There are two study questions we are asking in this randomized phase II/III trial based on a blood biomarker, Epstein Barr virus (EBV) deoxyribonucleic acid (DNA) for locoregionally advanced non-metastatic nasopharyngeal cancer. All patients will first undergo standard concurrent chemotherapy and radiation therapy. When this standard treatment is completed, if there is no detectable EBV DNA in their plasma, then patients are randomized to either standard adjuvant cisplatin and fluorouracil chemotherapy or observation. If there is still detectable levels of plasma EBV DNA, patients will be randomized to standard cisplatin and fluorouracil chemotherapy versus gemcitabine and paclitaxel. Radiation therapy uses high energy x rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, fluorouracil, gemcitabine hydrochloride, and paclitaxel work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving cisplatin and fluorouracil is more effective than gemcitabine hydrochloride and paclitaxel after radiation therapy in treating patients with nasopharyngeal cancer.
PRIMARY OBJECTIVES: I. To determine whether substituting adjuvant concurrent high dose cisplatin (CDDP) and fluorouracil (5-FU) with gemcitabine (gemcitabine hydrochloride) and paclitaxel will result in superior progression-free survival. (Detectable Plasma Epstein Barr Virus \[EBV\] Deoxyribonucleic Acid \[DNA\] Cohort randomized Phase II) II. To determine whether omitting adjuvant CDDP and 5-FU (observation alone in the adjuvant setting) will result in non-inferior overall survival as compared with those patients receiving adjuvant CDDP and 5-FU chemotherapy. (Undetectable Plasma EBV DNA Cohort Phase III) SECONDARY OBJECTIVES: I. Time to distant metastasis. (Randomized Phase II and Phase III) II. Time to local progression. (Randomized Phase II and Phase III) III. Time to regional progression. (Randomized Phase II and Phase III) IV. Progression-free survival (Undetectable Cohort). V. Overall survival (Detectable Cohort). VI. Acute and late toxicity profiles based on clinician-reported Common Terminology Criteria for Adverse Events (CTCAE), version (v.) 4. (Randomized Phase II and Phase III) VII. Death during or within 30 days of end of protocol treatment. (Randomized Phase II and Phase III) VIII. Quality of life (general and physical well-being). (Randomized Phase II and Phase III) IX. Quality of life (hearing). (Randomized Phase II and Phase III) X. Quality of life (peripheral neuropathy). (Randomized Phase II and Phase III) XI. Cost effectiveness. (Randomized Phase II and Phase III) OUTLINE: Patients undergo intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 6.5 weeks and receive low-dose cisplatin intravenously (IV) over 30-60 minutes once weekly during IMRT. Beginning 1 week after chemoradiation, plasma samples are collected for EBV DNA analysis. PHASE II: Patients with detectable EBV DNA from pre-treatment analysis are randomized to 1 of 2 treatment arms. ARM I: Patients receive PF regimen comprising cisplatin IV over 60-120 minutes and fluorouracil IV over 96 hours continuously beginning at least 4 weeks after completion of IMRT. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive GT regimen comprising paclitaxel IV over 1 hour and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 at least 4 weeks after completion of IMRT. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. PHASE III: Patients with undetectable EBV DNA from pre-treatment analysis are randomized to 1 of 2 treatment arms. ARM III: Patients receive PF regimen as in Arm I. ARM IV: Patients undergo clinical observation. After completion of study treatment, patients are followed up every 4 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
685
Given IV
Undergo clinical observation
Given IV
Given IV
Undergo IMRT
Correlative studies
Given IV
Ancillary studies
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
The Kirklin Clinic at Acton Road
Birmingham, Alabama, United States
Banner University Medical Center - Tucson
Tucson, Arizona, United States
Sutter Cancer Centers Radiation Oncology Services-Auburn
Auburn, California, United States
Alta Bates Summit Medical Center-Herrick Campus
Berkeley, California, United States
Overall survival (OS) (Undetectable Plasma EBV DNA Cohort Phase III)
Estimated using the Kaplan-Meier method for each arm. Their distributions will be compared between treatment arms with a 1-sided log rank test. The confidence interval approach will be used for the final analysis of OS.
Time frame: Up to 7 years
Progression-free survival (PFS) (Detectable Plasma EBV DNA Cohort Phase II)
Estimated using the Kaplan-Meier method for each arm. Their distributions will be compared between treatment arms with a 1-sided log rank test. A one-sided log rank test will be used to compare the PFS at a significance level of 0.1379.
Time frame: Up to 7 years
Changes in pure tone audiometry (Phase II and III)
Correlation between categorical measures will be summarized by odds ratios, chi-square tests, and associated measures. Adjusted correlation may be derived from analysis of covariance (ANCOVA) models or derived directly using nonparametric analysis of variance (ANOVA) models if normality assumption is violated. Correlations between HHIE-S PRO scores and PTA and FACT-NP hearing, and PTA will be compared as dependent statistics
Time frame: Baseline to up to 1 year
Changes in QOL (hearing) as assessed by the Hearing Handicap Inventory for the Elderly-Screening version (HHIE-S) (Phase II and III)
QOL analysis including overall score and change from baseline will be summarized using mean and standard deviation at each time point for each arm. Overall and nasopharyngeal-specific QOL, hearing QOL (FACT-NP hearing domain, HHIE-S scores), peripheral neuropathy QOL over the short and long term and pure-tone audiometry (PTA) scores will be compared using a two sample independent t test and paired t test if the comparison is within the experimental arm between different time points.
Time frame: Baseline to up to 24 months
Changes in QOL (peripheral neuropathy) as assessed by the FACT-Taxane (Phase II and III)
Time frame: Baseline to up to 24 months
Changes in quality of life (QOL) (general and physical well-being) assessed using the Functional Assessment of Cancer Therapy (FACT)-Nasopharyngeal (NP) (Phase II and III)
Changes in patient reported outcome (PRO) scores will be correlated to clearance or non-clearance of EBV titers. Descriptive statistics derived from FACT-NP will be used to enrich the understanding of QOL as it pertains to the 2 phase III arms of observation versus additional adjuvant chemotherapy. Univariable and multivariable analysis will be performed using the Cox proportional hazards model for OS and distant metastasis. Pearson correlation will be estimated between general and physical well-being. QOL measures and change from baseline will be correlated to EBV DNA.
Time frame: Baseline to up to 24 months
Cost effectiveness as assessed by the health-related QOL (HRQOL) from the EuroQol (EQ-5D) instrument (Phase II and III)
Incremental cost effectiveness ratios will be compared to determine the probability of cost effectiveness of various interventions, with sensitivity analyses to identify model weaknesses. The expected value of perfect information will be determined to delimit the upper boundary for cost-effective future investment in this area of research.
Time frame: Up to 24 months
Incidence of acute grade 3-5 adverse events (Phase II and III)
Rates of specific acute toxicity profiles and late toxicity profiles will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test between the 2 treatment arms.
Time frame: Up to 7 years
Incidence of death (Phase II and III)
Time frame: Up to 30 days of end of protocol treatment
Incidence of late grade 3-5 adverse events (Phase II and III)
Rates of specific acute toxicity profiles and late toxicity profiles will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test between the 2 treatment arms.
Time frame: Up to 7 years
OS (Detectable Plasma EBV DNA Cohort Phase II)
Estimated using the Kaplan-Meier method for each arm. Their distributions will be compared between treatment arms with a 1-sided log rank test.
Time frame: Up to 7 years
PFS (Undetectable Plasma EBV DNA Cohort Phase III)
Estimated using the Kaplan-Meier method for each arm. Their distributions will be compared between treatment arms with a 1-sided log rank test.
Time frame: Up to 7 years
Time to distant metastasis (DM) (Phase II and III)
The cumulative incidence method will be used to estimate local, regional, and distant failure rates. The failure rates for the experimental treatment will be compared against the control using a failure-specific log-rank test. Multivariate analysis will be performed using the Cox proportional hazards model.
Time frame: Up to 7 years
Time to local progression (Phase II and III)
The cumulative incidence method will be used to estimate local, regional, and distant failure rates. The failure rates for the experimental treatment will be compared against the control using a failure-specific log-rank test. Multivariate analysis will be performed using the Cox proportional hazards model.
Time frame: Up to 7 years
Time to regional progression (Phase II and III)
Defined as an estimated increase in the size of the tumor (product of the perpendicular diameters of the two largest dimensions) of greater than 25%, taking as reference the smallest value of all previous measurements or appearance of new areas of malignant disease. The cumulative incidence method will be used to estimate local, regional, and distant failure rates. The failure rates for the experimental treatment will be compared against the control using a failure-specific log-rank test. Multivariate analysis will be performed using the Cox proportional hazards model.
Time frame: Up to 7 years
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