ARTSCAN III: A Randomized Phase III Study Comparing Chemoradiotherapy With Cisplatin Versus Cetuximab in Patients With Locoregionally Advanced Head and Neck Squamous Cell Cancer

Abstract

PURPOSE We performed an open-label randomized controlled phase III study comparing treatment outcome and toxicity between radiotherapy (RT) with concomitant cisplatin versus concomitant cetuximab in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC; stage III-IV according to the Union for International Cancer Control TNM classification, 7th edition). MATERIALS AND METHODS Eligible patients were randomly assigned 1:1 to receive either intravenous cetuximab 400 mg/m2 1 week before start of RT followed by 250 mg/m2/wk, or weekly intravenous cisplatin 40 mg/m2, during RT. RT was conventionally fractionated. Patients with T3-T4 tumors underwent a second random assignment 1:1 between standard RT dose 68.0 Gy to the primary tumor or dose escalation to 73.1 Gy. Primary end point was overall survival (OS) evaluated using adjusted Cox regression analysis. Secondary end points were locoregional control, local control with dose-escalated RT, pattern of failure, and adverse effects. RESULTS Study inclusion was prematurely closed after an unplanned interim analysis when 298 patients had been randomly assigned. At 3 years, OS was 88% (95% CI, 83% to 94%) and 78% (95% CI, 71% to 85%) in the cisplatin and cetuximab groups, respectively (adjusted hazard ratio, 1.63; 95% CI, 0.93 to 2.86; P = .086). The cumulative incidence of locoregional failures at 3 years was 23% (95% CI, 16% to 31%) compared with 9% (95% CI, 4% to 14%) in the cetuximab versus the cisplatin group (Gray’s test P = .0036). The cumulative incidence of distant failures did not differ between the treatment groups. Dose escalation in T3-T4 tumors did not increase local control. CONCLUSION Cetuximab is inferior to cisplatin regarding locoregional control for concomitant treatment with RT in patients with locoregionally advanced HNSCC. Additional studies are needed to identify possible subgroups that still may benefit from concomitant cetuximab treatment.

Statistical fundamentals on cancer research for clinicians: Working with your statisticians

“…It is critical for H1 to be based on sound clinical judgement and updated knowledge, otherwise it risks exposing patients to unnecessary and/or inferior treatment. For example, the H1 for the recently published ARTSCAN III trial [11] posited a 10% higher 5-year OS for cetuximab versus cisplatin which was based on one trial of cetuximab compared to radiotherapy-alone [12] without considering the effect from concurrent chemotherapy (CCRT) [13]. However, after the trial initiation, the authors responded to emerging evidence showing inferior outcome of cetuximab-radiation versus chemoradiation [14], prompting an unplanned interim analysis that resulted in early trial termination due to inferior outcomes in the intervention (cetuximab-radiotherapy) arm.…”

“…There should be a credible judgement about the likely rate for the primary end-point (e.g., OS) in the control group, followed by a similar appreciation of the conceivable medically important impact of the experimental intervention on the end-point. Researchers should avoid overly optimistic effect differences that could result in early trial closure [11]; alternatively, it may undermine study power as occurred in another study with an ambitious assumption of 15% absolute difference [28], and may impact ability to detect smaller differences. The likelihood of a false-positive result is normally expressed as the Type I error (or a, typically set at 0.05), and the false negative rate as the Type II error (or b).…”

“…Clear superiority of one treatment compared to another may be grounds for closure for ethical reasons, especially when the primary question may have been addressed and there is no further rationale to continue expending resources, and further patients could continue receiving a proven inferior approach: this was seen with the experimental treatment in the highly influential trial of chemoradiotherapy in nasopharyngeal carcinoma that changed practice globally [49], 3). Unexpected significantly worse performance of an experimental arm also warrants immediate closure as was evident in the DAHANCA 10 trial using darbepoetin alfa to improve anemia in HNC (HR for OS: 1.30) or the ARTSCAN III trial (NCT01969877) [11] comparing cetuximab versus cisplatin-chemoradiotherapy (HR for OS: 1.63), 4). Other reasons for premature closure include futility, relating to inadequate power consequent on slow accrual.…”

“…Examples include the rare trial that compared chemoradiotherapy versus definitive surgery in HNC [50,51] and the PARADIGM induction chemotherapy trial [52]. Unplanned interim analysis may occasionally be useful if the investigators respond to new evidence from other studies during the course of the trial [11], and may result in amendments or premature closure.…”

The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis

“…The predominant histological type of head and neck tumors is squamous cell carcinomas (HNSCC) [ 11 ]. HNSCC is the 7th most common cancer worldwide [ 11 , 12 , 13 ]. Risk factors include tobacco, alcohol, and human papillomavirus (HPV) infection.…”