Yasuhiro Hagiwara

Multicenter, randomized, open-label Phase II study comparing S-1 alternate-day oral therapy with the standard daily regimen as a first-line treatment in patients with unresectable advanced pancreatic cancer

PurposeNon-inferiority for overall survival (OS) following alternate-day treatment with the oral anticancer drug S-1 compared with standard daily treatment was assessed in Japanese patients with unresectable advanced pancreatic cancer in a multicenter, randomized, phase II study. This trial was registered at the UMIN Clinical Trials Registry (no. 000008604).MethodsChemotherapy-naïve patients with locally advanced or metastatic pancreatic cancer were randomly assigned 2:1 to treatment with alternate-day (twice daily on alternate days from days 1 through 42 of a 42-day cycle) or daily (twice daily on days 1 through 28 of a 42-day cycle) treatment with S-1. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), time to treatment failure, response rate, quality of life assessments, and safety.ResultsA total of 190 patients were enrolled, of which 185 were included in the final analysis (alternate-day: 121; daily: 64). Median OS was 9.4 for the alternate-day group and 10.4 months for the daily group [hazard ratio (HR), 1.19; 95% credible interval, 0.86 to 1.64], indicating that non-inferiority of alternate-day treatment to daily treatment was not demonstrated. Median PFS was 3.0 for the alternate-day group and 4.2 months for the daily group (HR, 1.65; 95% credible interval, 1.20–2.29). The incidence of anorexia, fatigue, neutrophils, pigmentation, and pneumonitis was lower in alternate-day treatment compared with daily treatment.ConclusionS-1 for advanced pancreatic cancer should be taken daily as recommended, based on the decreased OS and PFS and marginal improvement in safety observed in the alternate-day group.

Impact of resection and ablation for single hypovascular hepatocellular carcinoma ≤2 cm analysed with propensity score weighting

Small hypovascular hepatocellular carcinoma (HCC) ≤2 cm is biologically less aggressive than hypervascular one, however, the optimal treatment is still undetermined. The efficacy of surgical resection (SR), radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) was evaluated.

Patient-Reported Outcome Results from the Open-Label Randomized Phase III SELECT BC Trial Evaluating First-Line S-1 Therapy for Metastatic Breast Cancer

Objective: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial. Methods: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis. Results: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness. Conclusion: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients.

Health-related quality of life in a randomised phase III study of gemcitabine plus S-1, S-1 alone and gemcitabine alone for locally advanced or metastatic pancreatic cancer: GEST study

Objective: This study was performed to compare health-related quality of life (HRQOL) of gemcitabine plus S-1 (GS), S-1 alone and gemcitabine alone as first-line chemotherapy for locally advanced or metastatic pancreatic cancer in the GEST (Gemcitabine and TS-1 Trial) study and to assess the impacts of adverse events and tumour response on HRQOL. Methods: Patients were randomly assigned to receive gemcitabine alone (1000 mg/m2 weekly for 3 of 4 weeks), S-1 alone (80, 100 or 120 mg/day twice daily for 4 of 6 weeks) or GS (gemcitabine at 1000 mg/m2 weekly plus S-1 at 60, 80 or 100 mg/day twice daily for 2 of 3 weeks). HRQOL was assessed using the EuroQoL-5D (EQ-5D) questionnaire at baseline and weeks 6, 12, 24, 48 and 72. EQ-5D scores, quality-adjusted life months (QALMs), quality-adjusted progression-free months (QAPFMs) and time until definitive HRQOL deterioration (TUDD) were compared among the three groups. The impacts of adverse events and tumour response on EQ-5D scores were analysed. Results: Including EQ-5D scores after death as 0, the mean profile was significantly better in the GS than gemcitabine group (difference, 0.069; p=0.003), but not the S-1 group (difference, −0.011; p=0.613). The mean profiles until death were similar in the three groups. QALMs, QAPFMs and TUDD were significantly longer in the GS than gemcitabine group (p<0.001, p<0.001 and p=0.004, respectively), but not the S-1 group (p=0.563, p=0.741 and p=0.701, respectively). Fatigue, anorexia and tumour response were significantly associated with changes in EQ-5D scores. Conclusions: GS achieved better HRQOL than gemcitabine alone, resulting a good balance between overall survival and HRQOL benefits. S-1 alone provides HRQOL similar to that provided by gemcitabine alone. Preventing fatigue and anorexia and maintaining better response would improve HRQOL.

Long-Term Eq-5d Score For Patients With Metastatic Breast Cancer; Comparison Of First-Line Oral S-1 And Taxane Therapies In The Randomized “Select” Trial

PCN210 LoNg-Term eq-5d SCore For PaTieNTS WiTh meTaSTaTiC BreaST CaNCer; ComPariSoN oF FirST-LiNe oraL S-1 aNd TaxaNe TheraPieS iN The raNdomized “SeLeCT” TriaL Fukuda T1, Shiroiwa T1, Shimozuma K2, Mouri M3, Doihara H4, Akabane H5, Kashiwaba M6, Watanabe T7, Hagiwara Y8, Ohashi Y9, Mukai H10 1National Institute of Public Health, Wako, Japan, 2Ritsumeikan University, Kusatsu, Japan, 3Japan Clinical Research Support Unit (J-CRSU), Tokyo, Japan, 4Okayama University Hospital, Okayama, Japan, 5Hokkaido P.W.F.A.C. Asahikawa-Kosei General Hospital, Asahikawa, Japan, 6Iwate Medical University, Morioka, Japan, 7Sendai Medical Center, Sendai, Japan, 8the University of Tokyo, Tokyo, Japan, 9Chuo University, Tokyo, Japan, 10National Cancer Center Hospital East, Kashiwa, Japan Objectives: The present study used long-term EQ-5D scores to evaluate patients with metastatic breast cancer (MBC) in a randomized control trial (RCT). MethOds: Patients with HER2-negative MBC were randomly allocated to the S-1 (an oral fluoropyrimidine) or taxane (paclitaxel or docetaxel) group. The primary endpoint was overall survival (OS), and QOL was a secondary endpoint. EQ-5D scores were surveyed at pre-treatment, three months after randomization, and every six months thereafter. Mean scores were assessed by repeated measured ANOVA including baseline, group, time and interaction of group and time. Minimal important difference (MID) analysis was also performed by defining the MID of EQ-5D as 0.05 or 0.1. When MID analysis was applied to the score during fist-line therapy, progression was treated as a competing risk. Results: A total of 618 patients with MBC were randomly allocated to both groups (N= 309 each). S-1 was non-inferior to taxanes for OS (median OS: S-1, 35.0 months; taxanes, 37.2 months). The number of patients in the EQ-5D population was 208 and 175 in S-1 and taxane groups, respectively. Mean duration of the EQ-5D response was 21 months for both groups. Mean EQ-5D scores up to 60 months were 0.748 and 0.741 in S1 and taxane groups, respectively. No significant difference was observed by ANOVA or MID analysis. During first-line therapy, mean EQ-5D score was 0.810 and 0.781 in S-1 and taxane groups up to 36 months, although in the post-progression period, scores decreased to 0.729 and 0.703, respectively. Gray’s test revealed that S-1 significantly delayed the decrease in QOL score. The size of the MID (0.05 or 0.1) did not influence the results. cOnclusiOns: This study analyzed long-term EQ-5D scores of patients with MBC from RCT data. The QOL score of S-1 was higher during first-line therapy.

The Number of Events per Confounder for Valid Estimation of Risk Difference Using Modified Least-Squares Regression

Risk difference is a relevant effect measure in epidemiologic research. Although it is well known that when there are few events per confounder, logistic regression is not suitable for confounding control, it is not clear how many events per confounder are required for valid estimation of risk difference using linear binomial models. Because the maximum likelihood method has a convergence problem, we investigated the number of events per confounder necessary to validly estimate risk difference using modified least-squares regression in a simulation. We simulated 864 scenarios, according to the number of confounders (2-20), the number of events per confounder (2-12), marginal risk (0.5%-40%), exposure proportion (20% and 40%), and 3 sizes of risk difference. Our simulation showed that modified least-squares regression provided unbiased risk difference-regardless of the number of events per confounder-and reliable confidence intervals when more than 5 events were expected in the exposed and in the unexposed, irrespective of the number of events per confounder. We illustrated the modified least-squares regression analysis using perinatal epidemiologic data. Modified least-squares regression is considered to be a useful analytical tool for rare binary outcomes relative to the number of confounders.

The Impact of Treatment Preferences in Second-Line Chemotherapy on the Prognosis of HER2-Negative Metastatic Breast Cancer

Objective: We assessed the impact of treatment preferences in second-line chemotherapy on breast cancer prognosis using the SELECT BC study. Methods: The SELECT BC study was performed in patients with HER2-negative metastatic breast cancer treated with initial chemotherapy. From these patients, 618 were assigned to 2 groups (S-1 group, 309; taxane group, 309). The S-1 and taxane groups were each subdivided into 3 groups: crossover group, protocol-recommended group, and other group, and the analysis of overall survival (OS) was performed using Cox regression with inverse probability weighting, to adjust for postrandomization confounding. Results: In the taxane group, the OS of the crossover group (39.6 months) was better than that of the protocol-recommended group (35.7 months) and the other chemotherapy group (36.9 months) (vs. the protocol-recommended group, HR 0.72 [95% CI 0.52-0.98], p = 0.037; vs. the other chemotherapy group, HR 0.71 [95% CI 0.43-1.18], p = 0.183). In the S-1 group, there was no statistically significant difference in OS between the 3 groups. Conclusion: The study of the combination of first-line chemotherapy and second-line chemotherapy showed that S-1 might be recommended as a second-line chemotherapy in patients in whom taxane was the primary chemotherapy.