compatibility between mrTRG and
pTRG, as expected, but this compatibility was found
to be low. A standard should be established for more
reliable mrTRG evaluation, and further studies should
be performed.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: Institutional Review Board
approval was obtained for this study. The study was approved
by the Non-Interventional Clinical Research Ethics Committee
of Erciyes University Faculty of Medicine (No: 2019/837,
Date: 11/12/2019).
Financial Support: None declared.
Authorship contributions: Concept - A.A., G.T., İ.P.A.;
Design - A.A., S.K.E., İ.P.A.; Supervision - A.A.; Funding
- None; Materials - A.A., G.T., E.A.; Data collection and/or
processing - A.A., G.T., N.Ö., E.A., S.K.E.; Data analysis and/
or interpretation - A.A., G.T., E.A.; Literature search - A.A.,
G.T., N.Ö., E.A., S.K.E.; Writing - A.A., N.Ö., İ.P.A.; Critical
review - A.A.
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