Development and validation of a novel MR imaging predictor of response to induction chemotherapy in locoregionally advanced nasopharyngeal cancer: a randomized controlled trial substudy (NCT01245959).
BACKGROUND
In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone.


METHODS
All patients, including retrospective training (n = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts.


RESULTS
Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25-0.74, p = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups (p = 0.063), with a significant treatment interaction (pinteraction <  0.001). This trend was also found in the validation cohort with high (n = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06-0.51, p <  0.001) and low ICTOS (n = 175, p = 0.31), with a significant treatment interaction (pinteraction = 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors.


CONCLUSION
An imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment.


TRIAL REGISTRATION
ClinicalTrials.gov , NCT01245959 . Registered 23 November 2010.
['Dong|Di|D|', 'Zhang|Fan|F|', 'Zhong|Lian-Zhen|LZ|', 'Fang|Meng-Jie|MJ|', 'Huang|Cheng-Long|CL|', 'Yao|Ji-Jin|JJ|', 'Sun|Ying|Y|', 'Tian|Jie|J|', 'Ma|Jun|J|', 'Tang|Ling-Long|LL|']
D000328:Adult D000368:Aged D000971:Antineoplastic Combined Chemotherapy Protocols D059248:Chemoradiotherapy D017326:Clinical Trials, Phase III as Topic D015331:Cohort Studies D003657:Decision Making D018450:Disease Progression D005260:Female D006801:Humans D060828:Induction Chemotherapy D008279:Magnetic Resonance Imaging D008297:Male D008875:Middle Aged D015337:Multicenter Studies as Topic D000077274:Nasopharyngeal Carcinoma D009303:Nasopharyngeal Neoplasms D011237:Predictive Value of Tests D011379:Prognosis D011880:Radiotherapy Planning, Computer-Assisted D016032:Randomized Controlled Trials as Topic D012189:Retrospective Studies D012307:Risk Factors D016896:Treatment Outcome
Induction chemotherapy Locoregionally advanced nasopharyngeal cancer Survival benefit Individualized imaging biomarker Treatment decision