Metformin use and improved response to therapy in esophageal adenocarcinoma

Figures & data

Table I. Patient demographics and treatment characteristics.

	All patients		Non-diabetic		Diabetic, Metformin		Diabetic, No metformin
	N	%	N	%	N	%	N	%	p-value
All patients	285	100.0%	235	100.0%	29	100.0%	21	100.0%
Median age	60	(20–83)	60	(20–81)	62	(40–77)	61	(51–83)	p = 0.11
Gender
Male	261	91.6%	215	91.5%	25	86.2%	21	100.0%	p = 0.22
Female	24	8.4%	20	8.5%	4	13.8%	0	0.0%
Race
African-American	1	0.4%	0	0.0%	1	3.4%	0	0.0%	p = 0.05
Arabic	3	1.1%	2	0.9%	1	3.4%	0	0.0%
Asian	2	0.7%	1	0.4%	1	3.4%	0	0.0%
Caucasian	272	95.4%	226	96.2%	26	89.7%	20	95.2%
Hispanic	7	2.5%	6	2.6%	0	0.0%	1	4.8%
PS
100	20	7.0%	13	5.5%	4	13.8%	3	14.3%	p = 0.08
90	98	34.4%	87	37.0%	5	17.2%	6	28.6%
80	142	49.8%	117	49.8%	17	58.6%	8	38.1%
70	25	8.8%	18	7.7%	3	10.3%	4	19.0%
Smoking status
Never	77	27.0%	65	27.7%	6	20.7%	6	28.6%	p = 0.57
Former	155	54.4%	124	52.8%	20	69.0%	11	52.4%
Current	53	18.6%	46	19.6%	3	10.3%	4	19.0%
Tumor stage
T1	2	0.7%	2	0.9%	0	0.0%	0	0.0%	p = 0.99
T2	36	12.6%	30	12.8%	4	13.8%	2	9.5%
T3	240	84.2%	197	83.8%	24	82.8%	19	90.5%
T4	6	2.1%	5	2.1%	1	3.4%	0	0.0%
TX	1	0.4%	1	0.4%	0	0.0%	0	0.0%
Nodal stage
N0	101	35.4%	85	36.2%	11	37.9%	5	23.8%	p = 0.86
N1	179	62.8%	145	61.7%	18	62.1%	16	76.2%
N2	1	0.4%	1	0.4%	0	0.0%	0	0.0%
NX	4	1.4%	4	1.7%	0	0.0%	0	0.0%
Location
Distal/GEJ	274	96.1%	224	95.3%	29	100.0%	21	100.0%	p = 0.30
Other	11	3.9%	11	4.7%	0	0.0%	0	0.0%
Differentiation
Well	1	0.4%	0	0.0%	1	3.4%	0	0.0%	p = 0.14
Moderate	96	33.7%	78	33.2%	11	37.9%	7	33.3%
Poor	186	65.3%	155	66.0%	17	58.6%	14	66.7%
Unknown	2	0.7%	2	0.9%	0	0.0%	0	0.0%
LVSI
Absent	217	76.1%	181	77.0%	22	75.9%	14	66.7%	p = 0.57
Present	68	23.9%	54	23.0%	7	24.1%	7	33.3%
Insulin use
No	38	13.3%			20	69.0%	18	85.7%	p = 0.17
Yes	12	4.2%			9	31.0%	3	14.3%
Median F/U (months)	21	(0–162)	21.5	(0–162)	24	(3–70)	13	(1–60)	p = 0.27

Table II. Treatment characteristics of the patient population.

	All patients		Non-diabetic		Diabetic, Metformin		Diabetic, No metformin		p-value
Induction
No	188	66.0%	154	65.5%	17	58.6%	17	81.0%	p = 0.24
Yes	97	34.0%	81	34.5%	12	41.4%	4	19.0%
Induction type
None	188	66.0%	154	65.5%	17	58.6%	17	81.0%	p = 0.12
5-FU and platinum	30	10.5%	27	11.5%	2	6.9%	1	4.8%
CPT-11 based	9	3.2%	9	3.8%	0	0.0%	0	0.0%
5-FU, platinum and taxane	50	17.5%	38	16.2%	9	31.0%	3	14.3%
Platinum and taxane	3	1.1%	3	1.3%	0	0.0%	0	0.0%
Epirubicin based	4	1.4%	4	1.7%	0	0.0%	0	0.0%
Platinum alone	1	0.4%	0	0.0%	1	3.4%	0	0.0%
XRT type
3D-CRT	59	20.7%	48	20.4%	7	24.1%	4	19.0%	p = 0.99
IMRT	154	54.0%	127	54.0%	15	51.7%	12	57.1%
Protons	72	25.3%	60	25.5%	7	24.1%	5	23.8%
Concurrent chemotherapy type
5-FU/Taxane-based	103	36.1%	81	34.5%	13	44.8%	9	42.9%	p = 0.31
Xeloda or 5-FU only	19	6.7%	15	6.4%	2	6.9%	2	9.5%
5-FU and platinum	113	39.6%	96	40.9%	9	31.0%	8	38.1%
CPT-11 alone	2	0.7%	2	0.9%	0	0.0%	0	0.0%
CPT-11 based	10	3.5%	7	3.0%	2	6.9%	1	4.8%
5-FU, platinum and taxane	25	8.8%	23	9.8%	2	6.9%	0	0.0%
Platinum and taxane	12	4.2%	11	4.7%	0	0.0%	1	4.8%
Other	1	0.4%	0	0.0%	1	3.4%	0	0.0%
Median XRT dose (Gy)	50.4 (30–59.4)		50.4 (43–54.4)		50.4 (45–54)		50.4 (30–59.4)		p = 0.20

Table III. Multivariate regression analysis of factors affecting pathologic CR rates.

Multivariate logistic regression	Comparison	Sig.	OR	95%	CI
Tumor stage	T3/4 vs. T1/2	0.04	0.44	0.21	0.96
Differentiation	Well/moderate vs. Poor/unknown	0.07	1.45	0.96	2.17
Metformin use	Yes vs. No	0.04	2.65	1.07	6.55
LVSI	Present vs. Absent	0.004	0.05	0.01	0.38

Figure 1. Pathologic and radiolographic response rates between groups. (A) Pathologic CR rates and maximum tumor SUV between groups. (B & C) Bar graphs showing pathologic CR rate and post-treatment tumor SUV of each treatment group. (D) Pathologic response in diabetics stratified by daily dose of metformin (mg/day). p represents the p value of the comparison.

Figure 2. Outcomes for the study population. (A) Overall survival (OS), (B) Disease free survival (DFS), (C) Time to loco-regional recurrence (LRR) & (D) Time to distant metastatic disease (DM). LRR was significantly less in patients taking metformin compared to non-diabetics (p = 0.05) or diabetics not taking metformin (p = 0.04).