Download Effectiveness of dynamic contrast

Effectiveness of dynamic contrast-enhanced MRI in evaluating
clinical responses to neoadjuvant chemotherapy in breast cancer
LIU Yin-Hua, YE Jing-Ming, XU Ling, HUANG Qing-Yun, ZHAO Jian-Xin, DUAN Xue-Ning,
QIN Nai-Shan, WANG Xiao-Ying
LIU Yin-Hua ( ), YE Jing-Ming, HUANG Qing-Yun, ZHAO Jian-Xin, DUAN Xue-Ning,
Department of General Surgery, Breast Disease Center, Peking University First Hospital, Xi Shi
Ku Street 8, 100034 Beijing, P. R. China
e-mail: [email protected]
Tel.: +86-(0)10-83575053
XU Ling
Department of Medical Oncology, Breast Disease Center, Peking University First Hospital,
Beijing, P. R. China
QIN Nai-Shan, WANG Xiao-Ying
Department of Radiology, Peking University First Hospital, Beijing, P. R. China
Abstract Purpose: To investigate the effectiveness of dynamic contrast-enhanced MRI for
evaluating clinical responses to neoadjuvant chemotherapy in breast cancer patients. Patients
and Methods: We examined patients receiving neoadjuvant chemotherapy for primary breast
cancer between October 2007 and September 2008. Dynamic contrast-enhanced MRI was
used to examine breast tumors prior to and after neoadjuvant chemotherapy. This MRI
examination assesses tumors using Response Evaluation Criteria in Solid Tumors (RECIST).
The Miller-Payne grading system was used as a histopathological examination to assess the
effect of the treatment. We examined the relationship between the results of RECIST and
histopathological criteria. In addition, we used time-signal intensity curves (MRI T-SI) to
further evaluate the effects of neoadjuvant chemotherapy on tumor response. Results: MRI
examination of patients completing four three-week anthracycline-taxanes chemotherapy
treatment revealed that there were no CR cases, 58 PR cases, 29 SD cases, and four PD cases.
The effectiveness of neoadjuvant chemotherapy (CR + PR) was 63.7% (58/ 91). The
postoperative histopathological evaluations revealed the following: seven G5 (pCR) cases
(7.7%), 39 G4 cases (42.9%), 16 G3 cases (17.6%), 23 G2 cases (25.3%), and six G1 cases
(6.6%). The effectiveness (G5 + G4 + G3) is 68.1% (62/91). MRI T-SI standards classified 53
effective cases, 29 stable cases, and nine progressing cases. These results indicate that the
treatment was 58.2% effective (53/91) overall. Conclusions: Dynamic contrast-enhanced MRI
and histopathological standards were highly correlated. Importantly, MRI T-SI evaluation was
found to be useful in assessing the clinical significance of neoadjuvant chemotherapy.
Key words Breast cancer, neoadjuvant chemotherapy, MRI, time-signal intensity curve,
response evaluation
Introduction
Breast cancer treatment has advanced over the past two decades, achieving a better outcome
for women. Neoadjuvant chemotherapy has become an established part of treatment of stage
Ⅱ and Ⅲ breast cancer, and the indications for use of this modality are constantly
expanding [1]. Use of neoadjuvant chemotherapy allows for assessment of response to
cytotoxic drugs in vivo, which is not only clinically relevant but also critical in terms of
research endeavors assessing chemoresistance and response [2]. Accurate assessment of
neoadjuvant response is a critical element in monitoring and assessing treatment strategies.
Recently magnetic resonance imaging (MRI) has become increasingly popular in breast
imaging, and several studies have demonstrated a high correlation between tumor size as
measured by MRI and histopathologic examination after neoadjuvant chemotherapy [3] [4].
But tumor imaging is unable to identify changes in the tumor density or tumor angiogenesis.
The enhancement kinetics, as represented by the time-signal intensity (T-SI) curves, differ
significantly for benign and malignant enhancing lesions [5] and may therefore changed after
neoadjuvant chemotherapy. So in this study, we examined the changes in T-SI curves to
further evaluate breast cancer treatment response besides the changes of tumor size by MRI
and tried to assess the neoadjuvant chemotherapy response multifold.
Patients and Methods
1.1 Patients:
Women under 70 years of age admitted to our center between October 2007 and September
2008 for primary breast cancer took part in this study. Ninety-one patients met the following
criteria for inclusion in the study: all exhibited measurable breast lesions, and pre-B
ultrasound-guided core needle biopsy diagnosis of breast invasive ductal carcinoma (not
otherwise specified ). All patients underwent ultrasound-guided fine needle aspiration
cytology of the axillary lymph nodes. No patients had contraindications to neoadjuvant
chemotherapy, and all completed a full course of the treatment. The neoadjuvant
chemotherapy consisted of four three-week anthracycline-taxane treatments. Complete MRI
results were obtained for each patient, and abdominal B-type ultrasounds, chest X-rays and
bone scans (except for distant metastasis) were conducted. We found no indication of serious
damage to the heart, liver or kidney function (indicated by a Karnofsky score greater than 70)
in any patient.
1.2 Methods:
1.2.1 Neoadjuvant chemotherapy: A complete course of neoadjuvant chemotherapy involved
four three-week cycles of anthracyclines-taxanes chemotherapy treatment. Each patient took
50 mg/m2 of pirarubicin or epirubicin 75 mg/m2 on the first day of each three-week cycle, and
75 mg/m2 of docetaxel or 175 mg/m2 of paclitaxel on the second day. Patients were then
required to repeat the same medications on the first and second day 21 days after the start of
the previous cycle. The same three-week cycle was repeated four times for a complete course
of neoadjuvant chemotherapy, and all patients completed the treatment course. Dynamic
contrast-enhanced MRI was then conducted within 10 to 14 days of the first day of the second
and fourth cycles to evaluate the effectiveness of the neoadjuvant chemotherapy.
1.2.2 Imaging examination methods: The dynamic contrast-enhanced MRI was conducted
using a GE Signa infinity 1.5T Twinspeed MRI scanners, with breast dedicated four-channel
phased-array surface coils, in a three plane scan. Dynamic contrast-enhanced scanning
utilized volume imaging for breast assessment (VIBRANT) sequence sagittal scan: repetition
time: 6.9 ms; echo time: 2.7 ms;flip angle: 15°; field of vision (FOV): 20*20mm; matrix: 324
×288; thickness 5 mm, zero difference technique Zip2; scan time: 58 s) Continuous scans
were taken eight times (eight phrases) before and after injection of the contrast agent
Gd-DTPA to enhance the clarity of the image. A dose of 0.2 mmol/kg Gd-DTPA was injected
to the vein in front of the elbow at a speed of 2.0 ml/s. Post-image processing was performed
with an AW4.2 workstation using FuncTool software (region of interest; ROI) to test for
significant changes, as well as to perform 3D image reconstruction, measure the longest
diameter of the breast tumor, draw dynamic enhanced curves, and identify curve type
according to curve shape (Figure 1) [5].
1.2.3 Dynamic contrast-enhanced breast MRI examination: MRI examinations were
conducted before the first cycle chemotherapy and within 10 to 14 days after the first day of
the second and fourth three-week treatments to evaluate the clinical significance of
neoadjuvant chemotherapy. The MRI examination measure of tumor size was based on the
RECIST (1.0) [6] , and the measurement of tumor progress was based on changes in T-SI
curves, as shown in Table 2. MRI measurement of neoadjuvant chemotherapy efficiency =
(CR + PR) / total number of cases × 100%. MRI measurement of time - signal intensity curve
efficiency = effective case/ total number of cases × 100%.
1.2.4 Surgical procedure: Ten to fourteen days after four cycles of neoadjuvant chemotherapy,
the treatment response was evaluated, and used to determine whether breast-conserving
surgery or modified radical mastectomy were appropriate.
1.2.5 Histopathological response evaluation of neoadjuvant chemotherapy: The removed
tissue was routinely converted into paraffin embedded sections, and the largest diameter of
tumor was measured under a microscope. We used the Miller-Payne histopathological grading
system to assess treatment response (Table 1) [7] . The total effectiveness rate of the
neoadjuvant chemotherapy was calculated by (G3 + G4 + G5) cases / total number of cases ×
100%.
1.2.6 Statistical methods: Pearson correlation analyses were used to test the relationship
between MRI and the histopathological assessment of the longest diameter of the residual
tumor after neoadjuvant chemotherapy. We considered a difference to be statistically
significant if P <0.05. Analysis was performed using SPSS15.0 software.
Results
2.1 Patient data: Ninety-one patients met the experimental inclusion criteria. Ages ranged
between 27 and 69 years, with a median age of 49 years. Twenty-six patients were diagnosed
with clinical stage IIA (28.57%), Forty-seven (51.65%) exhibited clinical stage IIB, and
eighteen (19.78%) exhibited clinical stage IIIA. Modified radical mastectomies were
performed in sixty-five cases, and breast-conserving surgery was performed on the remaining
twenty-six patients.
2.2 Dynamic contrast-enhanced MRI evaluation of neoadjuvant chemotherapy: The outcome
data of the complete neoadjuvant chemotherapy course according to RECIST criteria (1.0)
was as follows: no cases of CR, fifty-eight cases of PR, twenty-nine cases of SD, and four
cases of PD. The effectiveness of neoadjuvant chemotherapy according to MRI assessment
was 63.7% (CR + PR cases / total cases = 58/91).
2.3 MRI T-SI evaluation of neoadjuvant chemotherapy: MRI T-SI standards classified
fifty-three effective cases, twenty-nine stable cases and nine progressive cases. The overall
effectiveness of neoadjuvant chemotherapy according to MRI T-SI evaluation was 58.2%
(53/91).
2.4 Histopathological evaluation of neoadjuvant chemotherapy: We conducted
histopathological evaluation of breast tumors using the Miller-Payne grading system to
evaluate the clinical effectiveness of neoadjuvant chemotherapy. There were seven cases
(7.7%) classed as G5 (pCR), thirty-nine (42.9%) as G4, sixteen (17.6%) as G3, twenty-three
(25.3%) as G2, and six (6.6%) as G1. The overall effectiveness of neoadjuvant chemotherapy
according to the Miller-Payne assessment was 68.1% (G5 + G4 + G3 cases/ total cases =
62/91).
2.5 Relationship between dynamic contrast-enhanced MRI and histopathological evaluation
of neoadjuvant chemotherapy: The average residual tumor diameter measured by MRI was
2.12 ± 1.37 cm, while the microscopic residual tumor pathology-ray measurement of the
average diameter was 1.83 ± 1.53 cm. Pearson correlation tests revealed that MRI and
histopathology measurements of residual tumor tissue were highly correlated (r = 0.650, P
<0.001). Fifty-eight cases exhibited PR according to MRI evaluation, whereas sixty-two cases
were judged effective according to histopathological evaluation. Consistency between the two
measurements was 79.3% (Table 3). There were thirty-three SD + PD cases according to MRI
evaluation, and the treatment in seventeen cases was judged ineffective by histopathlogical
evaluation. The consistency between the two measurements was 69.2%.
2.6 Relationship between MRI T-SI and histopathological evaluation: Fifty-three cases were
judged effective by MRI T-SI assessment, compared to sixty-two effective cases classified by
histopathological examination. Consistency between the two measurements was 79.2%. The
other thirty-eight cases were found to be ineffective by MRI T-SI criteria, and eighteen cases
were judged ineffective by histopathological examination. The consistency between these two
measures was 69.2%, as shown in Table 4.
2.7 The relationship between the RECIST measure of the dynamic contrast-enhanced MRI
and MRI T-SI evaluation: Thirty-six cases were found to be effective using RECIST
evaluation standards, whereas twenty-nine cases were classified as effective using MRI T-SI
measures. The consistency between the two measurements was 80.6%. Figure 2 was a case
which was judged as PR using RECIST evaluation standards and also classified as effevtive
using MRI T-SI measures. Sixteen cases were judged to be SD and PD cases by RECIST
standards, whereas thirteen cases were classified ineffective by MRI T-SI. The consistency
between these two measurements was 82.3%. RECISTS standards also classified twenty-nine
cases as SD, whereas sixteen of which were classified as effective by MRI T-SI criteria.
Twelve of these cases were judged effective by histopathological examination. The
consistency between MRI T-SI and histopathological measurements was 75% (12/16) (Table
5). Four cases were PD under RECIST and effective under MRI T-SI. One of these four cases
was classified as G5, and three were classified as G2 according to histopathological
examination. Thirty-eight cases were classified as stable or progressive according to MRI
T-SI, twenty-two of which were judged effective under MRI. The consistency between the
measurements was 77.3%.
Discussion
Neoadjuvant chemotherapy is a potentially useful breast cancer treatment. However, the
effectiveness of this therapy relies on the accuracy of tumor progression measurements. The
World Health Organization (WHO) established a tumor classification system in the 1980s.
The topic of solid tumor cancer therapy evaluation criteria remains contentious. In 2000, the
European Association for Cancer Research and Treatment (EORTC), the National Cancer
Research (NCI) and the National Cancer Institute of Canada (NCIC) amended the WHO
standards developing and publishing a new evaluation standard called the RECIST 1.0. These
new criteria involve precise and accurate single-track diameter measurement, instead of the
conventional two-track diameter measurement. The RECIST 1.0 evaluation standard is now
widely used in clinical practice. In 2009, the European Journal of Cancer published an
updated and more comprehensive version of the RECIST, version 1.1 [8] . Recently, some
researchers have explored different combinations of MRI evaluation criteria used to assess the
effectiveness of neoadjuvant chemotherapy for breast cancer [9] [10], but the use of
histopathological examination and MRI T-SI curves to evaluate of neo-adjuvant
chemotherapy has been largely neglected.
In the present study we examined the clinical response of breast cancer patients receiving
neo-adjuvant chemotherapy. Tumor evaluation standards including RECIST criteria and
histopathological examination (the Miller-Payne grading system) were used to assess tumor
response. In addition, changes in MRI T-SI were also used to evaluate the clinical
effectiveness of neoadjuvant chemotherapy. The results revealed that microscopic
measurements of residual tumor tissue following neoadjuvant chemotherapy using dynamic
contrast-enhanced MRI and histopathological evaluation were highly correlated (r = 0.650, P
<0.001). Among the fifty-eight cases classified as PR under RECIST, forty-six were also
classified as effective under histopathological examination. Consistency between these two
measurements was found to be 51.5%. The overall measurement consistency between
RECIST criteria, dynamic contrast-enhanced MRI measures and histopathological
examination was 69.2%. It could be concluded that dynamic contrast-enhanced MRI
examination is an effective method for assessing the clinical response of neoadjuvant
chemotherapy according to RECIST, and our data indicate that it has a relatively high
correlation with histopathological measures. We found that the measurement consistency
between MRI T-SI curve and histopathological standards for effective cases was 79.2%, and
47.4% for ineffective cases respectively. RECISTS evaluation used in conjunction with MRI
T-SI curves may enhance the accuracy of tumor assessment. Of the twenty-nine SD cases
classified by RECIST in the present study, sixteen were considered to be effective using MRI
T-SI, and twelve were considered effective by histopathological examination. The
measurement consistency between MRI T-SI curves and histopathological examination was
75% (12/16). RECIST criteria also classified four cases as PD. MRI T-SI measures also
indicated those cases as effective. One of those four cases was classified as G5, and three
were considered G2 according to histopathological examination. These results suggest that
more attention should be paid to the related MRI T-SI curve evaluation for cases classified as
SD or PD using RECISTS standards. For cases classified as effective by MRI T-SI curve
evaluation, histopathological examination could help to provide a better insight into tumor
response, which may allow physicians to assess whether there is a need to alter the
medication involved in neoadjuvant chemotherapy. Core needle biopsy could be used as an
additional tool for identifying the tumor response.
Tumor imaging anatomy and physical plane measurement are the basis of the RECIST
standards. Physical measurement is unable identify changes in the tumor density or tumor
angiogenesis. Change in tumor size is an important indicator of tumor response. However,
other indicators can also be used. Many variables impact on MRI imaging, and may have
affected image quality and measurement accuracy in our present study. Histopathological
examination measures are independent of tumor size variation, so bias can occur depending
on the physician’s assessment. More research is necessary to examine the effectiveness of
joint standards in evaluating the clinical significance of neoadjuvant chemotherapy. MRI T-SI
measures can help as an indication of tumor blood flow dynamics and perfusion parameters.
The use of MRI T-SI curves in conjunction with core needle biopsy may help to better
identify and avoid mismeasurement of tumor progress.
We examined the effectiveness of MRI in evaluating the effects of neo-adjuvant
chemotherapy. Our data indicated that the use of dynamic contrast-enhanced MRI together
with MRI T-SI improved evaluations of neo-adjuvant chemotherapy. In addition, the results
suggested that histopathological evaluation should be used in conjunction with dynamic
contrast-enhanced MRI and MRI T-SI, and that these three measures were relatively highly
correlated. Related functional MRI parameters, such as dynamic contrast-enhanced [11] ,
diffusion-weighted imaging (DWI) [12] and proton magnetic resonance spectroscopy (MRS)
[13] are other potentially useful clinical tools that require further investigation.
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.
Figure 1 Schematic drawing of the time-signal intensity curve types. Type Ⅰ corresponds to
a straight (Ⅰa) or curved (Ⅰb) line; enhancement continues over the entire dynamic study.
Type Ⅱ is a plateau curve with a sharp bend after the initial upstroke. Type Ⅲ is a wash
out time course.
A
B
C
D
E
F
Figure 2 A case was judged as PR using RECIST evaluation standards and also classified as
effevtive using MRI T-SI measures. (Figure 2A and 2B were dynamic contrast-enhanced
breast MRI and T-SI curves taken before the first cycle chemotherapy. Figure 2C and 2D were
taken at 10 days after the 2nd cycle chemotherapy. Figure 2E and 2F were taken at 12 days
after the 4th cycle chemotherapy.
Table 1 Miller-Payne histological grading system
Grade
Definition
No change or some alteration to individual malignant cells but no
Grade 1 (G1)
reduction in overall cellularity
A minor loss of tumor cells but overall cellularity still high; up to
Grade 2 (G2)
30% loss
Grade 3 (G3)
Between an estimated 30% and 90% reduction in tumor cells
A marked disappearance of tumor cells such that only small
Grade 4 (G4)
clusters or widely dispersed individual cells remain; more than
90% loss of tumor cells
No malignant cells identifiable in sections from the site of the
tumor; only vascular fibroelastotic stroma remains often
Grade 5 (G5)
containing macrophages. However, ductal carcinoma in situ
(DCIS) may be present
Table 2 Time-Signal Intensity (T-SI) curve types and corresponding clinical significance.
Clinical
Changes in the Type of T-S1 Curves
Evaluation
Effective
Type III T-SI curve became Type I or Type II, Type II
T-SI curve became type I
Stable
No change
Progressive
Type II T-SI curve became type III
Table 3: MRI and histopathological evaluations of neoadjuvant chemotherapy
MRI
Evaluation
PD
PR
SD
Total
G1
0
2
4
6
Histopathological Evaluation
G2
G3
G4
3
0
0
10
10
31
10
6
8
23
16
39
G5
1
5
1
7
Total
4
58
29
91
Table 4: MRI T-SI curve and histopathological evaluations of neoadjuvant chemotherapy
MRI T-SI
Evaluation
Effective
Stable
Progressive
Total
G1
4
2
0
6
Histopathological Evaluation
G2
G3
G4
7
10
27
11
4
11
5
2
1
23
16
39
G5
5
1
1
7
Total
53
29
9
91
Table 5: MRI T-SI curves and histopathological evaluation of neoadjuvant chemotherapy for SD
patients
Histopathological Evaluation
MRI T-SI
Evaluation
Effective
Total
G1
G2
G3
G4
G5
2
2
5
6
1
16
Stable &
Progressive
Total
2
8
1
2
0
13
4
10
6
8
1
29