Predicting Pathologic Response of Esophageal Cancer to Neoadjuvant Chemotherapy: The Implications of Metabolic Nodal Response for Personalized Therapy

John M. Findlay; Kevin M. Bradley; Lai Mun Wang; James M. Franklin; Eugene J. Teoh; Fergus V. Gleeson; Nicholas D. Maynard; Richard S. Gillies; Mark R. Middleton

doi:10.2967/jnumed.116.176313

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TABLE 1

Baseline Patient Characteristics

Characteristic	Overall (n = 301)	Pathologic response (n = 82)	No pathologic response (n = 219)	P (α = 4.55 × 10⁻³ pre-NAC, α = 2.63 × 10⁻³ post-NAC)
Median age (y)	64.0 (IQR, 58.0–70.0; range, 36.0–80.0)	62.5 (IQR, 57.3–69.0; range, 36.0–79.0)	64.0 (IQR, 58.0–70.0; range, 38.0–80.0)	0.369^*
Sex				0.764^†
Male	228 (75.7%)	61 (74.4%)	167 (76.3%)
Female	73 (24.3%)	21 (25.6%)	52 (23.7%)
Cell type				0.979^†
Adenocarcinoma	249 (82.7%)	68 (82.9%)	181 (82.6%)
Squamous cell carcinoma	44 (14.6%)	13 (15.9%)	31 (14.2%)
Adenosquamous	5 (1.66%)	1 (1.22%)	4 (1.83%)
Small cell carcinoma	1 (0.33%)	0 (0.00%)	1 (0.46%)
Anaplastic	2 (0.66%)	0 (0.00%)	2 (0.91%)
Grade of differentiation				0.338^†
Well	28 (9.30%)	5 (6.10%)	23 (10.5%)
Moderate	128 (42.5%)	35 (42.7%)	93 (42.0%)
Poor	140 (46.5%)	42 (51.2%)	98 (44.7%)
Undifferentiated	5 (1.66%)	0 (0.00%)	5 (2.28%)
Tumor site				0.033^†
Mid 1/3	18 (5.98%)	9 (11.0%)	11 (5.02%)
Distal 1/3	52 (17.3%)	11 (13.4%)	41 (18.7%)
GEJ 1	72 (23.9%)	23 (28.0%)	49 (22.4%)
GEJ 2	107 (35.5%)	20 (24.4%)	85 (38.8%)
GEJ 3	51 (16.9%)	19 (23.2%)	32 (14.6%)
Multifocal	1 (0.33%)	0 (0.00%)	1 (0.46%)
Surgical approach				0.003^*
LTE	200 (66.4%)	12 (14.6%)	156 (71.3%)
ILE	46 (15.3%)	44 (53.7%)	34 (15.5%)
3 stage	10 (3.32%)	5 (6.10%)	5 (2.28%)
THE	1 (0.33%)	1 (1.22%)	0 (0.00%)
ETG	44 (14.6%)	20 (24.4%)	24 (11.0%)

↵* Mann–Whitney test.
↵† Fisher exact test.
IQR = interquartile range.

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TABLE 2

Pre-NAC Staging Results

Parameter	Overall (n = 301)	Pathologic response (n = 82)	No pathologic response (n = 219)	P (α = 4.55 × 10⁻³ pre-NAC, α = 2.63 × 10⁻³ post-NAC)
T stage				0.114^*
1	7 (2.33%)	2 (2.43%)	5 (2.28%)
2	46 (15.3%)	19 (23.2%)	27 (12.3%)
3	231 (76.7%)	56 (68.3%)	175 (79.9%)
4a	17 (7.76%)	5 (6.10%)	12 (35.48%)
4b	0 (0.00%)	0 (0.00%)	0 (0.00%)
N stage				0.090^*
0	88 (29.3%)	58 (26.5%)	30 (36.6%)
1	213 (70.7%)	161 (73.5%)	52 (63.4%)
Initial PET/CT				0.011^*
¹⁸F-FDG–avid	290 (96.7%)	75 (91.5%)	215 (98.2%)
¹⁸F-FDG–negative	11 (3.65%)	7 (8.54%)	4 (1.83%)
Initial PET/CT scanner				0.897^*
1	142 (47.7%)	38 (46.3%)	104 (47.5%)
2	159 (52.3%)	44 (55.7%)	115 (52.5%)
NA	0 (0.00%)
Restaging PET/CT scanner				0.739^*
1	62 (20.6%)	16 (19.5%)	46 (21.0%)
2	158 (52.5%)	46 (56.1%)	112 (51.19%)
CT	81 (26.9%)	20 (24.4%)	61 (27.9%)
mN stage				0.371^*
0 (0 nodes)	209 (69.4%)	54 (65.9%)	155 (70.8%)
1 (1–2 avid nodes)	54 (17.9%)	14 (17.1%)	40 (18.3%)
2 (>2 avid nodes)	38 (12.6%)	14 (17.1%)	24 (11.0%)
NA	0 (0.00%)
Impassable at EGD?				0.633^*
No	278 (92.4%)	77 (93.9%)	201 (92.8%)
Yes	23 (7.60%)	5 (6.10%)	18 (8.20%)

↵* Fisher exact test.
NA = not applicable; EGD = esophagogastroduodenoscopy.

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TABLE 3

Surgical Approach and Response to Chemotherapy

Parameter	Overall (n = 301)	Pathologic response (n = 82)	No pathologic response (n = 219)	P (α = 4.55 × 10⁻³ pre-NAC, α = 2.63 × 10⁻³ post-NAC)
Response to chemotherapy
Regimen				2.69 × 10⁻⁵^*
Dual	230 (76.4%)	48 (58.5%)	182 (83.1%)
Triple	71 (23.6%)	34 (41.5%)	37 (16.9%)
Median days to restaging scan	82.0 (IQR, 71.0–93.0)	88.5 (IQR, 71.3–106.8; range, 43.0–167)	82.0 (IQR, 71.0–91.0; range, 40.0–165)	0.036^*
Median days from scan to surgery	24.0 (17.0–33.0)	23.0 (IQR, 18.3–31.8; range, 5.0–52.0)	23.0 (IQR, 15.0–33; range, 4.0–72.0)	0.283*
pTR		NA	NA	NA
No	82 (27.2%)
Yes	219 (72.8%)
mTR				5.38 × 10⁻¹³^*
Nonavid	7 (2.33%)	5 (8.06%)	2 (1.27%)
CMR	48 (15.9%)	33 (53.3%)	15 (9.49%)
PMR	108 (35.9%)	20 (32.4%)	88 (55.7%)
SMD	43 (14.3%)	4 (1.33%)	39 (24.7%)
PMD	14 (4.65%)	0 (0.00%)	14 (8.86%)
NA	81 (26.9%)	20 (NA)	61 (NA)
mNR				1.23 × 10⁻⁴^*
No avid nodes	138 (45.8%)	39 (62.9%)	99 (62.6%)
CMR	50 (16.6%)	21 (33.9%)	29 (18.4%)
PMR/SMD/PMD	32 (10.6%)	2 (3.22%)	30 (19.0%)
NA	81 (26.9%)	20 (NA)	61 (NA)

↵* Fisher exact test.
LTE = left thoracoabdominal esophagectomy; ILE = Ivor-Lewis esophagectomy; THE = transhiatal esophagectomy; ETG = extended total gastrectomy; IQR = interquartile range; pTR = pathologic tumor response; mTR = metabolic tumor response; CMR = complete metabolic response; PMR = partial metabolic response; SMD = stable metabolic disease; PMD = progressive metabolic disease; NA = not applicable.

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TABLE 4

Baseline Factors Associated with Pathologic Response to NAC: Univariate and Multivariate Regression

	Response
Factor	Univariate OR (95% CI)	P	Multivariate OR (95% CI)	P
Median age (y)	1.00 (1.00–1.00)	0.536	1.00 (1.00–1.00)	0.949
Sex
Female	Ref	Ref	Ref	Ref
Male	0.90 (0.50–1.62)	0.722	0.94 (0.45–1.95)	0.859
Cell type
Adenocarcinoma	Ref	Ref	Ref	Ref
Squamous cell carcinoma	1.14 (0.56–2.32)	0.716	0.87 (0.31–2.45)	0.792
Grade
Well	Ref	Ref	Ref	Ref
Moderate	1.77 (0.62–5.02)	0.284	1.07 (0.33–3.49)	0.906
Poor	1.99 (0.71–5.58)	0.194	1.53 (0.47–4.97)	0.477
Site
Mid 1/3	Ref	Ref	Ref	Ref
Distal 1/3	0.30 (0.10–0.91)	0.034	0.21 (0.05–0.79)	0.021
GEJ 1	0.51 (0.18–1.54)	0.200	0.34 (0.09–1.26)	0.106
GEJ 2	0.28 (0.10–0.78)	0.015	0.17 (0.04–0.69)	0.013
GEJ 3	0.68 (0.23–1.98)	0.480	0.15 (0.03–0.64)	0.020
T stage
1	Ref	Ref	Ref	Ref
2	1.76 (0.31–10.0)	0.525	2.33 (0.34–16.0)	0.390
3	0.83 (0.16–4.42)	0.830	0.98 (0.15–6.27)	0.986
4a	1.05 (0.15–7.27)	0.967	1.13 (0.13–10.0)	0.916
N stage
0	Ref	Ref	Ref	Ref
1	0.64 (0.37–1.10)	0.105	0.60 (0.13–1.16)	0.129
Passable at EGD?
Yes	Ref	Ref	Ref	Ref
No	0.63 (0.20–1.93)	0.416	0.50 (0.13–1.95)	0.317
Chemotherapy
Regimen
Dual	Ref	Ref	Ref	Ref
Triple	3.48 (1.97–6.14)	1.76 × 10⁻⁵	5.98 (2.44–14.7)	8.94 × 10⁻⁵
Log time to restaging	63.9 (4.24–964)	2.66 × 10⁻³	10.8 (0.42–280)	0.152
Log time to surgery	0.93 (0.31–2.79)	0.896	1.12 (0.29–4.33)	0.873
PET/CT variables
PET scanner
1	Ref	Ref	Ref	Ref
2	1.07 (0.64–1.79)	(0.796)	0.69 (0.36–1.32)	0.267
mN stage
0	Ref	Ref	Ref	Ref
1	0.94 (0.46–1.89)	0.857	1.42 (0.60–3.34)	0.426
2	1.67 (0.80–3.48)	0.720	1.72 (0.67–4.45)	0.261
Log SUV_max	0.43 (0.16–1.11)	0.081	0.54 (0.15–1.92)	0.343
Log ¹⁸F-FDG–avid length	0.90 (0.81–1.01)	0.070	0.89 (0.77–1.04)	0.145
Subset of patients^*
SUV_mean	1.47 (0.09–23.4)	0.784	1.56 (0.04–65.8)	0.814
SUV_peak	2.53 (0.41–15.8)	0.320	1.85 (0.50–6.77)	0.356
MTV	1.55 (0.79–3.04)	0.203	1.70 (0.66–4.39)	0.276
TGV_max	1.53 (0.84–2.76)	0.163	1.72 (0.74–3.99)	0.230
TGV_mean	1.45 (0.86–2.44)	0.164	1.64 (0.78–3.42)	0.189

*This subset of patients was staged using second PET/CT scanner (n = 155).
CI = confidence interval; Ref = reference; NA = not applicable; EGD = esophagogastroduodenoscopy.
Data in parentheses are IQRs.

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TABLE 5

Postchemotherapy Factors Associated with Pathologic Response to NAC: Univariate and Multivariate Regression, Adjusted for Baseline Variables

	Response
Factor	Univariate OR (95% CI)	P	Multivariate OR (95% CI)	P
Chemotherapy
Regimen
Dual	Ref	Ref	Ref	Ref
Triple	4.30 (2.16–8.55)	3.23 × 10⁻⁵	17.6 (4.39–70.1)	5.00 × 10⁻⁵
Log time to restaging	25.1 (1.10–574)	0.044	0.32 (0.00–69.2)	0.678
Log time to surgery	2.28 (0.57–9.07)	0.241	0.52 (0.06–4.82)	0.567
PET/CT variables
PET scanner
1	Ref	Ref	Ref	Ref
2	1.09 (0.58–2.07)	0.782	0.10 (0.02–0.55)	0.008
Restaging PET scanner
1	Ref	Ref	Ref	Ref
2	1.30 (0.66–2.57)	0.446	5.24 (0.95–28.9)	0.057
Restaging mN stage
0 (0 avid nodes)	Ref	Ref	Ref	Ref
1 (1–2 avid nodes)	0.16 (0.02–1.28)	0.084	1.07 (0.07–16.8)	0.959
2 (>2 avid nodes)	0.16 (0.02–1.28)	0.084	2.39 (0.18–31.6)	0.509
Restaging log SUV_max	2.37 × 10⁻³ (4.21 × 10⁻⁴ to 0.01)	6.93 × 10⁻¹²	3.84 × 10⁻⁴ (1.17 × 10^–5 to 0.02)	9.89 × 10⁻⁶
Restaging log avid length	0.61 (0.51–0.73)	3.80 × 10⁻⁸	1.01 (0.76–1.34)	0.951
Restaging log MTL	0.03 (0.01–0.10)	3.88 × 10⁻¹⁰	0.02 (4.03 × 10⁻³ to 0.06)	6.19 × 10⁻⁹
Subset of patients with ¹⁸F-FDG–avid nodes (n = 30)
Log nodal SUV_max	8.71 (0.01–5787)	0.514	NA	NA
Subset of patients staged using second PET/CT scanner (n = 155)
Log SUV_mean	1.58 × 10⁻⁴ (7.51 × 10⁻⁶ to 3.23 × 10⁻³)	1.78 × 10⁻⁴	1.13 × 10⁻⁷ (8.55 × 10⁻¹² to 1.46 × 10⁻³)	9.32 × 10⁻⁵
SUV_peak	5.05 × 10⁻³ (1.81 × 10⁻⁴ to 0.14)	1.85 × 10⁻³	0.57 (0.39–0.84)	3.90 × 10⁻³
Log MTV	0.28 (0.18–0.44)	0.203	0.09 (0.03–0.28)	2.03 × 10⁻⁵
Log TGV_max	0.32 (0.21–0.48)	3.91 × 10⁻⁸	0.11 (0.04–0.31)	2.72 × 10⁻⁵
Log TGV_mean	0.30 (0.19–0.46)	3.27 × 10⁻⁸	0.10 (0.03–0.29)	2.29 × 10⁻⁵

CI = confidence interval; Ref = reference; MTL = metabolic tumor length; NA = not applicable.

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TABLE 6

Metabolic Response and Other Factors Associated with Pathologic Response to NAC: Univariate and Multivariate Regression (Patients Staged and Restaged Using Same PET Scanner), Adjusted for Baseline Variables

	Response
Factor	Univariate OR (95% CI)	P	Multivariate OR (95% CI)	P
Chemotherapy
Regimen
Dual	Ref	Ref	Ref	Ref
Triple	4.30 (2.16–8.55)	3.23 × 10⁻⁵	20.3 (4.50–91.4)	8.84 × 10⁻⁵
Log time to restaging	69.1 (1.86–2571)	0.022	0.22 (0.00–172)	0.658
Log time to surgery	1.75 (0.41–7.44)	0.452	0.70 (0.06–8.36)	0.781
PET/CT variables
Initial/restaging PET scanner
1	Ref	Ref	Ref	Ref
2	0.87 (0.40–1.88)	0.718	0.71 (0.21–2.38)	0.580
nMR
Negative	Ref	Ref	Ref	Ref
CMR	1.93 (0.93–4.01)	0.076	2.01 (0.54–7.51)	0.300
PMR	0.45 (0.05–3.87)	0.465	11.2 (0.64–197.3)	0.098
SMD	0.27 (0.03–2.18)	0.219	1.15 (0.09–14.4)	0.911
PMD	NA (NA)	NA	NA (NA)	NA
Reduction logSUV_max (%)	1.04 (1.02–1.05)	6.65 × 10⁻⁸	1.03 (1.01–1.06)	3.24 × 10⁻³
Reduction avid length (%)	1.03 (1.02–1.04)	9.37 × 10⁻⁸	1.02 (1.00–1.03)	0.019
Additional metrics in all patients (n = 202)
Reduction MTL (%)	1.05 (1.03–1.07)	2.86 × 10⁻⁶	1.11 (1.05–1.16)	1.16 × 10⁻⁵
PERCIST (30.0%)
CMR	Ref	Ref	Ref	Ref
PMR	0.10 (0.04–0.22)	2.24 × 10^–8	0.08 (0.02–0.32)	3.53 × 10⁻⁵
SMD/PMD	0.04 (0.01–0.14)	2.18 × 10^–7	0.06 (0.01–0.49)	8.46 × 10⁻⁴
MUNICON (35.0%)
No response	Ref	Ref	Ref	Ref
Response	5.21 (2.08–13.0)	4.22 × 10^–5	1.63 (0.41–6.45)	0.484
Subset of patients staged using second PET/CT scanner (n = 155)
Reduction SUV_mean (%)	1.03 (1.02–1.04)	2.25 × 10⁻⁸	1.05 (1.02–1.09)	1.90 × 10⁻³
Reduction SUV_peak (%)	1.09 (1.03–1.15)	1.91 × 10⁻⁵	1.04 (1.02–1.05)	2.20 × 10⁻³
Reduction MTV (%)	1.44 (1.09–1.92)	2.70 × 10⁻⁵	1.16 (1.07–1.25)	0.011
Reduction TGV_max (%)	1.30 (1.12–1.52)	5.82 × 10⁻³	2.31 (1.27–4.20)	2.72 × 10⁻⁵
Reduction TGV_mean (%)	1.23 (1.10–1.37)	3.91 × 10⁻⁸	1.87 (1.20–2.90)	2.29 × 10⁻⁵

CI = confidence interval; Ref = reference; mNR = metabolic nodal response; MTL = metabolic tumor length; CMR = complete metabolic response; PMR = partial metabolic response; SMD = stable metabolic disease; PMD = progressive metabolic disease; NA = not applicable.

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TABLE 7

Comparison of Tumor and Nodal Metabolic Response

	mNR
Tumor response	NA	CMR	PMR	SMD	PMD
Pathologic response
pTR	39 (17.7%)	21 (9.55%)	1 (0.45%)	1 (0.45%)	0 (0.00%
No pTR	99 (45.0%)	29 (13.2%)	12 (5.45%)	13 (5.91%)	5 (22.7%)
Metabolic response
NA	6 (2.73%)	1 (0.45%)	0 (0.00%)	0 (0.00%)	0 (0.00%)
CMR	32 (14.5%)	14 (1.82%)	1 (0.45%)	1 (0.45%)	0 (0.00%)
PMR	68 (30.9%)	29 (13.2%)1	8 (3.64%)	2 (0.91%)	0 (0.00%)
SMD	22 (9.09%)	5 (2.27%)	4 (1.82%)	10 (4.55%)	3 (1.36%)
PMD	10 (4.55%)	1 (0.45%)	0 (0.00%)	1 (0.45%)	2 (0.91%)

NA = not applicable; CMR = complete metabolic response; PMR = partial metabolic response; SMD = stable metabolic disease; PMD = progressive metabolic disease.