Mediational g-formula for time-varying treatment and repeated-measured multiple mediators: Application to atorvastatin's effect on cardiovascular disease via cholesterol lowering and anti-inflammatory actions in elderly type 2 diabetics.

Modern causal mediation theory has formalized several types of indirect and direct effects of treatment on outcomes regarding specific mediator variables. We reviewed and unified distinct approaches to estimate the "interventional" direct and indirect effects for multiple mediators and time-varying variables. This study was motivated by a clinical trial of elderly type-2 diabetic patients in which atorvastatin was widely prescribed to control patients' cholesterol levels to reduce diabetic complications, including cardiovascular disease. Among atorvastatin's preventive side-effects (pleiotropic effects), we focus on its anti-inflammatory action as measured by white blood cell counts. Hence, we estimate atorvastatin's interventional indirect effects through cholesterol lowering and through anti-inflammatory action, and interventional direct effect bypassing these two actions. In our analysis, total effect (six-year cardiovascular disease risk difference) estimated by standard plug-in g-formula of -3.65% (95% confidence interval: -10.29%, 4.38%) is decomposed into indirect effect via low-density lipoprotein cholesterol (-0.90% [-1.91%, -0.07%]), via white blood cell counts (-0.03% [-0.22%, 0.11%]), and direct effect (-2.84% [-9.71%, 5.41%]) by the proposed parametric mediational g-formula. The SAS program and its evaluation via simulated datasets are provided in the Supplemental materials.

Comparison of efficacy and safety between intravenous ferric carboxymaltose and saccharated ferric oxide in Japanese patients with iron-deficiency anemia due to hypermenorrhea: a multi-center, randomized, open-label noninferiority study.

The intravenous formulation for supplementing iron currently available in Japan requires frequent administration. In contrast, ferric carboxymaltose (FCM) can improve iron-deficiency anemia (IDA) with only a small number of administrations; however, its efficacy and safety have not been established in Japanese patients. In this randomized, open-label study, we verified the noninferiority of FCM to saccharated ferric oxide (SFO) in Japanese patients with IDA due to hypermenorrhea, with the mean change from baseline to the highest observed hemoglobin level as the primary endpoint. Two hundred and thirty-eight eligible subjects (119 in FCM group, 119 in SFO group) were administered the investigational medicinal product and included in the analysis. The adjusted mean change from baseline to the highest observed hemoglobin level (95% CI) was 3.90 g/dL (3.77, 4.04) in the FCM group and 4.05 g/dL (3.92, 4.19) in the SFO group, and the difference between the groups (95% CI) was - 0.15 g/dL (- 0.35, 0.04). The noninferiority of FCM was verified. Incidence of adverse events was < 60% in both groups, and no significant difference was observed between the treatment groups. These results indicate that FCM can be a new, well-tolerated, and rapid treatment option for Japanese patients with IDA.

Adjuvant Oral Uracil-Tegafur with Leucovorin for Colorectal Cancer Liver Metastases: A Randomized Controlled Trial.

BACKGROUND: The high recurrence rate after surgery for colorectal cancer liver metastasis (CLM) remains a crucial problem. The aim of this trial was to evaluate the efficacy of adjuvant therapy with uracil-tegafur and leucovorin (UFT/LV). METHODS: In the multicenter, open-label, phase III trial, patients undergoing curative resection of CLM were randomly assigned in a 1:1 ratio to either the UFT/LV group or surgery alone group. The UFT/LV group orally received 5 cycles of adjuvant UFT/LV (UFT 300mg/m2 and LV 75mg/day for 28 days followed by a 7-day rest per cycle). The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included overall survival (OS). RESULTS: Between February 2004 and December 2010, 180 patients (90 in each group) were enrolled into the study. Of these, 3 patients (2 in the UFT/LV group and 1 in the surgery alone group) were excluded from the efficacy analysis. Median follow-up was 4.76 (range, 0.15-9.84) years. The RFS rate at 3 years was higher in the UFT/LV group (38.6%, n = 88) than in the surgery alone group (32.3%, n = 89). The median RFS in the UFT/LV and surgery alone groups were 1.45 years and 0.70 years, respectively. UFT/LV significantly prolonged the RFS compared with surgery alone with the hazard ratio of 0.56 (95% confidence interval, 0.38-0.83; P = 0.003). The hazard ratio for death of the UFT/LV group against the surgery alone group was not significant (0.80; 95% confidence interval, 0.48-1.35; P = 0.409). CONCLUSION: Adjuvant therapy with UFT/LV effectively prolongs RFS after hepatic resection for CLM and can be recommended as an alternative choice. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000013.

Superselective transarterial chemoembolization for hepatocellular carcinoma. Validation of treatment algorithm proposed by Japanese guidelines.

BACKGROUND & AIMS: Transcatheter arterial chemoembolization with lipiodol (TACE) is widely performed in patients with hepatocellular carcinoma (HCC) unsuitable for curative treatment. It has recently been recommended for patients with 2 or 3 tumors >3 cm or ≥4 tumors in a treatment algorithm proposed by Japanese guidelines. However, the best indication and appropriateness of the algorithm for TACE are still unclear. METHODS: In 4966 HCC patients who underwent TACE, survival was evaluated based on tumor number, size and liver function; and the adequacy of the algorithm for TACE was validated. Exclusion criteria were: vascular invasion, extrahepatic metastasis, and prior treatment. The mean follow up period was 1.6 years. RESULTS: The overall median and 5-year survivals were 3.3 years and 34%, respectively. Multivariate analysis revealed that Child-Pugh class, tumor number, size, alpha-fetoprotein, and des-gamma carboxy-prothrombin were independent predictors. The survival rate decreased as the tumor number (p=0.0001) and size increased (p=0.04 to p=0.0001) in all but one subgroup in both Child-Pugh-A and -B. The stratification of these patients to four treatments in the algorithm showed potential ability to discriminate survivals of the resection and ablation (non-TACE) groups from those of the TACE group in Child-Pugh-B and partially in A. CONCLUSIONS: TACE showed higher survival rates in patients with fewer tumor numbers, smaller tumor size, and better liver function. The treatment algorithm proposed by the Japanese guidelines might be appropriate to discriminate the survival of patients with non-TACE from TACE therapy.

Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis.

OBJECTIVE: Although iodized oil transarterial chemoembolization (TACE) has been found to have survival benefit in the care of patients with unresectable hepatocellular carcinoma, iodized oil infusion chemotherapy without embolization has not been clearly found inferior to or equal to TACE. The purpose of this study was to determine whether one of these therapies is superior to the other or the two are equal in survival benefit and whether embolization with gelatin sponge particles is indispensable to prolonging survival. SUBJECTS AND METHODS: A prospective nonrandomized observational cohort study was conducted over 8 years. Among 11,030 patients with unresectable hepatocellular carcinoma, 8,507 underwent TACE, and 2,523 underwent transarterial infusion therapy with an emulsion of iodized oil and an anticancer agent as initial treatment. Patients with extrahepatic metastasis or any previous treatment were excluded. The primary end point was all-cause mortality. To minimize selection bias, propensity score analysis was used to compare the two groups. RESULTS: During the follow-up period, 5,044 patients (46%) died. In the analysis of all patients, TACE was associated with a significantly higher survival rate than infusion therapy without embolization (hazard ratio, 0.60; 95% CI, 0.56-0.64; p = 0.0001). The propensity score analysis showed that the hazard ratio for death in the TACE group (n = 1,699 patients) compared with the group who underwent infusion therapy without embolization (n = 1,699) was 0.70 (95% CI, 0.63-0.76; p = 0.0001). The median survival time of the TACE group was 2.74 years, and the 1-, 3-, and 5-year survival rates were 81%, 46%, and 25%. The corresponding values for the group who underwent transarterial infusion therapy without embolization were 1.98 years and 71%, 33%, and 16%. CONCLUSION: Propensity score analysis showed that in the treatment of patients with unresectable hepatocellular carcinoma, TACE was associated with significantly better overall survival rates than was transarterial infusion therapy without embolization. TACE can be recommended as initial treatment of these patients.

Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients.

BACKGROUND & AIMS: To elucidate the survival of the patients with unresectable hepatocellular carcinoma (HCC) who underwent transcatheter arterial lipiodol chemoembolization (TACE) and to analyze the factors affecting the survivals. METHODS: During the last 8 years, a nationwide prospective cohort study was performed in 8510 patients with unresectable HCC who underwent TACE using emulsion of lipiodol and anticancer agents followed by gelatin sponge particles as an initial treatment. Exclusion criteria were extrahepatic metastases and/or any previous treatment prior to the present TACE. The primary end point was survival. The survival rates were calculated by the Kaplan-Meier method. The multivariate analyses for the factors affecting survival were evaluated by the Cox proportional hazard model. The mean follow-up period was 1.77 years. RESULTS: For overall survival rates by TACE, median and 1-, 3-, 5-, and 7-year survivals were 34 months, 82%, 47%, 26%, and 16%, respectively. Both the degree of liver damage and the tumor-node-metastasis (TNM) system proposed by the Liver Cancer Study Group of Japan demonstrated good stratification of survivals (P = .0001). The multivariate analyses showed significant difference in degree of liver damage (P = .0001), alpha-fetoprotein value (P = .0001), maximum tumor size (P = .0001), number of lesions (P = .0001), and portal vein invasion (P = .0001). The last 3 factors could be replaced by TNM stage. The TACE-related mortality rate after the initial therapy was .5%. CONCLUSIONS: TACE showed safe therapeutic modality with a 5-year survival of 26% for unresectable HCC patients. The degrees of liver damage, TNM stage, and alpha-fetoprotein values were independent risk factors for patient survival.