Trial Outcomes & Findings for Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer (NCT NCT02186847)

Last Updated: 2025-10-09

Results Overview

Progression is defined per RECIST v1.1 as change in a known lesion(s) meeting one of the following criteria: \[1\] At least a 20% increase in the sum of the longest diameter of target lesions such that the absolute increase must be \> 5 mm. \[2\] Appearance of ≥1 new lesions. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. One-year rates are provided. Analysis occurred after 102 progression-free survival events were reported.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

170 participants

Primary outcome timeframe

From randomization to last follow-up. Maximum follow-up at time of analysis was 47.2 months.

Results posted on

2025-10-09

Participant Flow

Participant milestones

Participant milestones
Measure	Chemoradiation 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Metformin + Chemoradiation Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin
Overall Study STARTED	84	86
Overall Study Eligible Population	81	86
Overall Study Eligible and Started Protocol Treatment	76	82
Overall Study COMPLETED	81	86
Overall Study NOT COMPLETED	3	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Chemoradiation 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Metformin + Chemoradiation Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin
Overall Study Protocol Violation	3	0

Baseline Characteristics

Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Chemoradiation n=81 Participants 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Metformin + Chemoradiation n=86 Participants Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Total n=167 Participants Total of all reporting groups
Age, Customized ≤ 49	6 Participants n=93 Participants	3 Participants n=4 Participants	9 Participants n=27 Participants
Age, Customized 50-59	22 Participants n=93 Participants	26 Participants n=4 Participants	48 Participants n=27 Participants
Age, Customized 60-69	29 Participants n=93 Participants	35 Participants n=4 Participants	64 Participants n=27 Participants
Age, Customized ≥ 70	24 Participants n=93 Participants	22 Participants n=4 Participants	46 Participants n=27 Participants
Sex: Female, Male Female	48 Participants n=93 Participants	49 Participants n=4 Participants	97 Participants n=27 Participants
Sex: Female, Male Male	33 Participants n=93 Participants	37 Participants n=4 Participants	70 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=93 Participants	1 Participants n=4 Participants	4 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	77 Participants n=93 Participants	80 Participants n=4 Participants	157 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants	5 Participants n=4 Participants	6 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=93 Participants	0 Participants n=4 Participants	2 Participants n=27 Participants
Race (NIH/OMB) Asian	5 Participants n=93 Participants	2 Participants n=4 Participants	7 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) Black or African American	7 Participants n=93 Participants	7 Participants n=4 Participants	14 Participants n=27 Participants
Race (NIH/OMB) White	67 Participants n=93 Participants	70 Participants n=4 Participants	137 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	5 Participants n=4 Participants	5 Participants n=27 Participants
Zubrod performance status 0	38 Participants n=93 Participants	45 Participants n=4 Participants	83 Participants n=27 Participants
Zubrod performance status 1	43 Participants n=93 Participants	41 Participants n=4 Participants	84 Participants n=27 Participants
American Joint Committee on Cancer (AJCC ) Stage, 7th edition IIIA (M0:T1a-b,N2;T2a-b,N2;T3,N1-2;T4,N0-1)	52 Participants n=93 Participants	58 Participants n=4 Participants	110 Participants n=27 Participants
American Joint Committee on Cancer (AJCC ) Stage, 7th edition IIIB (M0: T1a-b,N3;T2a-b,N3;T3,N3;T4,N2-3)	28 Participants n=93 Participants	26 Participants n=4 Participants	54 Participants n=27 Participants
American Joint Committee on Cancer (AJCC ) Stage, 7th edition N2,TX, M0	1 Participants n=93 Participants	2 Participants n=4 Participants	3 Participants n=27 Participants
Histology Adenocarcinoma	31 Participants n=93 Participants	42 Participants n=4 Participants	73 Participants n=27 Participants
Histology Adenosquamous	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Histology Non-small cell lung cancer NOS	11 Participants n=93 Participants	9 Participants n=4 Participants	20 Participants n=27 Participants
Histology Squamous cell carcinoma	38 Participants n=93 Participants	35 Participants n=4 Participants	73 Participants n=27 Participants
Did the patient use cigarettes? No	5 Participants n=93 Participants	6 Participants n=4 Participants	11 Participants n=27 Participants
Did the patient use cigarettes? Yes, but quit	47 Participants n=93 Participants	52 Participants n=4 Participants	99 Participants n=27 Participants
Did the patient use cigarettes? Yes, currently smokes	22 Participants n=93 Participants	20 Participants n=4 Participants	42 Participants n=27 Participants
Did the patient use cigarettes? Unknown	7 Participants n=93 Participants	8 Participants n=4 Participants	15 Participants n=27 Participants

PRIMARY outcome

Timeframe: From randomization to last follow-up. Maximum follow-up at time of analysis was 47.2 months.

Population: Eligible participants

Outcome measures

Outcome measures
Measure	Chemoradiation n=81 Participants 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Metformin + Chemoradiation n=86 Participants Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin
Percentage of Participants Alive Without Progression (Progression-free Survival)	60.4 percentage of participants Interval 48.5 to 70.4	51.3 percentage of participants Interval 39.8 to 61.7

SECONDARY outcome

Timeframe: From randomization to last follow-up. Maximum follow-up at time of analysis was 47.2 months.

Population: Eligible participants

Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. One-year rates are provided. Analysis occurred after 102 progression-free survival events were reported.

Outcome measures

Outcome measures
Measure	Chemoradiation n=81 Participants 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Metformin + Chemoradiation n=86 Participants Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin
Percentage of Participants Alive (Overall Survival)	38.5 percentage of participants Interval 26.3 to Not reached	40.1 percentage of participants Interval 27.9 to Not reached

SECONDARY outcome

Timeframe: From randomization to last follow-up. Maximum follow-up at time of analysis was 47.2 months.

Population: Eligible participants

Local-regional progression (LRP) is defined as progression within the planned treatment volume (PTV) or outside the PTV but within the same lobe(s) of the lung as the primary tumor or in regional lymph nodes. Progression is defined as change in a known lesion(s) meeting one of the following criteria: \[1\] ≥ 20% increase in the sum of the longest diameter of target lesions such that the absolute increase must be \> 5 mm. \[2\] Appearance of ≥1 new lesions. LRP time is defined as time from randomization to the date of first LRP, death without LRP (competing risk), or last known follow-up (censored). LRP rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. One-year rates are provided. Analysis occurred after 102 LRP events were reported.

Outcome measures

Outcome measures
Measure	Chemoradiation n=81 Participants 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Metformin + Chemoradiation n=86 Participants Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin
Percentage of Participants With Local-regional Progression	17.2 percentage of participants Interval 9.7 to 26.6	20.5 percentage of participants Interval 12.4 to 30.2

SECONDARY outcome

Timeframe: From randomization to last follow-up. Maximum follow-up at time of analysis was 47.2 months.

Population: Eligible participants

Distant metastasis (DM) is defined as the appearance of ≥ 1 new lesions at any site (including pleural or pericardial effusion) outside of the following: the planned treatment volume, the same lobe(s) of the lung as the primary tumor, or regional lymph nodes. Time to DM is defined as time from randomization to the date of first DM, death without DM (competing risk), or last known follow-up (censored). DM rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. One-year rates are provided. Analysis occurred after 102 progression-free survival events were reported.

Outcome measures

Outcome measures
Measure	Chemoradiation n=81 Participants 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Metformin + Chemoradiation n=86 Participants Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin
Percentage of Participants With Distant Metastases	17.2 percentage of participants Interval 9.7 to 26.6	20.5 percentage of participants Interval 12.4 to 30.2

SECONDARY outcome

Timeframe: From start of treatment to last follow-up. Maximum follow-up at time of analysis was 47.2 months.

Population: Eligible participants who started protocol treatment

Adverse events (AE) were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to adverse event. "Treatment-related" is defined definitely, probably, or possibly related to treatment.

Outcome measures

Outcome measures
Measure	Chemoradiation n=76 Participants 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Metformin + Chemoradiation n=82 Participants Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin
Percentage of Participants With Treatment-related Grade 3 or Higher Adverse Events	67.1 percentage of participants Interval 55.4 to 77.5	63.4 percentage of participants Interval 52.1 to 73.8

Adverse Events

Chemoradiation

Serious events: 31 serious events

Other events: 75 other events

Deaths: 31 deaths

Metformin + Chemoradiation

Serious events: 27 serious events

Other events: 79 other events

Deaths: 34 deaths

Serious adverse events

Other adverse events

Additional Information

Wendy Seiferheld

NRG Oncology

Phone: 215-574-3208

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Chemoradiation n=76 participants at risk 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Metformin + Chemoradiation n=82 participants at risk Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin
Blood and lymphatic system disorders Anemia	3.9% 3/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Blood and lymphatic system disorders Febrile neutropenia	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Cardiac disorders Atrial fibrillation	2.6% 2/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Cardiac disorders Atrial flutter	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Cardiac disorders Cardiac disorders - Other	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Cardiac disorders Heart failure	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Cardiac disorders Sinus tachycardia	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Diarrhea	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Dysphagia	2.6% 2/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Esophageal pain	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Esophagitis	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	6.1% 5/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Mucositis oral	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Nausea	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Death NOS	2.6% 2/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Fatigue	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	2.4% 2/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Fever	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Infusion related reaction	2.6% 2/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Malaise	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Endocarditis infective	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Esophageal infection	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Infections and infestations - Other	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	2.4% 2/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Lung infection	6.6% 5/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	7.3% 6/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Pleural infection	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Sepsis	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	2.4% 2/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Urinary tract infection	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Injury, poisoning and procedural complications Dermatitis radiation	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Injury, poisoning and procedural complications Fall	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations Investigations - Other	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations Lymphocyte count decreased	3.9% 3/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations Neutrophil count decreased	6.6% 5/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	3.7% 3/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations Platelet count decreased	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations Weight loss	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations White blood cell decreased	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	2.4% 2/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Metabolism and nutrition disorders Dehydration	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Metabolism and nutrition disorders Hypercalcemia	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Metabolism and nutrition disorders Hypokalemia	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	2.4% 2/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	0.00% 0/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	2.4% 2/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	1.3% 1/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	0.00% 0/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.

Other adverse events
Measure	Chemoradiation n=76 participants at risk 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin	Metformin + Chemoradiation n=82 participants at risk Metformin plus 60 Gy Radiation therapy with concurrent paclitaxel and carboplatin followed by consolidation paclitaxel and carboplatin
Blood and lymphatic system disorders Anemia	65.8% 50/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	56.1% 46/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Cardiac disorders Atrial fibrillation	2.6% 2/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	6.1% 5/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Cardiac disorders Sinus tachycardia	3.9% 3/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	8.5% 7/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Ear and labyrinth disorders Hearing impaired	6.6% 5/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Eye disorders Blurred vision	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	4.9% 4/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Abdominal pain	7.9% 6/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	4.9% 4/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Constipation	46.1% 35/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	35.4% 29/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Diarrhea	32.9% 25/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	56.1% 46/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Dry mouth	7.9% 6/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	8.5% 7/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Dyspepsia	14.5% 11/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	18.3% 15/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Dysphagia	40.8% 31/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	35.4% 29/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Esophageal pain	6.6% 5/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	11.0% 9/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Esophagitis	38.2% 29/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	45.1% 37/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Flatulence	2.6% 2/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	6.1% 5/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Gastroesophageal reflux disease	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	12.2% 10/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Gastrointestinal disorders - Other	2.6% 2/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	6.1% 5/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Mucositis oral	11.8% 9/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	4.9% 4/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Nausea	56.6% 43/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	58.5% 48/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Gastrointestinal disorders Vomiting	23.7% 18/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	41.5% 34/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Chills	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	9.8% 8/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Edema limbs	11.8% 9/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	11.0% 9/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Fatigue	80.3% 61/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	80.5% 66/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Fever	14.5% 11/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	15.9% 13/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Infusion related reaction	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	7.3% 6/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Localized edema	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	2.4% 2/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Non-cardiac chest pain	17.1% 13/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	18.3% 15/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
General disorders Pain	27.6% 21/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	25.6% 21/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Bronchial infection	6.6% 5/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	2.4% 2/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Infections and infestations - Other	9.2% 7/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	3.7% 3/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Lung infection	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	8.5% 7/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Skin infection	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	1.2% 1/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Upper respiratory infection	10.5% 8/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	8.5% 7/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Infections and infestations Urinary tract infection	6.6% 5/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	4.9% 4/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Injury, poisoning and procedural complications Dermatitis radiation	19.7% 15/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	23.2% 19/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Injury, poisoning and procedural complications Fall	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	8.5% 7/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations Alanine aminotransferase increased	13.2% 10/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	8.5% 7/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations Alkaline phosphatase increased	17.1% 13/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	11.0% 9/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations Aspartate aminotransferase increased	13.2% 10/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	4.9% 4/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations Blood bilirubin increased	5.3% 4/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	3.7% 3/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.
Investigations Creatinine increased	11.8% 9/76 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.	8.5% 7/82 • Adverse events were to be reported weekly during dose escalation on metformin arm, end of chemoradiation, end of post-radiation chemotherapy/metformin, 4-6 weeks follow-up, every 3 months for 2 years follow-up, every 6 months through 5 years follow-up, yearly until study termination completion.