A total of 8,392 patients newly diagnosed with HCC were reported to the Taiwan Cancer Registry in 2003 and 2004; 7,644 of them had an initial diagnosis of primary HCC (). A total of 3,503 patients had stage I or II disease at diagnosis, and 1,413 (40%) of them received surgical resection or local ablation therapy (RFA or PEI) as the initial therapy with curative intent. Of these, 931 met the eligibility criteria of the current study, and 185 (20%) of them had DM prior to the HCC diagnosis ().
Baseline characteristics were similar between groups except that patients in the DM group were older and had a higher frequency of congestive heart failure and renal disease compared with the no-DM group. There were no significant differences in gender, tumor stage, tumor size, treatment modalities received, history of cirrhosis, cerebrovascular disease, dementia, chronic pulmonary disease, and rheumatic disease between patients with and without DM ().
At the end of follow-up period, 363 (39%) patients had died. Of these patients, 288 were registered as having HCC as the primary cause of death; 321 patients were indicated as having died due to liver disease. The median follow-up time was 62.8 months for all patients. The LCS, LDS, and OS rates of patients with DM were worse than those of patients without DM (). The differences in survival were all statistically significant (all p < .001). The LCS rates for patients without and with DM were 87.7% and 80.9% at 2 years and 71.8% and 57.1% at 5 years, respectively. The LDS rates for patients without and with DM were 86.8% and 76.1% at 2 years and 69.8% and 52.2% at 5 years, respectively. The OS rates for patients without and with DM were 85.7% and 75.1% at 2 years and 66.8% and 48.1% at 5 years, respectively.
Figure 2. Kaplan-Meier analysis of (A) liver cancer-specific survival, (B) liver disease-related survival, and (C) overall survival of patients with stage I or II hepatocellular carcinoma who received surgery or local therapy. Patients were grouped by diabetes (more ...)
After adjusting for patient characteristics and comorbidities, DM was significantly associated with increased risk of liver cancer-specific mortality (HR = 1.57; 95% CI, 1.20–2.05; p < .001), liver disease-related mortality (HR = 1.70; 95% CI, 1.33–2.18; p < .001) and overall mortality (HR = 1.69; 95% CI, 1.34–2.14; p < .001; ). Older age, male sex, tumor size >2 cm, stage II cancer, local treatments (as compared to surgery), and cirrhosis of the liver were also associated with higher hazards of death. The results were consistent among LCS, LDS, and OS rates in terms of direction of risk, size of effect, and statistical significance for all the factors analyzed.
Subgroup analyses revealed consistent effects of DM on all three types of mortality endpoints across different patient populations (). No significant heterogeneity of effects was observed among the analyzed subgroups defined by sex, age, disease stage, tumor size, treatment, or liver cirrhosis status. For patients with DM who received medication control, the use of insulin was not associated with LCS (p = .953; A), LDS (p = .755; B), or OS rates (p = .422; C). Likewise, patients using metformin for DM control and patients not using metformin had similar LCS (p = .984; D), LDS (p = .966; E), and OS rates (p = .753; F).
Figure 3. Subgroup analysis of adjusted hazard ratios of mortality for patients with and without diabetes mellitus (DM) using the Cox proportional hazard model (the no-DM group is the reference). Every analysis was adjusted for all other factors not involving the (more ...)
Figure 4. Kaplan-Meier analysis of (A) liver cancer-specific survival, (B) liver disease-related survival, and (C) overall survival of patients with diabetes mellitus, grouped by the usage of insulin or not. Kaplan-Meier analysis of (D) liver cancer-specific survival, (more ...)