This phase II/III trial compares whether cisplatin given weekly with radiation therapy is better tolerated than cisplatin given every three weeks with radiation therapy for the treatment of head and neck cancer that has spread to other places in the body (advanced). The second part of this study will also help to find out if the cisplatin given weekly approach will extend patients' life by at least the same amount of time as the cisplatin given every three weeks approach. Cisplatin is in a class of medications known as platinum-containing compounds that work by killing, stopping or slowing the growth of cancer cells. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Radiation with low-dose cisplatin given weekly may be effective in shrinking or stabilizing head and neck cancer or preventing its recurrence.
PRIMARY OBJECTIVES: I. To determine whether radiation with cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with cisplatin every 3 weeks for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). (Phase II) II. To determine whether radiation with cisplatin weekly is non-inferior to radiation with cisplatin every 3 weeks in terms of overall survival (OS) for patients with locoregionally advanced SCCHN. (Phase III) III. To determine whether radiation with cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with cisplatin every 3 weeks for patients with locoregionally advanced SCCHN. (Phase III) SECONDARY OBJECTIVES: I. To assess and compare progression-free survival (PFS) between arms. II. To assess and compare locoregional failure and distant metastasis between arms. III. To assess acute and late toxicity (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0). IV. To assess patient-reported outcomes quality of life (PRO/QOL), as measured by the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H\&N) (primary PRO), between arms. V. To assess hearing loss, as measured by audiograms and the modified TUNE grading scale between arms. VI. To assess hearing loss, as measured by speech audiometry Consonant-Nucleus-Consonant word scores and tympanometry (subject to the modified TUNE grading scale testing results; otherwise, it will be an exploratory objective). VII. To assess hearing-related QOL as measured by the Hearing Handicap Inventory-Screening (HHIA-S) (secondary PRO), between arms. VIII. To assess long-term PFS, OS, and toxicity between arms. IX. To assess 3-year restricted-mean survival time for OS and PFS between arms (if long-term update is warranted). EXPLORATORY OBJECTIVE: I. To collect blood and tissue specimens for future translational science studies. For instance, to examine how germline and somatic genetic variants, such as TP53, CDKN2A, PIK3CA, PTEN, NFE2L2, and KEAP1, may influence cisplatin-related efficacy and toxicity, and to assess the effect of regular nonsteroidal anti-inflammatory drugs (NSAIDs) use and genomic activation of PIK3CA (mutation or amplification) or loss of PTEN, the negative regulator of PI3K, on disease-free survival or overall survival. OUTLINE: Patients are assigned to 1 of 2 arms. ARM I (NON-OROPHARYNGEAL CANCER \[OPC\]/p16-NEGATIVE OPC group and p16-NEGATIVE OPC/CANCER OF UNKNOWN PRIMARY \[CUP\] group): Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive cisplatin intravenously (IV) once every 3 weeks (Q3W) (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity. ARM II (NON-OROPHARYNGEAL CANCER \[OPC\]/p16-NEGATIVE OPC group and p16-NEGATIVE OPC/CANCER OF UNKNOWN PRIMARY \[CUP\] group): Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive cisplatin IV once a week (QW) for 7 weeks during radiation therapy in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, or magnetic resonance imaging (MRI) or position emission tomography (PET) scan throughout the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,714
Given cisplatin IV every 3 weeks
Given cisplatin IV weekly
Undergo CT scan
Undergo MRI
Undergo PET scan
Ancillary studies
Ancillary studies
Undergo radiation therapy
Mobile Infirmary Medical Center
Mobile, Alabama, United States
NEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro
Jonesboro, Arkansas, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Kaiser Permanente-Anaheim
Anaheim, California, United States
Kaiser Permanente-Deer Valley Medical Center
Antioch, California, United States
Incidence of acute toxicity (Phase II)
Measured by the T-scores.
Time frame: Up to 180 days post-treatment
Overall survival (OS) (Phase III)
OS rates will be estimated using the Kaplan-Meier method.
Time frame: From randomization to death of any cause, assessed up to 9 years
Incidence of acute toxicity (Phase III)
Measured by the T-scores.
Time frame: Up to 180 days post-treatment
Locoregional failure rates
Time frame: Up to 9 years
Distant metastasis
Time frame: Up to 9 years
Progression-free survival (PFS)
PFS rates will be estimated using the Kaplan-Meier method and between-arm differences compared using the log-rank test with a two-sided alpha of 0.05 (Kaplan 1958).
Time frame: From randomization to locoregional failure, distant metastasis, or death due to any cause, whichever occurs first, assessed up to 9 years
Restricted mean survival time (RMST) for OS
Compared using a Wald-type test based on Kaplan-Meier estimates. Adjusted RMST estimates at 3 years and 95% confidence intervals will be provided using RMST regression with pseudo-observations.
Time frame: At 3 years
RMST for PFS
Compared using a Wald-type test based on Kaplan-Meier estimates. Adjusted RMST estimates at 3 years and 95% confidence intervals will be provided using RMST regression with pseudo-observations.
Time frame: At 3 years
Incidence of acute toxicity
Measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
Time frame: Up to 180 days post-treatment
Incidence of late toxicity
Measured by CTCAE v5.0.
Time frame: Up to 9 years
Incidence of late toxicity
Measured by the A-scores.
Time frame: Up to 9 years
Quality of life
Measured by Functional Assessment of Cancer Therapy Head and Neck.
Time frame: At 6 months post-radiation therapy
Hearing loss
Measured by Hearing Handicap Inventory for Adults-Screening.
Time frame: At 6 months post-radiation therapy
Hearing loss (cochleotoxicity)
Measured by audiograms and the modified TUNE grading scale.
Time frame: At 6 months post-radiation therapy
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