Download Accuracy of physical examination, ultrasonography, and magnetic

Accuracy of physical examination, ultrasonography, and magnetic resonance
imaging in predicting response to neoadjuvant chemotherapy for breast cancer
CHEN Man, ZHAN Wei-wei, HAN Bao-san, FEI Xiao-chun, JIN Xiao-long, CHAI Wei-min, WANG Deng-bing,
SHEN Kun-wei, and WANG Wen-ping
Department of Diagnostic Ultrasound, Zhong Shan Hospital, School of Medicine, Fudan University, Shanghai
200032,China (Chen M, Wang WP)
Department of Diagnostic Ultrasound, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University,
Shanghai 200025, China(Chen M, Zhan WW)
Department of Comprehensive Breast Health Center, Rui Jin Hospital, Shanghai Jiao Tong University School of
Medicine, Shanghai 200025, China(Han BS, Shen KW)
Department of Pathology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025,
China (Fei XC, Jin XL)
Department of Radiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai
200025, China (Chai WM, Wang DB)
Correspondence to: Dr. WANG WP, Department of Diagnostic Ultrasound, Zhong Shan Hospital, Fudan
University School of Medicine, Shanghai 200032, China. (Tel: 86-21-64041990. Fax: 86-21-52768751. E-mail:
[email protected])
Keywords ： breast cancer; neoadjuvant chemotherapy; physical examination; ultrasonography; magnetic
resonance imaging
Background
Accurate evaluation of response following chemotherapy treatment is essential for surgical
decision making in patients with breast cancer. Modalities that have been used to monitor response to
neoadjuvant chemotherapy include physical examination, ultrasound, and magnetic resonance imaging. The
purpose of this study was to evaluate the accuracy of physical examination, ultrasound, and magnetic
resonance imaging in predicting the response to neoadjuvant chemotherapy in patients with breast cancer.
Methods
According to the response evaluation criteria in solid tumors guidelines, the largest unidimensional
measurement of the tumor diameter evaluated by physical examination, ultrasound, and magnetic resonance
imaging before and after neoadjuvant chemotherapy was classified as four grades, including: clinical complete
response, clinical partial response, clinical progressive disease, clinical stable disease, and compared with final
histopathological examination.
Results
Of the 64 patients who received neoadjuvant chemotherapy, the pathologic complete response was
shown in 13 of 64 patients (20%). The sensitivity of physical examination, ultrasound, and magnetic resonance
imaging in predicting the major pathologic response was 73, 75, respectively, and 80%, and the specificity was
45, 50, and 50%, respectively. For predicting a pathologic complete response, the sensitivity of physical
examination, ultrasound, and magnetic resonance imaging was 46, 46, and 39%, respectively, and the
specificity was 65, 98, and 92%, respectively.
Conclusions
Compared with final pathologic findings, all these three clinical and imaging modalities tended
to obviously underestimate the pathologic complete response rate. A more appropriate, universal, and practical
standard by clinical and imaging modalities in predicting the response to neoadjuvant chemotherapy in vivo is
essential.
体格检查、超声及磁共振在乳腺癌新辅助化疗疗效评估中的价值
关键词：乳腺癌；新辅助；体格检查；超声；磁共振
背景
准确评价原发性乳腺癌对新辅助化疗的反应是指导临床治疗方案的制定的关键。临床和影像学评估
方法众多，包括体格检查、超声和磁共振等。评价体格检查、超声和磁共振在原发性乳腺癌预测新辅助化
疗疗效评估中的准确性。
方法
根据实体瘤疗效评估指南，根据体格检查、超声和磁共振技术测量新辅助化疗前后肿瘤的最大径变
化，与病理对照，将其分成四种类型，包括临床完全缓解、临床部分缓解、临床缓解不明显和临床进展。
结果
64例乳腺癌新辅助化疗患者，13例患者病理上完全缓解（13/64，20%）。体格检查、超声和磁共振
评价新辅助疗效的病理显著缓解的敏感性分别为73%、75%和80%，特异性分别为45%、50%和50%。体格检查、
超声和磁共振评价新辅助疗效的病理完全缓解的敏感性分别为463%、46%和39%，特异性分别为65%、98%和
92%。
结论
体格检查、超声和磁共振这三种评价方法都明显低估病理完全缓解率，因此临床上急需更加适宜、
普遍、切合实际的体格检查、超声和磁共振的新辅助化疗疗效评价标准和方法。
The clinical value of neoadjuvant chemotherapy (NAC) in the management of breast cancer is well documented.
The benefits of NAC include downstaging the tumor load, which increases the rate of breast-conserving surgery,
with an improvement of disease-free and overall survival1,2.
Accurate evaluation of tumor response following chemotherapy treatment is essential for surgical decision making.
Modalities used to monitor tumor response to NAC include physical examination (PE), ultrasound (US), and
magnetic resonance imaging (MRI) 3-10. However, a considerable number of investigations have shown the
accuracy of clinical and imaging techniques in predicting the response of the breast cancer is conflicting3-7,10. Prati
R et al3 found PE was a reliable method to evaluate size of residual breast carcinoma, and to accurately assess the
complete response to NAC. In the same study, they indicated that MRI might overestimate the residual tumor
among patients with a pathologic complete response (pCR). However, previous studies5,6 have showed that MRI is
the most accurate modality in assessing residual disease when compared to final pathology measurements. There
are methodological differences between these studies, found no repeatability and reproducibility.
The purpose of this study was to evaluate the feasibility and accuracy of different clinical and imaging methods
(PE, US, and MRI) in predicting the response to neoadjuvant chemotherapy in patients with breast cancer,
compared with final histopathological examination.
METHODS
Patients
All patients with breast cancer at our institution treated by a multidisciplinary team approach were entered
prospectively into a database approved by institutional review board committee. The study cohort consisted of
those women with histologically confirmed stage II or III breast cancer treated with preoperative neoadjuvant
chemotherapy during the period of Jan 2009 through Dec 2010. Prior to NAC, core needle biopsy of the breast
cancer was taken under ultrasound guidance to determine the histological subtype. In all cases, the primary tumor
before and after NAC (usually less than a week before the surgical resection) were evaluated by physical
examination (PE), ultrasonography (US), and magnetic resonance imaging (MRI). All patients subsequently
underwent surgery (modified radical mastectomy or radical mastectomy/conservative breast surgery) within one
month after completion of 4 or 6 cycles of NAC. Patients those with bilateral breast cancer, or with evidence of
distant metastases, any radiotherapy or endocrine therapy before surgery, or not undergoing surgery, were excluded.
The US and MRI measurements were analyzed by a radiologist with 10 years of experience at performing and
interpreting from a picture archiving and communications system according to Breast Imaging Reporting and Data
System (BI-RADS) 11, without knowledge of physical examination findings or pathologic information.
Physical examination
The largest unidimensional measurement of the tumor diameter was documented before and after NAC. Patients
were considered to have clinically negative results if there were no palpable tumors.
Ultrasound
US was performed with either Esaote Mylab 60 or Mylab 90 (Esaote, Genoa, Italy) ultrasound machines equipped
with a 13-4 MHz transducer by an experienced breast radiologist. In all cases, the largest unidimensional
measurement of the tumor diameter by US was documented before and after NAC.
Breast MR Imaging
Breast MR imaging was performed on a dedicated breast magnetic resonance imaging (DBMRI) system (Aurora
Dedicated Breast MRI Systems, USA) with a dedicated breast coil while the patients were in the prone position.
After a localizer on the axial image and coil calibration, a dynamic series of axial T1-weighted fat-suppression
images(TR 29 ms, TE 4.8 ms, slice thickness 1.1 mm, matrix：360X360X128，FOV 36cm), including one pre- and
four post-contrast scans, was obtained. Gd-DTPA (Magnevist, Germany) was administered using a bolus
intravenous injection (1.5 mL/s) at a dose of 0.2 mmol/kg body weight followed by a 20 mL saline solution flush.
The dynamic images were acquired 90s after the contrast media injection. The scan time was three minutes per
scan,and the total time was 12 min. The largest unidimensional measurement of the tumor diameter was performed
on the first phase of the four post-contrast scans before and after NAC.
Assessment of response by PE/US/MRI
The response to treatment at the time of surgery was taken as an end point. According to the RECIST
guidelines(response evaluation criteria in solid tumors), the largest unidimensional measurement of the tumor
diameter evaluated by physical examination, ultrasound, and magnetic resonance imaging was classified as follows:
clinical complete response (CR), the disappearance of disease; clinical partial response (PR), at least a 30%
decrease; clinical progressive disease (PD), at least a 20% increase in the sum of the longest diameter of target
lesions or the appearance of new lesions; clinical stable disease (SD), neither sufficient shrinkage to qualify for PR
nor sufficient increase to qualify for PD12.
Pathologic analysis
The final pathologist was blinded to the results of PE/US/MRI. Pathological tumor regression was used as the gold
standard to evaluate treatment response. A positive tumor was defined by hematoxylin and eosin staining.
Pathologic response in breast cancer was classified into 5 grades according to the Miller-Payne histopathological
grading system13, while Grade 3, Grade 4, and Grade 5were defined as the major pathologic response(Table 1).
The cCR as measured by each imaging modality and physical examination was correlated with the pCR, the overall
clinical response (cCR + cPR) classified as having a complete or partial response correlated with the major
pathologic response (G3+G4+G5), whereas clinical non-response (cSD + cPD) classified as having a stable or
progressive response correlated with the minor pathologic response (G1+G2).
Statistical analysis
The accuracy of PE/AUS/MRI in the assessment of treatment response was evaluated comparing with the final
histopathological results. Chi-square test and Fisher's exact test were used wherever indicated. A P value of 0.05 or
less was considered statistically significant. Data analysis was performed with SPSS 17.0 statistical software (SPSS
Inc., Chicago, IL).
RESULTS
Patient and tumor characteristics at Baseline
A total of 64 patients were enrolled on this study, aged between 29 and 76 (median age 50 years). Patient age,
primary tumor histological subtype, clinical stage, menopausal status, hormonal receptor status are listed in Table
2.
Pathologic response to neoadjuvant chemotherapy
Of the 64 patients received NAC, the pathologic response according to the Miller-Payne histopathological grading
system was as follows: two G1, eighteen G2, eighteen G3, thirteen G4, and thirteen G5. A pathologic complete
response (pCR) was shown in 13 of 64 patients (20%). The major pathologic response (G3+G4+G5) was shown in
44 of the 64 patients (68%), while the minor pathologic response (G1+G2) was occurred in the remaining 20
patients (32%).
Assessment by clinical and radiologic modality
For the assessment of the tumor response to NAC, PE correctly predicted a pathologic complete response in 6 of
the 13 patients, for predicting the major pathologic response in 32 of the 44 patients, while for predicting the minor
pathologic response in 9 of the 20 patients. US predicted a complete regression in 6 of the 13 patients with pCR,
while the major pathologic response in 33 of the 44 patients, and the minor pathologic response in 10 of the 20
patients. MRI correctly predicted a pCR in 5 of the 13 patients, for predicting the major pathologic response in 35
of the 44 patients, and the minor pathologic response in 10 of the 20 patients. (Table 3). There was no statistically
difference between the 2 imaging modalities (P>0.05, respectively).The sensitivity of PE, US, and MRI for
predicting the major pathologic response was 73, 75, and 80%, and the specificity was 45, 50, and 50%,
respectively. For predicting a pCR, the sensitivity of PE, US, and MRI was 46, 46, and 39%, and the specificity
was 65, 98, and 92%, respectively (Table 4).
DISSUSSION
With the rapid development of imaging techniques and worldwide acceptation of NAC, the evaluation of response
to NAC with clinical and imaging modalities has evolved over the past few years. The aim of clinical and imaging
modalities in assessment of response to NAC is not only to document morphological information and measurement
of residual disease, but also to try to predict the pathological response after NAC. It is generally held that tumor
size is not only an independent indicator of prognosis for local treatment selection, but also an assessment of
response to NAC in patients with breast cancer.
However, predicting residual tumor size and predicting a pCR after NAC are considered even more challenging7,14.
In this study, the response assessment by physical examination, ultrasound, and magnetic resonance imaging
clearly demonstrated that the clinical and radiologic prediction tended to obviously underestimate the pCR rate,
and no difference in the accuracy of PE, US or MRI for predicting the pCR rate. The sensitivity of these three
clinical and imaging modalities in predicting a pCR was lower, although the specificity was higher in the imaging
modalities (98% by US and 92% by MRI, respectively) than the physical examination(65%). This result is
consistent with previous studies 3,15. In a series by Keune JD et al, the combined sensitivity of both mammography
and US in predicting pCR was 45.8%, the specificity was 93.8%, and the probability of a pCR is 68.8%. However,
if only one imaging modality, either mammography or US, the probability of a pCR was 53.3%15. Schott AF et al
documented 9.8% of forty-three patients achieved a pCR after NAC. In these 4 patients achieved pCR , PE ,
mammography, US, and MRI predicted pCR in only one case . The sensitivity of all these four clinical and
imaging modalities for detecting a pCR was 50, 50, 25, and 25%, respectively 16. Based on Prati R et al3‘s study,
only 2 of 9 patients with pCR were correctly predicted by a negative MRI after NAC, and the false positive rate
(7/9, 78%) was high, indicated that MRI might overestimate the residual tumor among patients with pCR(such as
Figure 1). On the other hand, one patient in this series whose residual tumor size was remarkable reduced on PE,
US, and MRI, was finally confirmed minor pathologic response, with no reduction in overall cellularity after NAC
(Figure 2).
These results recommend that attention should be paid to different patterns of tumor regression and reduction after
NAC. Chemotherapy itself may induce significant biologic changes of the tumor, affecting clinical and imaging
findings differently. Fibrotic or necrotic tissue caused by NAC may mimic a residual tumor mass on palpation,
even on US. Moreover, concentric shrinkage, dendritic shrinkage or fragmentation into multiple foci in
multifocal/multicentric cancer or solitary masses may cause intra- and inter-observer variability17. This may be
explained by many previous studies concerning postchemotherapeutic fibroglandular changes as the main reason
for the inaccuracies frequently associated with clinical and imaging modalities as well18.
Furthermore, for lesions without circumscribed margins, especially after NAC, according to different pattern of
tumor appearances on US, the measurements were carried out in the different ways. This result is consistent with
the finding of Meier-Meitinger M et al.19 Additionally, the ill-defined and irregularity of lesions have shown
considerable inter-observer variability20, and even decrease the concordance in tumor response assessment by
clinical and imaging modalities between the RECIST and WHO methods 21. To the best of our knowledge, there
are no strict guidelines for the tumor size measurement by imaging modalities. A previous study indicated MRI
with enhancement as the most accurate way to assess residual tumor size after NAC because it can differentiate
residual cancer (with enhancement) from fibrosis (without enhancement) 7, while underestimation and/or
overestimation of residual disease and false negatives after NAC were notable also in previous studies even though
MRI as a good potential predictor for monitoring response to NAC were reported5,7. According to Bahri S et al. 22,
the diagnostic performance of MRI defined as the mass lesions or the non-mass lesions (showing diffuse contrast
enhancements on MRI) pre-NAC, and residual tumor distribution post- NAC were categorized into three types,
including: 1) pCR- no residual invasive cancer; 2) nodular pattern- with confined cancer nodules; and 3) scattered
cell pattern- with small cancer nodules and scattered cancer cells/clusters distributed in a large fibrotic region. For
mass lesions that shrink down to nodules, the size measured by MRI is very close to the pathological size. In
contrast, for non-mass lesions, the size is already difficult to assess pre-NAC, and that leads to additional difficulty
in evaluating the treatment response with MRI. Therefore, they concluded that MRI has a limitation in detecting
residual disease broken down to small foci and scattered cells/clusters. US and PE may also face the challenge to
this intrinsic limitation.
This study has some limitations. Firstly, it followed a small cohort of patients. Larger studies with longer follow-up
may provide some further information. Secondly, although the Response Evaluation Criteria in Solid Tumors
(RECIST) was simple and clearly defined, using only the unidimensional measurement of the tumor diameter by
PE/US/MRI, may not be the best way to measure primary tumor response to neoadjuvant chemotherapy. Thirdly, a
major disadvantage of breast ultrasound is its high intra- and inter-observer variability.
CONCLUSION
In conclusion, all these three clinical and imaging modalities tended to obviously underestimate the pCR rate,
although the specificity was higher in the imaging modalities.A more appropriate, universal, and practical
standards by clinical and imaging modalities in predicting the response to NAC in vivo is essential, and also to
develop a much better pathological assessment criteria.
Acknowledgements
We would like to thank Mrs. Guang Hua Xiang for her help with data collection, Mrs. Lei Tang for her assistance
with the statistical analysis, and Mr. Michael Carroll for his help in improvement of English expression.
Conflict of interest statement
The authors have no conflicts of interest to declare.
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Table 1. Miller-Payne histological grading system
Grade
Grade 1 (G1)
Definition
No change or some alteration to individual malignant cells but no reduction in
overall cellularity.
Grade 2 (G2)
A minor loss of tumor cells but overall cellularity still high; up to 30% loss
Grade 3 (G3)
Between an estimated 30% and 90% reduction in tumor cells
Grade 4 (G4)
A marked disappearance of tumor cells such that only small clusters or widely
dispersed individual cells remain; more than 90% loss of tumor cells
Grade 5 (G5)
No malignant cells identifiable in sections from the site of the tumor; only vascular
fibroelastotic stroma remains often containing macrophages. However, ductal
carcinoma in situ (DCIS) may be present
Table 2. The patient and tumor characteristics at baseline
Characteristics
n=64
Percentage (%)
≤50
34
53%
>50
30
47%
Pre-menopausal
38
59%
Post-menopausal
26
41%
Invasive ductal cancer
56
88%
Mixed
7
11%
Other
1
1%
IIA
5
8%
II B
33
52%
III A
17
27%
III B
5
8%
III C
4
5%
ER positive
37
57%
PR positive
30
47%
Age(years)
Menopausal status
Tumor histology
Clinical stage
Hormone receptors
ER:Estrogen Receptor;PR:Progesterone Receptor
Table 3. Physical examination, ultrasound, magnetic resonance imaging, and histopathological evaluations of
breast tumor responses to neoadjuvant chemotherapy
Histopathological evaluation
Assessment by clinical and radiologic
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Total
complete response
1
6
4
7
6
24
partial response
0
4
5
6
4
19
stable disease
1
5
8
0
3
17
progressive disease
0
3
1
0
0
4
complete response
0
0
0
1
6
7
partial response
1
9
12
9
5
36
stable disease
1
7
5
3
2
18
progressive disease
0
2
1
0
0
3
complete response
0
0
0
4
5
9
partial response
1
9
12
9
5
36
stable disease
1
7
6
0
3
17
progressive disease
0
2
0
0
0
2
modality
Physical examination Evaluation
Ultrasound Evaluation
Magnetic resonance imaging Evaluation
Table 4. Primary breast tumor response to neoadjuvant chemotherapy by clinical and Imaging Modality
(Comparison Between PE /US/MRI With Final Pathologic Finding)
Modality
Z
Sensitivity
Specificity
Area under the curve(95%CI)
The major pathologic response (CR+PR)
PE Evaluation
-1.389
0.73
0.45
0.59(0.43~0.74)
US Evaluation
-1.959
0.75
0.50
0.63(0.47~0.78)
MRI Evaluation
-2.379
0.80
0.50
0.65(0.50~0.80)
The complete pathologic response (CR)
PE Evaluation
-0.716
0.46
0.65
0.55(0.38~0.73)
US Evaluation
-4.522
0.46
0.98
0.72(0.54~0.90)
MRI Evaluation
-2.813
0.39
0.92
0.65(0.47~0.84)
PE: physical examination; US: ultrasound; MRI: magnetic resonance imaging; CR: complete response; PR: partial
response
,
Figure 1. Assessment of response to NAC by ultrasound and MRI in a 61-year-old woman with pathological
complete response. Figure 1A: Ultrasound before NAC shows a primary lesion with irregular shape, spiculated
margin, and posterior acoustic shadowing. Figure 1B: After NAC, no mass t but a faint hypoechoic strips area
appears in the previous tumor bed, thus a complete clinical response evaluated by US. Figure 1C: Prior to NAC,
MRI shows a 3.0cm linearly enhanced lesion in the right breast. Figure 1D: After NAC, the lesion is reduced to 2.2
cm, thus a partial clinical response diagnosed by MRI.
Figure 2. Assessment of response to NAC by US and MRI in a 60-year-old woman confirmed minor pathologic
response, with a minor loss of tumor cells but overall cellularity still high after NAC. Figure 2A: Baseline US prior
to NAC shows a 2.5 cm mass in the left breast with irregular shape, spiculated margin, and posterior acoustic
shadowing. Figure 2B: After NAC, the tumor shrinks down to 0.8 cm, thus a clinical partial response evaluated by
US. Figure 2C: Prior to NAC, MRI shows a primary lesion of 2.8 cm enhanced mass. Figure 2D: After NAC, the
lesion is reduced to 1.2 cm, thus a clinical partial response diagnosed by MRI.