Abstract
The gold standard endpoint in trials of locoregionally advanced nasopharyngeal carcinoma (NPC) is overall survival (OS). Using data from a phase III randomized trial, we evaluated whether progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) or locoregional failure-free survival (LR-FFS) could be reliable surrogate endpoints for OS. Between July 2002 and September 2005, 316 eligible patients with stage III-IVB NPC were randomly assigned to receive either radiotherapy alone or chemoradiotherapy. 2- and 3-year PFS, FFS, D-FFS, and LR-FFS were tested as surrogate endpoints for 5-year OS using Prentice’s four criteria. The Spearman’s rank correlation coefficient was calculated to assess the strength of the associations. After a median follow-up time of 5.8 years, 2- and 3-year D-FFS and LR-FFS were not significantly different between treatment arms, in rejection of Prentice’s second criterion. Being consistent with all Prentice’s criteria, 2- and 3-year PFS and FFS were valid surrogate endpoints for 5-year OS; the rank correlation coefficient was highest (0.84) between 3-year PFS and 5-year OS. In conclusion, PFS and FFS at 2 and 3 years may be candidate surrogate endpoints for OS at 5 years; 3-year PFS may be more appropriate for early assessment of long-term survival.
Highlights
Significantly better overall survival (OS) than the control arm
Patients were eligible for the trial if they met the following inclusion criteria: (1) histologically-proven, non-keratinizing or undifferentiated Nasopharyngeal carcinoma (NPC) (World Health Organization type II or III); (2) stage III-IVB (T3-4NxM0 or TxN2-3M0) disease according to the 1997 American Joint Commission on Cancer staging system; (3) an Eastern Cooperative Oncology Group system performance status of 0–2; (4) adequate renal function, as demonstrated by a creatinine clearance rate of at least 60 mL/min; and (5) adequate hematologic function, as demonstrated by a leukocyte count ≥ 4,000/ μ L and platelet count ≥ 100,000/ μ L
We examined secondary potential surrogate endpoints: 2- and 3-year D-failure-free survival (FFS) and locoregional failure-free survival (LR-FFS), which were defined as time from randomization to locoregional or remote failure, respectively
Summary
Significantly better overall survival (OS) than the control arm. The CRT therapeutic regimen established in this trial is considered a standard of care for locoregionally advanced NPC6. Identification of surrogate endpoints for OS would shorten trial duration and speed up the identification of effective treatments for NPC. To the best of our knowledge, no study has yet validated these endpoints at an early time-point (e.g., 2 and 3 years) as surrogates for long-term survival (e.g., 5-year OS) in locoregionally advanced NPC. To establish an endpoint as a surrogate, a set of statistical conditions, known as Prentice’s criteria, need to be met[7] The purpose of this analysis was to evaluate whether 2- and 3-year PFS, FFS, D-FFS or LR-FFS (as defined below) have potential as surrogate endpoints for 5-year OS according to Prentice’s criteria based on data from our phase III randomized trial
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