SUMMARYCurrently many dose finding clinical trial designs, including the continual reassessment method (CRM) and the standard '3+3' design, dichotomize toxicity outcomes based on pre-specified doselimiting toxicity criteria. This loss of information is particularly inefficient due to the small sample sizes in phase I trials. Common Toxicity Criteria (CTCAEv3.0) classify adverse events into grades 1 through 5, which range from 1 as a mild adverse event to 5 as death related to an adverse event.In this paper, we extend the CRM to include ordinal toxicity outcomes as specified by CTCAEv3.0 using the proportional odds model and compare results with the dichotomous CRM. A sensitivity analysis of the new design compares various target dose-limiting toxicity rates, sample sizes, and cohort sizes. This design is also assessed under various dose-toxicity relationship models including proportional odds models as well as those that violate the proportional odds assumption. A simulation study shows that the proportional odds CRM performs as well as the dichotomous CRM on all criteria compared (including safety criteria such as percentage of patients treated at highly toxic or suboptimal dose levels) and with improved estimation of the MTD when the PO assumption is not violated. These findings suggest that it is beneficial to incorporate ordinal toxicity endpoints into phase I trial designs.

BackgroundThis paper addresses the statistical use of accessibility and availability indices and the effect of study boundaries on these measures. The measures are evaluated via an extensive simulation based on cluster models for local outlet density. We define outlet to mean either food retail store (convenience store, supermarket, gas station) or restaurant (limited service or full service restaurants). We designed a simulation whereby a cluster outlet model is assumed in a large study window and an internal subset of that window is constructed. We performed simulations on various criteria including one scenario representing an urban area with 2000 outlets as well as a non-urban area simulated with only 300 outlets. A comparison is made between estimates obtained with the full study area and estimates using only the subset area. This allows the study of the effect of edge censoring on accessibility measures.ResultsThe results suggest that considerable bias is found at the edges of study regions in particular for accessibility measures. Edge effects are smaller for availability measures (when not smoothed) and also for short range accessibilityConclusionsIt is recommended that any study utilizing these measures should correct for edge effects. The use of edge correction via guard areas is recommended and the avoidance of large range distance-based accessibility measures is also proposed.

Background Various dose-finding clinical trial designs, including the continual reassessment method (CRM), dichotomize toxicity outcomes based on prespecified dose-limiting toxicity (DLT) criteria. This loss of toxicity information is particularly inefficient due to the small sample sizes in phase I trials, especially when Common Terminology Criteria for Adverse Events (CTCAE v4.0) are an established ordinal toxicity grading classification already used in the clinical practice. Purpose The purpose of this simulation study is to incorporate ordinal toxicity grades as specified by CTCAE v4.0 using a continuation ratio (CR) model in the likelihood-based CRM. Methods This simulation study compares the CR model design to the dichotomous CRM as well as an ordinal CRM that implements the proportional odds (PO) model. We compare six scenarios for model performance based on various safety and efficiency criteria and consider a range of dose–toxicity relationship models, including CR models, PO models, and models that violate the PO assumption. Results The ordinal CRM performs as well as the dichotomous CRM in all scenarios considered, especially in situations where the starting dose is overly toxic, the ordinal designs show slight improvement in the estimation of the maximum tolerated dose (MTD) and fewer median patients exposed to excessively toxic dose levels as compared to the binary CRM. We also find slight discrepancies in the performance between the PO model and CR model; however, the differences were not substantial enough to strongly recommend one model over the other. Limitations The CR model design does require slightly more input from clinical investigators prior to the start of the trial as compared to the dichotomous CRM. Investigators must specify the distribution of toxicity grades at the expected dose levels for a 10% and 90% DLT rate in this CR design. However, an R package will help with the implementation of this ordinal design. Conclusions While the ordinal designs did not perform significantly better than the binary counterpart, we were able to incorporate maximal toxicity information available into a feasible dose-finding design without compromising overall design performance.

Objective This study aims to report the long-term outcomes of a novel treatment approach utilizing induction low-dose fractionated radiation therapy (LDFRT) and chemotherapy for locally advanced squamous cell carcinoma of head and neck (SCCHN). Methods We prospectively enrolled 40 patients with locally advanced SCCHN (77 % stage IV) on a phase II clinical trial and treated with induction paclitaxel (225 mg/m2), carboplatin (AUC 6), and LDFRT (80 cGy BID on days 1 and 2) every 21 days for two cycles. Results Forty patients enrolled; 39 were evaluable. The acute toxicity and response data have been previously reported; overall response rate (RR) was 82 %. After induction, definitive therapy was concurrent chemoradiation (CRT) in 51 %, XRT alone in 39 %, surgery in 5 %, and surgery and XRT in 5 %. The long-term outcomes are now reported with a median follow-up of 83 months. Locoregional control (LRC) is 80 % and distant control (DC) is 77 %. Five-year overall survival (OS), disease-specific survival, and progression-free survival (PFS) are 62 %, 66 %, and 58 %, respectively. Conclusion Induction chemotherapy with LDFRT has a high initial RR, comparable toxicity to two-drug induction regimens, but adds a third novel and effective agent, LDFRT. Five-year follow-up shows favorable outcomes compared to historical controls and excellent compliance with definitive therapy. This novel treatment approach is now planned for phase 3 trial evaluation.