Response to tocilizumab and work productivity in patients with rheumatoid arthritis: 2-year follow-up of FIRST ACT-SC study.

OBJECTIVES: We evaluated long-term control of rheumatoid arthritis (RA) in Japanese paid workers (PWs) and house workers (HWs) treated with subcutaneous tocilizumab (TCZ-SC) and explored factors affecting response to TCZ-SC regarding work productivity. METHODS: This study collected data from patients with RA in the TCZ-SC +/- conventional synthetic disease-modifying antirheumatic drugs group. Factors affecting the response to tocilizumab regarding work productivity were explored using logistic regression. Differences in quality-adjusted life years (QALYs) between with/without response were analysed by a linear regression. RESULTS: Data were analysed for 357/360 patients. Patients with a ≥ 75% improvement in activity impairment (AI) were considered responders. EuroQol-5 Dimension (EQ-5D), six-item Kessler psychological distress scale score (K6), Health Assessment Questionnaire Disability Index (HAQ-DI), and the patient's disease global health by visual analogue scale were significant contributors to TCZ-SC response based on improvements in AI. Work Functioning Impairment Scale, presenteeism, EQ-5D, K6, and HAQ-DI significantly contributed to the improvement of overall work impairment in PWs. Shorter disease duration also was related to TCZ-SC response based on AI improvements. Responders had significantly larger mean QALYs than non-responders (difference = 0.2614; p < .001). CONCLUSIONS: These real-world clinical data support long-term work productivity control with TCZ-SC for biologic-naïve HWs and PWs with RA.

Performance of randomization-based causal methods with and without integrating external data sources for adjusting overall survival in case of extensive treatment switches in placebo-controlled randomized oncology phase 3 trials.

In recent placebo-controlled randomized phase 3 oncology trials, evaluation of overall survival with frequent crossover is crucial for regulatory and pricing decisions. The problem is that an intention-to-treat based analysis causes a substantial loss of power to detect causal survival effect without crossover, and performance of existing methods is not satisfactory. In this article, our aims were to evaluate properties of the existing and a proposed Bayesian power prior method where data from an external trial is available. Simulation results suggested that proposed method was the most powerful under typical scenarios where patients with better prognosis are likely to crossover.

Phase III randomised trial comparing 6 vs. 12-month of capecitabine as adjuvant chemotherapy for patients with stage III colon cancer: final results of the JFMC37-0801 study.

BACKGROUND: Up to 6-months oxaliplatin-containing regimen is now widely accepted as a standard adjuvant chemotherapy for stage III colorectal cancer (CRC). However, oral fluoropyrimidine monotherapy is used for some part of patients, especially in Asian countries including Japan, and its optimal duration is yet to be fully investigated. METHODS: A total of 1306 patients with curatively-resected stage III CRC were randomly assigned to receive capecitabine (2500 mg/m2/day) for 14 out of 21 days for 6 (n = 654) or 12 (n = 650) months. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were relapse-free survival (RFS), overall survival (OS), and adverse events. RESULTS: The 3- and 5-year DFS were 70.0% and 65.3% in the 6M group and 75.3% and 68.7% in the 12M group, respectively (p = 0.0549, HR = 0.858, 90% CI: 0.732-1.004). The 5-year RFS was 69.3% and 74.1% in the 6M and 12M groups, respectively (p = 0.0143, HR = 0.796, 90% CI: 0.670-0.945). The 5-year OS was 83.2% and 87.6%, respectively (p = 0.0124, HR = 0.727, 90% CI: 0.575-0.919). The incidence of overall grade 3-4 adverse events was almost comparable in both groups. CONCLUSIONS: Although 12-month adjuvant capecitabine did not demonstrate superior DFS to that of 6-month, the observed better RFS and OS in the 12-month treatment period could be of value in selected cases.

Risk Factors for Peritoneal Recurrence in Stage II to III Colon Cancer.

BACKGROUND: Most previous reports to analyze risk factors for peritoneal recurrence in patients with colon cancer have been observational studies of a population-based cohort. OBJECTIVE: This study aimed to determine the risk factors for peritoneal recurrence in patients with stage II to III colon cancer who underwent curative resection. DESIGN: This was a pooled analysis using a combined database obtained from 3 large phase III randomized trials (N = 3714). SETTINGS: Individual patient data were collected from the Japanese Foundation for Multidisciplinary Treatment of Cancer clinical trials 7, 15, and 33, which evaluated the benefits of postoperative 5-fluorouracil-based adjuvant therapies in patients with locally advanced colorectal cancer. PATIENTS: We included patients who had stage II to III colon cancer and underwent curative resection with over D2 lymph node dissection. MAIN OUTCOME MEASURES: Main outcomes measured were risk factors for peritoneal recurrence without other organ metastasis after curative surgery. RESULTS: Peritoneal recurrence occurred in 2.3% (86/3714) of all patients undergoing curative resection. Mean duration from operation to peritoneal recurrence was 17.0 ± 10.3 months. Of these patients with peritoneal recurrence, 29 patients (34%) had recurrence in ≥1 other organ. Multivariate analysis showed that age (≥60 y: HR = 0.531; p = 0.0182), pathological T4 (HR = 3.802; p < 0.0001), lymph node involvement (HR = 3.491; p = 0.0002), and lymphadenectomy (D2: HR = 1.801; p = 0.0356) were independent predictors of peritoneal recurrence. The overall survival was lower in patients who developed peritoneal recurrence than in those with other recurrence (HR = 1.594; p = 0.002). LIMITATIONS: The regimens of adjuvant chemotherapy were limited to oral 5-fluorouracil. CONCLUSIONS: Our findings clarified the risk factors for peritoneal recurrence in patients who underwent curative resection for colon cancer. See Video Abstract at http://links.lww.com/DCR/A609.

Clinical Signatures of Mucinous and Poorly Differentiated Subtypes of Colorectal Adenocarcinomas by a Propensity Score Analysis of an Independent Patient Database from Three Phase III Trials.

BACKGROUND: Although colorectal cancer comprises several histological subtypes, the influences of histological subtypes on disease progression and treatment responses remain controversial. OBJECTIVE: We sought to evaluate the prognostic relevance of mucinous and poorly differentiated histological subtypes of colorectal cancer by the propensity score weighting analysis of prospectively collected data from multi-institute phase III trials. DESIGN: Independent patient data analysis of a pooled database from 3 phase III trials was performed. SETTINGS: An integrated database of 3 multicenter prospective clinical trials (the Japanese Foundation for Multidisciplinary Treatment of Cancer 7, 15, and 33) was the source of study data. INTERVENTIONS: Surgery alone or postoperative adjuvant chemotherapy was offered in patients with resectable colorectal cancer. MAIN OUTCOME MEASURES: To balance essential variables more strictly for the comparison analyses, propensity score weighting was conducted with the use of a multinomial logistic regression model. We evaluated the clinical signatures of mucinous and poorly differentiated subtypes with regard to postoperative survival, recurrence, and chemosensitivity. RESULTS: Of 5489 patients, 136 (2.5%) and 155 (2.8%) were pathologically diagnosed with poorly differentiated and mucinous subtypes. The poorly differentiated subtypes were associated with a poorer prognosis than the "others" group (HR, 1.69; 95% CI, 1.00-2.87; p = 0.051), particularly in the patient subgroup of adjuvant chemotherapy (HR, 2.16). Although the mucinous subtype had a marginal prognostic impact among patients with stage I to III colorectal cancer (HR, 1.33; 95% CI, 0.90-1.96), it was found to be an independent prognostic factor in the subpopulation of patients with stage II disease, being associated with a higher prevalence of peritoneal recurrence. LIMITATIONS: The treatment regimens of postoperative chemotherapy are now somewhat outdated. CONCLUSIONS: Both mucinous and poorly differentiated subtypes have distinct clinical characteristics. Patients with the mucinous subtype require special attention during follow-up, even for stage II disease, because of the risk of peritoneal or local recurrence. See Video Abstract at http://links.lww.com/DCR/A531.

Questionnaire Survey From the Viewpoint of Concordance in Patient and Physician Satisfaction Concerning Hypertensive Treatment in Elderly Patients　- Patients Voice Study.

BACKGROUND: Patient-physician concordance is an important concern in the treatment of elderly patients with hypertension (HT). Treatment that considers concordance is necessary for mutual understanding and therapeutic satisfaction between patients and physicians. However, there have been no studies addressing concordance that objectively analyzed both patient and physician satisfaction before and after treatment.Methods and Results:An exploratory open-label, multicenter, intervention study was conducted. Patients with HT undergoing treatment with angiotensin-receptor blocker (ARB) or a calcium-channel blocker (CCB) monotherapy were enrolled. Medication was switched to an ARB/CCB combination tablet and taken for 12 weeks. Physicians and patients participated in satisfaction surveys concerning treatment. Discrepancies in satisfaction levels between patients and physicians were found at baseline for the following survey items: treatment, involvement in treatment, understanding of HT, reliance, medication, and blood pressure. After treatment, the satisfaction levels of both patients and physicians increased; discrepancies in satisfaction between the groups also improved. CONCLUSIONS: The rates of satisfaction were relatively higher for patients compared with physicians at baseline. After HT treatment addressing concordance, both patient and physician satisfaction rates and the gap in satisfaction rates between patients and physicians improved. This indicates that addressing concordance has clinical significance in the treatment of elderly HT patients. (UMIN000017270).

Sample size determination for the current strategy in oncology Phase 3 trials that tests progression-free survival and overall survival in a two-stage design framework.

The selection of progression-free survival (PFS) or overall survival (OS) as the most suitable primary endpoint (PE) in oncology Phase 3 trials is currently under intense debate. Because of substantial limitations in the single use of PFS (or OS) as the PE, trial designs that include PFS and OS as co-primary endpoints are attracting increasing interest. In this article, we report on the formulation of determining the sample size for a trial that sequentially tests PFS and OS by treating them as co-PEs. Using a three-component model of OS, the proposed method overcomes the drawbacks of an existing method that requires unreasonable assumption of the exponential distribution for OS, although the hazard function is nonconstant because effective subsequent therapy has prolonged postprogression survival in recent oncology trials. Alternative estimation method of hazard ratio for OS under a three-component mode is also discussed by checking the appropriateness of assuming proportionality of hazards for OS. In order to examine the performance of our proposed method, we performed three numerical studies using both simulated and actual data of cancer Phase 3 trials. We find that the proposed method preserves a prespecified target value of power with a feasible increment of trial scale.

Two-stage approach based on zone and dose findings for two-agent combination Phase I/II trials.

In Phase I/II trials for a combination therapy of two agents, we ideally want to explore as many dose combinations as possible with limited sample size in Phase I and to reduce the number of untried dose combinations before moving to Phase II. Efficient collection of toxicity data in Phase I would eventually improve the accuracy of optimal dose combination identification in Phase II. In this paper, we develop a novel dose-finding method based on efficacy and toxicity outcomes for two-agent combination Phase I/II trials. We propose a "zone-finding stage" that determines the most admissible toxicity zone on the dose combination matrix and subsequently select the dose combination allocated to the next patient from that zone in Phase I. Upon completion of this zone-finding stage, we allocate the next patient to the dose combination determined by adaptive randomization of the admissible toxicity and efficacy dose combinations in Phase II. Simulation studies demonstrated the utility of the proposed zone-finding stage and proved that the operating characteristic of the proposed method was no worse than the existing method. The sensitivity of the proposed method, as well as the operating characteristic of this method when the efficacy outcome is delayed, was also examined.

A Bayesian hierarchal modeling approach to shortening phase I/II trials of anticancer drug combinations.

In phase I/II anticancer drug-combination trials, trial design to evaluate toxicity and efficacy has been studied by dividing the trial into 2 stages, followed by seamless execution of the 2 stages. In the first stage, admissible dose combinations in toxicity are identified, followed by patient assignment among the identified admissible dose combinations using adaptive randomization in the second stage. When patients are assigned using adaptive randomization, it is desirable to determine a more appropriate dose combination by taking into consideration both drug efficacy and toxicity; however, during the course of this determination and evaluation of toxicity and efficacy, there remains a concern that the trial duration might be prolonged. Therefore, we proposed a trial design to assign patients adaptively to more appropriate dose combinations in both toxicity and efficacy and to shorten trial duration without compromising trial performance. When selecting the dose combination for subsequent cohorts, unobserved data are treated as missing data, which are imputed using a data augmentation algorithm involving a gamma process. Probabilities associated with toxicity and efficacy are estimated applying a Bayesian hierarchical model to the imputed data, thereby allowing more patients to be assigned more appropriate dose combinations in both toxicity and efficacy through adaptive randomization. Results of simulation studies suggested that the proposed approach shortened trial duration without significantly compromising the performance of the trial as compared with existing approaches. We believe that the proposed approach will expedite drug development time and reduce costs associated with clinical development.

Statistical analysis for toxicity studies.

Generally, multiple statistical analysis methods can be applied for certain kind of data, and conclusion could differ, depending on the selected statistical method. Therefore, it is necessary to fully understand the performance of each statistical method and to examine which method is appropriate to use and to standardize statistical methods for toxicity studies to be carried out routinely. Several viewpoints for selecting appropriate statistical methods are discussed in this review paper. According to the distribution form, i.e., whether a distribution has a bell shape without outliers or not, either a parametric or a nonparametric approach should be selected. The nonparametric approach is also available for categorical data. Depending on the design and purpose of a study, several forms of statistical analysis are available. Assuming dose dependency, comparisons with a control are conducted by Williams test (nonparametric: Shirley-Williams test). When a dose dependent relationship is not expected, comparisons with the control are conducted by Dunnett test (nonparametric: Steel test). All possible pairwise comparisons among groups are conducted by Tukey test (nonparametric: Steel-Dwass test). If we are interested in several specific comparisons among groups, the Bonferroni-adjusted Student's t-test (nonparametric: the Bonferroni-adjusted Wilcoxon test) can be used.

Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data.

BACKGROUND: Three randomised trials (GEST, JACCRO PC-01, and GEMSAP) were conducted to evaluate the efficacy of gemcitabine plus S-1 (GS) vs gemcitabine alone in patients with advanced pancreatic cancer (PC). In this pooled analysis, the efficacy and safety of GS vs gemcitabine were evaluated. METHODS: Additional follow-up was conducted and survival data were updated in each study. A total of 770 patients (gemcitabine 389; GS 381) were included in the pooled analysis. The efficacy and safety data were analysed according to disease extent: locally advanced PC (LAPC) or metastatic PC (MPC). RESULTS: There were 738 (95.8%) overall survival events. In patients with LAPC (n=193), the median survival was 11.83 months for gemcitabine and 16.41 months for GS (hazard ratio (HR)=0.708; 95% confidence intervals (CI), 0.527-0.951; P=0.0220). In patients with MPC (n=577), the median survival was 8.02 months for gemcitabine and 9.43 months for GS (HR=0.872; 95% CI, 0.738-1.032; P=0.1102). The rate of grade 3/4 toxicity (rash and thrombocytopenia in LAPC; rash, diarrhoea, vomiting, and neutropaenia in MPC) was significantly higher for GS than for gemcitabine. CONCLUSIONS: Gemcitabine plus S-1 is a viable treatment alternative to gemcitabine, which is one of the standard treatments in patients with LAPC.

Impact of progression type on overall survival in patients with advanced gastric cancer based on randomized phase III study of S-1 plus oxaliplatin versus S-1 plus cisplatin.

BACKGROUND: The association between progression type and survival has been reported in breast cancer, but remains unclear in advanced gastric cancer (AGC). Here, this association was assessed using data obtained from an earlier randomized phase III study demonstrating the non-inferiority of S-1 plus oxaliplatin (SOX) to S-1 plus cisplatin (CS) on progression-free survival and overall survival (OS) in the first-line treatment of AGC. METHODS: A Cox regression model including two time-dependent covariates, progression with new lesions and with no new lesions, was used to determine their effect on OS in each treatment group. When both types of progression were detected simultaneously, this was categorized as progression with new lesions. RESULTS: Progression with and with no new lesions was identified in 91 and 167 patients, respectively, in the SOX group (333 patients) and 95 and 147 patients, respectively, in the CS group (330 patients). The association between progression type and OS was similar in both treatment groups; both progression types were strong poor prognostic factors, particularly progression with new lesions [hazard ratio (HR), 7.26; 95% confidence interval (CI), 4.89-10.80 in SOX and HR, 5.78; 95% CI, 4.13-8.08 in CS] compared to no new lesions (HR, 4.66; 95% CI, 3.21-6.77 in SOX and HR, 2.71; 95% CI, 1.95-3.75 in CS). CONCLUSIONS: Progression accompanied by new lesions had a strong negative impact on OS in patients treated with S-1 and platinum for AGC.

The Effect of Tegafur-Uracil on Survival in T Categories as Defined in the Eighth Edition of the TNM Classification: An Exploratory Analysis of Postoperative Adjuvant Tegafur-Uracil on Survival in Patients with Adenocarcinoma of the Lung.

BACKGROUND: Tegafur-uracil (UFT) improves survival in patients with stage I adenocarcinoma of the lung. We evaluated the effect of UFT on survival in maximum primary tumor diameter (T) categories as defined in the eighth edition of the TNM Classification (TNM8). METHODS: Tumors were subgrouped on the basis of T category (TNM8) as follows: T1a, T ≤1 cm; T1b, 1 < T ≤2 cm; T1c, 2 < T ≤3 cm; T2a, 3 < T ≤4 cm; T2b , 4 < T ≤5 cm; T3, 5 < T ≤7 cm. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazard models. RESULTS: UFT was associated with improved survival. The adjusted HRs were as follows: for T1a, 0.79 (95% CI 0.14-4.50); for T1b, 1.16 (95% CI 0.63-2.12); for T1c, 0.74 (95% CI 0.43-1.27); for T2a, 0.45 (95% CI 0.21-0.96); for T2b, 0.55 (95% CI 0.10-3.07), and for T3, 0.70 (95% CI 0.20-2.50). CONCLUSIONS: The adjuvant chemotherapy with UFT tended to improve survival in patients with adenocarcinoma of the lung of each T category based on TNM8, except T1b.

Preplanned safety analysis of the JFMC37-0801 trial: a randomized phase III study of six months versus twelve months of capecitabine as adjuvant chemotherapy for stage III colon cancer.

BACKGROUND: Six months of adjuvant chemotherapy is regarded as the standard of care for patients with stage III colon cancer. However, whether longer treatment can improve prognosis has not been fully investigated. We conducted a phase III study comparing 6 and 12 months of adjuvant capecitabine chemotherapy for stage III colon cancer, and report here the results of our preplanned safety analysis. METHODS: Patients aged 20-79 years with curatively resected stage III colon cancer were randomly assigned to receive 8 cycles (6 months) or 16 cycles (12 months) of capecitabine (2500 mg/m2/day on days 1-14 of each 21-day cycle). Treatment exposure and adverse events (AEs) were evaluated. RESULTS: A total of 1304 patients (642 and 636 in the 6-month and 12-month groups, respectively) were analyzed. The most common AE was hand-foot syndrome (HFS). HFS, leukocytopenia, neutropenia, and hyperbilirubinemia (any grade) occurred more frequently in the 12-month group than in the 6-month group. HFS was the only grade ≥3 AE to have a significantly higher incidence in the 12-month group (23 vs 17%, p = 0.011). The completion rate for 8 cycles was 72% in both groups, while that for 16 cycles was 46% in the 12-month group. HFS was the most common AE requiring dose reduction and treatment discontinuation. CONCLUSIONS: Twelve months of adjuvant capecitabine demonstrated a higher cumulative incidence of HFS compared to the standard 6-month treatment period, while toxicities after 12 months of capecitabine were clinically acceptable. TRIAL REGISTRATION: UMIN-CTR, UMIN000001367.

Interim decision-making strategies in adaptive designs for population selection using time-to-event endpoints.

Adaptive designs in oncology clinical trials with interim analyses for population selection could be used in the development of targeted therapies if a predefined biomarker hypothesis exists. In this article, we consider an interim analysis using overall survival (OS), progression-free survival (PFS), and both OS and PFS, to determine whether the whole population or only the biomarker-positive population should continue into the subsequent stage of the trial, whereas the final decision is made based on OS data only. In order to increase the probability of selecting the most appropriate population at the interim analysis, we propose an interim decision-making strategy in adaptive designs with correlated endpoints considering the post-progression survival (PPS) magnitudes. In our approach, the interim decision is made on the basis of predictive power by incorporating information on OS as well as PFS to supplement the incomplete OS data. Simulation studies assuming a targeted therapy demonstrated that our interim decision-making procedure performs well in terms of selecting the proper population, especially under a scenario in which PPS affects the correlation between OS and PFS.

Adaptive phase I/II clinical trials for drug combination assessment in oncology using the outcomes of each cycle.

Many new anticancer agents can be combined with existing drugs, as combining a number of drugs may be expected to have a better therapeutic effect than monotherapy owing to synergistic effects. Furthermore, to drive drug development and to reduce the associated cost, there has been a growing tendency to combine these as phase I/II trials. With respect to phase I/II oncology trials for the assessment of dose combinations, in the existing methodologies in which efficacy based on tumor response and safety based on toxicity are modeled as binary outcomes, it is not possible to enroll and treat the next cohort of patients unless the best overall response has been determined in the current cohort. Thus, the trial duration might be potentially extended to an unacceptable degree. In this study, we proposed a method that randomizes the next cohort of patients in the phase II part to the dose combination based on the estimated response rate using all the available observed data upon determination of the overall response in the current cohort. We compared the proposed method to the existing method using simulation studies. These demonstrated that the percentage of optimal dose combinations selected in the proposed method is not less than that in the existing method and that the trial duration in the proposed method is shortened compared to that in the existing method. The proposed method meets both ethical and financial requirements, and we believe it has the potential to contribute to expedite drug development.

Application of Bayesian hierarchical models for phase I/II clinical trials in oncology.

Treatment during cancer clinical trials sometimes involves the combination of multiple drugs. In addition, in recent years there has been a trend toward phase I/II trials in which a phase I and a phase II trial are combined into a single trial to accelerate drug development. Methods for the seamless combination of phases I and II parts are currently under investigation. In the phase II part, adaptive randomization on the basis of patient efficacy outcomes allocates more patients to the dose combinations considered to have higher efficacy. Patient toxicity outcomes are used for determining admissibility to each dose combination and are not used for selection of the dose combination itself. In cases where the objective is not to find the optimum dose combination solely for efficacy but regarding both toxicity and efficacy, the need exists to allocate patients to dose combinations with consideration of the balance of existing trade-offs between toxicity and efficacy. We propose a Bayesian hierarchical model and an adaptive randomization with consideration for the relationship with toxicity and efficacy. Using the toxicity and efficacy outcomes of patients, the Bayesian hierarchical model is used to estimate the toxicity probability and efficacy probability in each of the dose combinations. Here, we use Bayesian moving-reference adaptive randomization on the basis of desirability computed from the obtained estimator. Computer simulations suggest that the proposed method will likely recommend a higher percentage of target dose combinations than a previously proposed method.

An adaptive dose-finding method using a change-point model for molecularly targeted agents in phase I trials.

The paradigm of oncology drug development is expanding from developing cytotoxic agents to developing biological or molecularly targeted agents (MTAs). Although it is common for the efficacy and toxicity of cytotoxic agents to increase monotonically with dose escalation, the efficacy of some MTAs may exhibit non-monotonic patterns in their dose-efficacy relationships. Many adaptive dose-finding approaches in the available literature account for the non-monotonic dose-efficacy behavior by including additional model parameters. In this study, we propose a novel adaptive dose-finding approach based on binary efficacy and toxicity outcomes in phase I trials for monotherapy using an MTA. We develop a dose-efficacy model, the parameters of which are allowed to change in the vicinity of the change point of the dose level, in order to consider the non-monotonic pattern of the dose-efficacy relationship. The change point is obtained as the dose that maximizes the log-likelihood of the assumed dose-efficacy and dose-toxicity models. The dose-finding algorithm is based on the weighted Mahalanobis distance, calculated using the posterior probabilities of efficacy and toxicity outcomes. We compare the operating characteristics between the proposed and existing methods and examine the sensitivity of the proposed method by simulation studies under various scenarios. Copyright © 2016 John Wiley & Sons, Ltd.

Efficacy and safety of S-1 and oxaliplatin combination therapy in elderly patients with advanced gastric cancer.

BACKGROUND: A randomized phase III study of Japanese patients with advanced gastric cancer, the G-SOX trial, revealed that S-1 and oxaliplatin (SOX) combination therapy was noninferior to S-1 and cisplatin (CS) combination therapy. However, it is unclear whether the efficacy and safety in elderly patients were different between the two regimens. METHODS: A total of 685 patients registered in the G-SOX trial were classified as elderly (70 years or older) or not elderly (younger than 70 years), and 663 patients (SOX therapy, elderly 113 of 333 patients, 34 %; CS therapy, elderly 99 of 330 patients, 30 %) and 673 patients (SOX therapy, elderly 114 of 338 patients, 34 %; CS therapy, elderly 101 of 335 patients, 30 %) were analyzed for efficacy and safety, respectively. Treatment delivery of SOX was also compared between elderly and nonelderly groups. RESULTS: No differences in efficacy were identified between the elderly and nonelderly groups for either regimen. In the elderly groups, SOX therapy showed better trends in progression-free survival (hazard ratio 0.805, 95 % confidence interval 0.588-1.102) and overall survival (hazard ratio 0.857, 95 % confidence interval 0.629-1.167) compared with CS therapy, although there were no significant differences. Grade 3 or worse adverse events were less frequent in the elderly group receiving SOX than in the elderly group receiving CS except for the low incidence of sensory neuropathy (5.3 % vs 0 %), neutropenia (25.4 % vs 42.6 %), anemia (21.1 % vs 42.6 %), febrile neutropenia (1.8 % vs 10.9 %), increased creatinine level (0.9 % vs 3.0 %), and hyponatremia (7.9 % vs 18.8 %). CONCLUSIONS: SOX is an effective and feasible therapy in both nonelderly and elderly patients with advanced gastric cancer. In elderly patients, SOX demonstrated favorable efficacy and safety compared with CS.

Meta-analysis supporting noninferiority of oxaliplatin plus S-1 to cisplatin plus S-1 in first-line treatment of advanced gastric cancer (G-SOX study): indirect comparison with S-1 alone.

BACKGROUND: The Randomized Phase III Study Comparing Oxaliplatin plus S-1 with Cisplatin plus S-1 in Chemotherapy-naïve Patients with Advanced Gastric Cancer (G-SOX) showed the noninferiority of S-1 (an oral fluoropyrimidine-derivative dihydropyrimidine dehydrogenase inhibitor) plus oxaliplatin combination therapy (SOX) to S-1 plus cisplatin therapy (CS) in overall survival [hazard ratio (HR) from proportional hazard model 0.958, 95 % confidence interval (CI) 0.803-1.142; noninferiority margin 1.15]. To further clarify the clinical position of SOX in advanced gastric cancer (AGC), a meta-analysis including information from other reported studies was conducted. METHODS: In addition to G-SOX, Japanese phase III clinical trials including S-1 monotherapy were included in the analyses. Individual patient data for SOX (318 patients) and CS (324 patients) from G-SOX, as well as those for S-1 (160 patients) from the Randomized Phase III Study Comparing the Efficacy and Safety of Irinotecan plus S-1 with S-1 Alone as First-line Treatment for Advanced Gastric Cancer (GC0301/TOP-002), were available. Published clinical information for S-1 from other studies (total 705 patients) was also collected. A Weibull distribution was assumed for overall survival time, and parameters for SOX, CS, and S-1 were estimated parametrically. Posterior HR distributions were obtained with a Bayesian approach. RESULTS: The HR of SOX to S-1 was 0.817 (95 % credible interval 0.704-0.939), and the probability of the HR <1.00 was 99.8 %. The HR of CS to S-1 was 0.871 (95 % credible interval; 0.754-0.998), and the probability of the HR <1.00 was 97.6 %. The HR of SOX to CS in G-SOX was 0.942 (95 % credible interval; 0.789-1.117), and the probability of HR <1.15 was 98.9 %. CONCLUSION: This meta-analysis indicates that SOX was superior to S-1 and noninferior to CS in AGC.