Cumulative metformin use and its impact on survival in gastric cancer patients after INDEX

Transcription

1 Supplementary Data Cumulative metformin use and its impact on survival in gastric cancer patients after gastrectomy Lee et al. INDEX Supplementary Figure 1. Survival analysis according to stage : DM versus non-dm Supplementary Figure 2. Kaplan Meier plot showing patients on insulin alone vs insulin and metformin Supplementary Figure 3. Kaplan Meier plot showing patients without insulin Supplementary Figure 4. Kaplan Meier plot showing recurrence-event free survival Supplementary Table 1. Pattern of recurrence among each groups Supplementary Table 2. Pattern of recurrence according to stage Supplementary Table 3. Number of Oral Hypoglycemic Agents taken by DM patients Supplementary Calculation 1.

2 Supplementary Figure 1. Survival analysis according to stage : DM versus non-dm Kaplan-Meier plots comparing diabetes versus non-diabetes patients (A,B,C: overall survival, D,E,F : cancer-specific survival, G,H,I ; recur-free survival) among stage I (A,D,G), stage II (B,E,H), and stage III (C,F,I).

3 Supplementary Figure 2. Kaplan Meier plot showing patients on insulin alone vs insulin and metformin Kaplan-Meier plots comparing insulin alone users versus insulin and metformin users are shown. There was no statistically significant difference, with small sample size (only 4 patients on insulin + metformin group and 30 patients on insulin alone group). P= P= P= Supplementary Figure 3. Kaplan Meier plot showing patients without insulin Kaplan-Meier plots comparing metformin without insulin users (n=128) versus non-metformin without insulin users (n=164) are shown. We could confirm the trend toward better survival in metformin users compared to non-metformin users, even excluding insulin users. Even though the p- value was more than 0.05, it might be due to small size of population since we subtracted the insulin users. Multivariable Cox proportional hazards model with time-dependent covariates, considering insulin use as one of the covariates, is shown in Table 3. We have shown that cumulative metformin use prolonged survivals (RFS, CSS, and OS) even considering insulin usage. P= P= P=0.0577

4 Supplementary Figure 4. Kaplan Meier plot showing recurrence-event free survival Since previous large phase III gastric cancer adjuvant trials, ACTS-GC (Sakuramoto et al. NEJM 2007) and CLASSIC (Bang et al. Lancet Oncology 2013), RFS was evaluated with the definition of the time from randomization to the time of recurrence or death from any cause, we have also used and showed results with the same definition. We conducted Kaplan-Meier plot also with only counting recurrence-event, not death, to give additive information. Kaplan-Meier plot of recurrence-event only (not death) free survival according to DM status was drawn, and significant less recurrence was found (Log-rank P-value = 0.006). Among DM patients, Kaplan-Meier plot of recurrence-event only free survival according to metformin use was drawn, and even-though no statistically significant difference was found among DM patients according to metformin use, there was trend toward less recurrence event to metformin group (Log-rank P-value = 0.12). It might be statistically significant if larger population was analyzed. P=0.006 P=0.12

5 Supplementary Table 1. Pattern of recurrence among each groups Site for the first relapse is described in the table, according to each group, among available 284 data out of total 323 recurrences. There was no statistically significant difference in distribution of first relapse site among three groups (non-dm vs. metformin DM vs. non-metformin DM) (P=0.325). Distant metastasis was most common recurrence pattern, and loco-regional recurrence was the most rare recurrence pattern. DM patients (N=326) Non-DM patients Metformin users Non-metformin users Site P-value Total no. of recur Total no. of recurs with first relapse site known Loco-regional 46 (20.1%) 5 (26.3%) 6 (16.7%) Peritoneal 65 (28.4%) 6 (31.6%) 12 (33.3%) Distant 118 (51.5%) 8 (42.1%) 18 (50.0%) Supplementary Table 2. Pattern of recurrence according to stage Site for the first relapse according to stage is described in the table. Since there was small number of first relapse site known to draw any significant conclusion, there was relatively larger rate of locoregional recurrence in stage I non-dm patients compared to Stage I DM patients. This might be one reason for worse recurrence free survival for stage I DM patients. Non-DM patients (n=1648) DM patients (n=326) Site Stage I Stage II Stage III Stage I Stage II Stage III Total no. of recur Total no. of recurs with first relapse site known Loco-regional 7 (36.8%) 6 (15.4%) 33 (19.3%) 0 (0.0%) 1 (14.3%) 10 (23.8%) Peritoneal 2 (10.5%) 9 (23.1%) 54 (31.6%) 1 (16.7%) 1 (14.3%) 16 (38.1%) Distant 10 (52.6%) 24 (61.5%) 84 (49.1%) 5 (83.6%) 5 (71.4%) 16 (38.1%)

6 Supplementary Table 3. Number of Oral Hypoglycemic Agents taken by DM patients The table shows the number of oral hypoglycemic agents (OHAs) the diabetic patients were taking according to their group. Metformin users tend to take 2 or more OHAs, whether non-metformin users mostly take only one OHA in this study. The fact that metformin group showed better survival despite higher rate of multiple drug users, adds strength to this study s conclusion, when considering that multiple drug users may have much worse glucose capacity. Metformin users Non-metformin users P-value Number of Oral Hypoglycemic Agents 0 or 1 37 (28.0%) 166 (85.6%) < (72.0%) 28 (14.4%)

7 Supplementary Calculation 1. There might be some DM patients who the investigators did not recognize as DM patient in this study. So, we randomly picked patients as if 20% of the DM patients were misattributed to a non-dm group, and allocated them into DM group. Those patients were allocated into metformin user group and nonmetformin user group as the same ratio of the original groups. Then, we compared survivals between 3 groups (Non-DM group, DM and metformin group, and DM and non-metformin group) in terms of OS, CSS, RFS. We repeated this calculation 100 times with randomly picked patients each time, and statistical significance (p-value < 0.05) was obtained 88 (OS), 54 (CSS), and 85 (RFS) times respectively. The power was over 80% for OS and RFS.