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. 2023 Sep 25;12(19):6195. doi: 10.3390/jcm12196195

Table 4.

Cancer characteristics and results of the clinical studies.

Study Location (Cancer) Histology (Cancer) Treatment Follow-Up (Months) Results Conclusion
Alcusky et al., 2019 [4] OPSCC: 873
Larynx: 3192
Undefined HNC: 3807		 / Surgery: 5528 (alone/combination)
Radiotherapy: 3822
Chemotherapy: 2549		 median follow-up: 35.2 (15.3–68.3) months Metformin has a protective effect but only during the first two years following the HNC diagnosis. The all-cause mortality rate among Met+ patients is 0.8, especially in the patient sub-group 60 years and younger.
Metformin exposure prior to the HNC diagnosis is not associated with a better survival.		 Metformin is associated with a lower rate of all-cause mortality during the first two years after diagnosis. Age seems to modify the association between metformin and HNC survival.
Chang et al., 2017 [23] HNC: 252
Met+:

  • Oral cavity: 20

  • Oropharynx: 9

  • Hypopharynx: 10

Met−:

  • Oral cavity: 81

  • Oropharynx: 71

  • Hypopharynx: 60

 SCC CRT 36 months No significant difference of OS or RFS during the two-years follow-up between Met+ and Met− groups. Metformin in HNC patients is not associated with an improved OS or RFS.
Gulati et al., 2019 [21] Oropharynx: 12
Larynx: 6		 SCC CRT median follow-up: 19 months The treatment combining CRT and metformin improves OS and PFS compared to the historical OS and PFS rates.
The most common grade ≥3 toxicities (diarrhoea (6%), nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anaemia (6%), and leukopenia (11%)), were mainly related to standard-of-care treatment rather than metformin. 		First phase 1 trial combining metformin with CRT. OS and PFS rates were encouraging in this limited patient population and warrant further investigation in a phase 2 trial.
Kwon et al., 2015 [26] HNC SCC Surgery
Radiotherapy
Chemotherapy		 65.1 (12.1–154.5) months Metformin use does not improve the OS nor CSS in HNC patients. Metformin treatment did not improve survival of HNC patients.
Lee et al., 2019 [25] Met+:

  • Oral Cavity: 68

  • Oropharynx: 44

  • Hypopharynx: 8

  • Larynx: 75

Met−:

  • Oral Cavity: 49

  • Oropharynx: 36

  • Hypopharynx: 5

  • Larynx: 44

 SCC Met+:

  • Surgery: 43

  • Adjuvant Rad: 24

  • Adjuvant Chemo/Rad: 6

  • Primary Rad: 93

  • Primary Chemo/Rad: 29

Met−:

  • Surgery: 30

  • Adjuvant Rad: 14

  • Adjuvant Chemo/Rad: 1

  • Primary Rad: 66

  • Primary Chemo/Rad: 23

 Met+: 3,1 (+/− 2.1) years
Met−: 3 (+/− 2.2) years		 Metformin use was not significantly associated with improved OS, RFS and DSS at 5-years follow-up. No association between metformin use and oncologic outcomes were observed.
Quimby et al., 2018 [24] Met+:

  • Nasopharynx: 12

  • Hypopharynx: 17

  • Glottic larynx: 105

  • Supraglottic larynx: 31

Met−:

  • Nasopharynx: 55

  • Hypopharynx: 152

  • Glottic larynx: 656

  • Supraglottic larynx: 203

 SCC Met+:

  • Surgery ± RT/CRT: 31

  • RT ± Surgery: 116

  • CRT ± Surgery: 18

Met−:

  • Surgery ± RT/CRT: 266

  • RT ± Surgery: 646

  • CRT ± Surgery: 154

 / Metformin does not improve OS nor DSS in HNSCC patients. Metformin does not give a survival advantage to HNSCC patients.
Sandulache et al., 2014 [19] All:

  • Glottic larynx: 120

  • Supraglottic larynx: 85

Non-diabetic:

  • Glottic larynx: 88

  • Supraglottic larynx: 74

Diabetic

  • Glottic larynx: 32

  • Supraglottic larynx: 11

Diabetic Met+:

  • Glottic larynx: 17

  • Supraglottic larynx: 4

Diabetic Met−:

  • Glottic larynx: 15

  • Supraglottic larynx: 7

 SCC / / Metformin users demonstrated a significantly improved OS compared to diabetic patients treated without metformin and a non-significant improved OS compared to non-diabetic patients. Diabetic patients taking metformin during treatment for Laryngeal SCC exhibited improved clinical outcome compared to diabetic patients treated without metformin.
Stokes et al., 2018 [22] Oral Cavity: 835

  • Non-diabetic: 583

  • Met+ diabetic: 72

  • Met− diabetic: 180

Hypopharynx: 585

  • Non-diabetic: 397

  • Met+ diabetic: 35

  • Met− diabetic: 153

Other: 226

  • Non-diabetic: 164

  • Met+ diabetic: 17

  • Met− diabetic: 45

 Surgery
Radiotherapy
Chemotherapy		 / Non-diabetic patients and diabetic patients treated without Met experience significantly worse CSS compared to diabetic patients treated with Met. However, No OS differences are observed in the three groups. Diabetic HNC patients treated with metformin experience improved CSS.
Tsou et al., 2019 [14] Hypopharynx / CRT 48 months Advanced hypopharyngeal SCC Met+ diabetic cohort exhibit significantly improved OS and DFS compared to Met− diabetic cohort. Advanced hypopharyngeal SCC diabetic patients treated with metformin exhibit improved OS and better DFS.
Spratt et al., 2016 [20] Oropharynx: 1745 (total)
Tonsil: 805

  • Non-diabetic:

  • Met+ diabetic:

  • Met− diabetic:

Base of the tongue: 845

  • Non-diabetic:

  • Met+ diabetic:

  • Met− diabetic:

Soft palate: 22

  • Non-diabetic:

  • Met+ diabetic:

  • Met− diabetic:

Pharyngeal wall 61

  • Non-diabetic:

  • Met+ diabetic:

  • Met− diabetic:

Others: 16

  • Non-diabetic:

  • Met+ diabetic:

  • Met− diabetic:

 SCC Radiotherapy
Chemotherapy		 51.6 (5-year actuarial rates) Diabetic patients treated with Met+ present a 5-year DMFS (90.1%) and OS (89.6%), similar to non-diabetic patients. Multivariate analysis (reference diabetic treated without metformin) demonstrated improved DMFS for non-diabetic patients and a trend toward improved DMFS with met+ users. LFFS and RFFS are high in all groups and are not significantly different by diabetic status or metformin use. Diabetic patients not using metformin independently have significantly higher rates of distant metastases than do nondiabetic patients, whereas metformin users have rates of distant metastases similar to those of nondiabetic patients.

Treatment of HNC. Abbreviation: CRT: Chemoradiotherapy; DSS: Disease-specific survival; HNC: Head and neck cancer; Met+: Patients treated with metformin; Met−: Patients not treated with metformin; OPSCC: Oropharyngeal squamous cell carcinoma; OS: Overall survival; RAD: radiotherapy RFS: Recurrence-free survival; SCC: squamous cell carcinoma DSS: Disease-specific survival; RFS: recurrence-free survival.