Rationale and Objectives
The aim of our study was to evaluate changes in growth kinetics of breast cancer liver metastasis in response to locoregional therapy and compare them to Response Evaluation Criteria in Solid Tumors (RECIST).
Materials and Methods
This Health Insurance Portability and Accountability Act–compliant retrospective study was Institutional Review Board approved. Thirty-four chemorefractory breast cancer liver metastases from 21 patients treated with yttrium-90 ( 90 Y) were evaluated. Pre- and posttreatment computed tomography (CT) scans were used to calculate tumor growth kinetics. The growth parameter analyzed was reciprocal of doubling time (RDT). RDT range for stable disease (SD) was defined by the measurement error rate. A negative RDT below the SD range defined response and was categorized as either partial response (PR) or complete response, whereas a positive RDT value above the SD range indicated progressive disease (PD). Comparison was made to tumor response classification according to percentage change in the lesion’s maximal diameter per RECIST. Lin’s concordance correlation coefficient, Bland–Altman plot, Wilcoxon signed rank test, and Student t test were used for analysis. Significance was set at 0.05.
Results
RDT range for SD ranged from −0.46 to +2.17. Six lesions with PR based on RECIST showed PR based on their volumetric growth rate (mean RDT of −17.3 ± 2.6). Similarly, one lesion with PD according to RECIST was categorized as PD based on its growth kinetics (RDT of 10.2). However, 14 (51.85%) lesions classified as SD by RECIST had PR according to growth kinetics (mean RDT of −7.8), six (22.22%) lesions were categorized as SD (mean RDT of 0.8), whereas seven (25.93%) lesions showed PD (mean RDT of 4.5). Growth kinetic parameters were significantly different for lesions with PR when compared to lesions with PD ( P < .0001).
Conclusions
In patients with breast cancer liver metastases undergoing locoregional therapy, RECIST categorization may not be an accurate reflection of treatment response.
Metastatic breast cancer is not considered a curable disease at present and accounts for most deaths associated with breast cancer . About 40%–50% of all patients diagnosed with breast cancer will develop liver metastasis during the course of their illness , but rarely (5% of cases) liver-only metastatic involvement can be seen . Management of liver metastases from breast cancer relies heavily on systemic therapies . Locoregional treatments are also available as adjuncts including surgical resection of liver metastases , local ablation , chemoembolization, transarterial chemoembolization, transarterial radioembolization (TARE) , and stereotactic body radiotherapy . Surgical resection of liver metastasis is performed in carefully selected patients and because only 10%–20% of patients are surgical candidates, alternatives must be considered. TARE with yttrium-90 ( 90 Y) is an effective alternative and has been successfully used for treatment of liver metastases in patients with chemorefractory breast cancer. Median overall survival in patients with breast cancer liver metastases undergoing treatment with 90 Y was recently reported at 11.5 months . Because of relatively poorer prognosis and shorter survival in patients with breast cancer liver metastases, there is a need for effective early response assessment to locoregional therapies.
Currently, Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is the commonly used treatment response evaluation tool in clinical cancer trials involving patients with metastatic breast cancer but has several limitations. First, RECIST are based on an assumption that tumors are spherical and change proportionally in response to treatment; however, some studies have shown that tumors may have irregular shape and nonspherical morphologies rendering RECIST unreliable . Second, novel locoregional therapies may induce changes in certain morphologic characteristics (density, necrosis, tumor margins, and so forth) of the tumor with or without any appreciable change in its size . RECIST are unable to account for these changes preventing it from assessing response accurately in such scenarios. This has led to the development of certain tumor and therapy specific criteria, which provide better depiction of response . Third, RECIST guideline categorizes treatment response as stable disease (SD) despite up to 30% decrease or 20% increase in tumor size. Therefore, it will be impossible to accurately assess response to novel locoregional treatments, which may cause clinically significant changes in tumors without crossing the thresholds drawn by RECIST.
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Methods and materials
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Patient Cohort
Patient selection
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TARE with 90 Y microspheres
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MDCT Imaging Protocol
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Imaging Evaluation
Lesion selection
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Tumor volumetry
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Calculation of Doubling Time and Reciprocal of Doubling Time
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DT=Δtlog2/(logV2−logV1), DT
=
Δ
t
log
2
/
(
log
V
2
−
log
V
1
)
,
where V 1 is volume of the lesion in the baseline study, V 2 is volume of the lesion in the follow-up study, and Δ t is the interval between the studies. As DT is an exponential function without normal distribution, reciprocal of DT (RDT) was calculated using the formula:
RDT=365/DT, RDT
=
365
/
DT
,
thus providing a linear representation of tumor growth rate . RDT is the number of times in a year that the tumor volume doubles and is dimensionless. RDT value of zero indicates no change in tumor size, a negative value indicates a decrease in size of the tumor, and a positive value shows tumor growth.
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Objective Response Assessment (RECIST 1.1)
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Treatment Response Based on Volumetric Growth Rate
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ΔV=V−VT. Δ
V
=
V
−
V
T
.
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ΔV=(ΔV1)2+(ΔV2)2−−−−−−−−−−−−−√. Δ
V
=
(
Δ
V
1
)
2
+
(
Δ
V
2
)
2
.
Replacing the values for ΔV1 Δ
V
1 and ΔV2 Δ
V
2 , Equation (1) can be written as
100%ΔV=p(V1)2+(V2)2−−−−−−−−−−−√. 100
%
Δ
V
=
p
(
V
1
)
2
+
(
V
2
)
2
.
Therefore, using Equation (2), we can write the conditions of measurement accuracy (V1−V2>ΔV) (
V
1
−
V
2
Δ
V
) as
100%|V1−V2|(V1)2+(V2)2√>p, 100
%
|
V
1
−
V
2
|
(
V
1
)
2
+
(
V
2
)
2
p
,
where p = 7.87% and determines the boundaries of SD, in a similar approach as WHO guidelines and RECIST.
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Assessment of Interobserver Reproducibility
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Statistical Analysis
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Results
Demographics
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Objective Response Assessment (RECIST 1.1) and Classification of Treatment Response
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Classification of Treatment Response Based on Volumetric Growth Rate
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Comparative Analysis: RECIST 1.1 Versus Volumetric Growth Rate
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Table 1
Characteristics of Lesions Classified as SD by RECIST 1.1
Lesions Interscan Interval (days) RECIST Change (%) RECIST Class Volume Change (%) DT (days) RDT Response according to RDT 1 56 −18.80 SD −78.20 −25.48 −14.32 PR 2 48 −28.1 SD −69.68 −27.88 −13.09 PR 3 48 −29.44 SD −67.80 −29.36 −12.43 PR 4 42 −22.22 SD −60.21 −31.59 −11.55 PR 5 22 −19.83 SD −36.01 −34.15 −10.69 PR 6 43 −13.22 SD −53.46 −38.97 −9.37 PR 7 52 −6.83 SD −59.70 −39.66 −9.20 PR 8 36 −6.70 SD −40.62 −47.87 −7.62 PR 9 34 −7.06 SD −27.81 −72.33 −5.05 PR 10 58 −12.35 SD −36.26 −89.27 −4.09 PR 11 27 −6.49 SD −15.77 −109.08 −3.35 PR 12 34 −8.38 SD −18.38 −116.06 −3.14 PR 13 52 −10.76 SD −25.46 −122.65 −2.98 PR 14 35 −1.12 SD −14.83 −151.17 −2.41 PR 15 28 −2.90 SD −2.40 −798.09 −0.46 SD 16 27 4.11 SD 0.33 5736.48 0.06 SD 17 39 −2.79 SD 5.93 469.08 0.78 SD 18 24 11.16 SD 4.57 372.61 0.98 SD 19 43 10.23 SD 10.64 294.68 1.24 SD 20 22 1.51 SD 9.48 168.41 2.17 SD 21 30 19.28 SD 13.44 164.86 2.21 PD 22 36 4.73 SD 27.21 103.67 3.52 PD 23 36 4.28 SD 27.68 102.13 3.57 PD 24 28 9.96 SD 25.21 86.34 4.23 PD 25 51 8.39 SD 52.26 84.09 4.34 PD 26 51 16.02 SD 64.23 71.26 5.12 PD 27 51 10.71 SD 125.27 43.53 8.39 PD
DT, doubling time; PD, progressive disease; PR, partial response; RDT, reciprocal of doubling time; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
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Interobserver Reproducibility and Agreement
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Discussion
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Acknowledgments
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