Effects of metformin treatment on radiotherapy efficacy in patients with cancer and diabetes: a systematic review and meta-analysis

Figures & data

Table 1 Characteristics of included studies investigating the metformin involved in radiotherapy

Study	Cancer site	Groupa n(%)	RT and dose	Concurrent treatment	Adjuvant therapy	Outcomes	HR (95% CI) DFS/DMFS	HR (95% CI) OS	Quality score (NOS)
Zaorsky et al (2017)^Citation20	Prostate	A: 251 (7.8) B: 363 (11.3) C: 2,603 (80.9)	3D-CRT/IMRT 76–80 Gy	ADT	ADT	5y-OS A: 93.35%, B: 85.19%, C: 92.25% 5y-DMFS A: 93.85%, B: 94.11%, C: 96.85%	None	None	7
Spratt et al (2013)^Citation27	Prostate	A: 157 (5.4) B: 162 (5.6) C: 2,582 (89)	RT	None	None	10y-OS A: 81.6%, B: 55.4%, C: 71.8% 10y-DMFS A: 89.7%, B: 66.1%, C: 86.1%	DMFS: 3.68 (1.7–7.62)	2.25 (1.38– 3.661)	8
Zannella et al (2013)^Citation28	Prostate	A: 114 (22.6) B: 390 (77.4)	RT 78 Gy	None	None	3y Biochemical recurrence-free rate: A=94.3%, C=85.1%	None	None	6
Taira et al (2014)^Citation29	Prostate	A: 126 (5.5) B: 144 (6.3) C: 2,028 (88.2)	Brachy RT 45–50.4 Gy	ADT	ADT	15y Biochemical failure rate: A=4.8%, B=2.8%, C=4.6%	None	None	8
Spratt et al (2016)^Citation34	Head and neck	A: 102 (5.8) B: 82 (4.7) C: 1,561 (89.5)	IMRT 70 Gy	CT	None	5y-OS A: 82.3%, B: 70.7%, C: 83% 5y-DMFS A: 90.1%, B: 78.7%, C: 89.6%	DMFS 0.46 (0.20–1.04)	0.76 (0.49–1.17)	8
Chang et al (2017)^Citation21	Head and neck	A: 39 (15.5) B: 213 (84.5)	IMRT 70–74 Gy	CT	None	2y-OS A: 71.8%, B: 64.3% 2y-RFS A: 69.2%, B: 60.6%	None	None	7
Skinner et al (2012)^Citation33	Head and neck	A: 10 (33.3) B: 20 (66.7)	RT	None	None	5y-OS A: 87%, B: 41%	None	None	6
Adeberg et al (2015)^Citation19	Glioblastoma	A: 20 (7.25) B: 20 (7.25) C: 236 (85.5)	RT 60 Gy	CT	None	PFS (mo) A: 10.13, B: 4.67, C: 6.7	None	1.37 (0.62–2.57)	7
Oh et al (2016)^Citation23	Rectal	A: 42 (7.7) B: 29 (5.3) C: 472 (87)	RT 44–54 Gy	CT	Surgery	pCR A: 26.2%, B: 20.7%, C: 15.7%	None	3.696 (1.03–13.21)	7
Skinner et al (2013)^Citation22	Rectal	A: 20 (4.1) B: 40 (8.3) C: 422 (87.6)	3D-CRT 50.4 Gy	CT	Surgery	pCR A: 35%, B: 7.5%, C: 16.6% 5y-OS A: 81%, B: 56%, C: 85 % 5y-DFS A: 81%, B: 41%, C: 77%	None	None	7
Ahmed et al (2015)^Citation24	Lung	A: 20 (12) B: 20 (12) C: 126 (76)	3D-CRT/IMRT 60–66 Gy	CT	None	2y-OS A: 25%, B: 35%, C: 30.9%	DFS 1.40 (0.65–3.04)	1.73 (0.78–3.85)	7
Wink et al (2016)^Citation25	Lung	A: 59 (8.7) B: 623 (91.3)	RT 66.1 Gy	CT	None	2y-OS A: 62.4%, B: 49% 2y-DMFS A: 74.4%, B: 53.3% 2y-LRFS A: 72%, B: 59.7%	DFS 0.63 (0.41–0.96)	0.86 (0.57–1.28)	7
Li et al (2016)^Citation18	Lung	A: 29 (29.9) B: 27 (27.8) C: 41 (42.3)	IMRT 60 Gy	CT	CT 1–4 cycles	OS (mo) A: 19.4±1.63, B: 18.2±2.91, C: 20.1±2.14 PFS (mo) A: 10.6±0.92, B: 10.5±1.73, C: 11.3±1.68	None	None	6
Skinner et al (2013)^Citation30	Esophageal	A: 29 (10.2) B: 21 (7.4) C: 235 (82.4)	3D-CRT/IMRT 45–50.4 Gy	CT	Surgery	pCR A: 34.5%, B: 4.8%, C: 19.6% OS (mo) A: 44, B: 51, C: 56	None	None	7
Spierings et al (2015)^Citation31	Esophageal	A: 32 (6.9) B: 429 (93.1)	RT 41.4 Gy	CT	Surgery	pCR A: 19%, B: 21% OS (mo) A: 43.6, B: 42.8 DFS (mo) A: 31.1, B: 47	DFS 1.11 (0.66–1.90)	1.12 (0.66–1.90)	8
van de Voorde et al (2015)^Citation32	Esophageal	A: 19 (9.7) B: 177 (90.3)	3D-CRT/VMRT 50.4 Gy	CT	Surgery	pCR A: 39%, B: 25% 2-y OS A: 82.9%, B: 56.5% 5-y OS A: 74.6%, B: 41% 2-y DMFS A: 93.3%, B: 69.6% 5-y DMFS A: 93.3%, B: 68.2%	DMFS 1.014 (0.024–1.253)	0.35 (0.13–0.97)	7
Jang et al (2015)^Citation26	Liver	A: 19 (8.7) B: 29 (13.4) C: 169 (77.9)	SBRT/HypoRT 25–60 Gy	None	None	2-y OS A: 76%, B: 37% 2-y PFS A: 46%, B: 16% (propensity score-matched)	None	0.36 (0.14–0.94)	7

Notes:

a Group A: patients with DM on metformin (D+M); Group B: patients with DM not on metformin (D–M); Group C: patients without DM and not on metformin (N–M).

Abbreviations: ADT, androgen deprivation therapy; CT, chemotherapy; DFS, disease-free survival; DMFS, distant metastasis–free survival; LRFS, locoregional recurrence–free survival; NOS, Newcastle–Ottawa scale; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival rate; RT, radiotherapy; pCR, pathologic complete response; IMRT, Intensity modulated radiation therapy; 3D-CRT, three dimensional conformal radiation therapy; SBRT, stereotactic body radiation therapy; mo, monthd.

Figure 1 Flow diagram showing study selection.

Figure 2 Findings of a meta-analysis of studies with discontinuation data on improvement in pathologic complete response for group A vs B and C, in terms of estimated ORs and 95% CIs.

Notes: Group A: patients with DM on metformin (D+M); Group B: patients with DM not on metformin (D–M); Group C: patients without DM and not on metformin (N–M).

Abbreviation: DM, diabetes mellitus.

Figure 3 Findings of a meta-analysis of studies with discontinuation data on improvement in 2y- or 5y-DMFS in group A vs B and C, with estimated ORs and 95% CIs.

Notes: Group A: patients with DM on metformin (D+M); Group B: patients with DM not on metformin (D–M); Group C: patients without DM and not on metformin (N–M).

Abbreviations: DM, diabetes mellitus; DMFS, distant metastasis–free survival.

Figure 4 Findings of a meta-analysis of studies with dichotomous data on improvement in 2y- or 5y-OS in group A vs B and C, with estimated ORs and 95% CIs.

Notes: Group A: patients with DM on metformin (D+M); Group B: patients with DM not on metformin (D–M); Group C: patients without DM and not on metformin (N–M).

Abbreviation: DM, diabetes mellitus.

Figure 5 Meta-analysis results of the effect of metformin use on survival outcomes (DFS, DMFS, and OS) in patients with cancer and DM who also received radiotherapy.

Abbreviations: DM, diabetes mellitus; DFS, disease-free survival; DMFS, distant metastasis–free survival; OS, overall survival.

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