Head and Neck Cancer
Conditions
Keywords
stage III squamous cell carcinoma of the larynx, stage III verrucous carcinoma of the larynx, stage IV squamous cell carcinoma of the larynx, stage IV verrucous carcinoma of the larynx, stage III squamous cell carcinoma of the lip and oral cavity, stage IV squamous cell carcinoma of the lip and oral cavity, stage III verrucous carcinoma of the oral cavity, stage IV verrucous carcinoma of the oral cavity, stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx, tongue cancer
Brief summary
RATIONALE: Giving radiation therapy that uses a 3-dimensional (3-D) image of the tumor to help focus thin beams of radiation directly on the tumor, and giving radiation therapy in higher doses over a shorter period of time, may kill more tumor cells and have fewer side effects. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether radiation therapy is more effective when given alone or together with cetuximab in treating patients with head and neck cancer that has been removed by surgery. PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared with radiation therapy given together with cetuximab in treating patients who have undergone surgery for locally advanced head and neck cancer.
Detailed description
OBJECTIVES: Primary * Determine whether the addition of cetuximab to postoperative intensity-modulated radiotherapy (IMRT) will improve overall survival (OS) in patients with locally advanced squamous cell carcinoma of the head and neck at intermediate risk following surgery. Secondary * Assess the impact of the addition of cetuximab to postoperative IMRT on disease-free survival (DFS) of these patients. * Assess the impact of the addition of cetuximab to postoperative IMRT on acute and late dysphagia, xerostomia, skin toxicity, and other toxicities according to common Toxicity Criteria for Adverse Effects (CTCAE), v. 4 and their relationships with patient-reported outcomes at 3, 12, and 24 months. * Analyze tumor for epidermal growth factor receptor (EGFR), specifically the extent of EGFR overexpression by immuno-histochemistry (IHC) and Fluorescence in situ hybridization (FISH) analysis, EGFRvIII expression, as well as the association of these assay data with OS and DFS. * Analyze tumor for human papillomavirus (HPV) infection (as defined by in situ hybridization), specifically, within the cohort of patients with oropharynx cancer, to perform an exploratory analysis of the impact of HPV on DFS and OS of this patient subset. * Analyze tumor DNA for TP53 mutations as a predictor of response to cetuximab and prognosis. * Analyze germline DNA of polymorphic variants in EGFR intron repeats as a predictor of response to cetuximab. Tertiary * Assess the impact of the addition of cetuximab to postoperative IMRT on loco-regional control. * Assess the impact of the addition of cetuximab to postoperative IMRT on patient-reported quality of life, swallowing, xerostomia, and skin toxicity based on head and neck specific instruments, including the Performance Status Scale for Head and Neck Cancer (PSS-HN), the Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N), the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS), and the Dermatology Life Quality Index (DLQI). * Assess the impact of the addition of cetuximab to postoperative IMRT on cost-utility analysis using the EuroQol (EQ-5D). * Evaluate the utility of image-guided radiotherapy (IGRT) as a means of enhancing the efficacy (i.e., loco-regional control) of IMRT while reducing the acute and/or late toxicity (particularly xerostomia) and improving patient-reported outcomes (particularly XeQOLS scores). * Retrospectively compare the loco-regional control rate in patients treated with IMRT alone (no IGRT or cetuximab) with similar patients treated with external beam radiotherapy alone in the postoperative clinical trial Radiation Therapy Oncology Group (RTOG)-95 01. OUTLINE: This is a multicenter study. Patients are stratified according to clinical stage (T1-3 vs T4a), EGFR expression (high \[≥ 80% of cells staining positive\] vs low \[\< 80% of cells staining positive\] vs not evaluable), primary site of disease (oral cavity vs larynx vs oropharynx p16+ vs oropharynx p16- vs oropharynx, p16 not evaluable), and use of image-guided radiotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients undergo intensity-modulated radiotherapy (IMRT) once daily 5 days a week for 6 weeks in the absence of disease progression or unacceptable toxicity. * Arm II: Patients undergo IMRT as in arm I. Patients also receive cetuximab IV over 1-2 hours once weekly beginning at least 5 days prior to the start of IMRT and continuing for 4 weeks after the completion of IMRT (for a total of 11 doses) in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline and at 3, 12, and 24 months. Tissue samples are collected periodically for further laboratory analysis. After completion of study treatment, patients are followed up at 1 and 3 months, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Interventions
BIOLOGICALcetuximab
intravenously
RADIATIONintensity-modulated radiation therapy
daily fractions
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Conditions for Patient Eligibility: * Pathologically (histologically) proven diagnosis of squamous cell carcinoma (including variants such as verrucous carcinoma, spindle cell carcinoma, carcinoma NOS \[not otherwise specified\], etc.) of the head/neck (oral cavity, oropharynx or larynx); Note: Hypopharynx primaries are excluded because these patients have both a poor prognosis and high likelihood of post- radiation complications. * Clinical stage T1, N1-2 or T2-4a, N0-2, M0 including no distant metastases, based upon the following minimum diagnostic workup: * General history and physical examination by a radiation oncologist and/or medical oncologist within 8 weeks prior to registration; * Examination by an otolaryngologists or Head & Neck Surgeon, within 8 weeks prior to registration; a laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is recommended but not required. * Chest x-ray (at a minimum) or chest computed tomography (CT) scan (with or without contrast) or CT/positron emission tomography (PET) of chest (with or without contrast) within 8 weeks prior to registration. * Gross total resection of the primary tumor with curative intent must be completed within 7 weeks of registration with surgical pathology demonstrating one or more of the following intermediate risk factors: * Perineural invasion; * Lymphovascular invasion; * Single lymph node \> 3 cm or ≥ 2 lymph nodes (all \< 6 cm) \[no extracapsular extension\]; * Close margin(s) of resection, defined as cancer extending to within 5 mm of a surgical margin, and/or an initially focally positive margin that is subsequently superseded by intraoperative negative margins. Similarly, patients whose tumors had focally positive margins in the main specimen but negative margins from re-excised samples in the region of the positive margin are eligible. * Pathologically confirmed T3 or T4a primary tumor. * T2 oral cavity cancer with \> 5 mm depth of invasion. * Zubrod Performance Status of 0-1 within 2 weeks prior to registration; * Age ≥ 18; * Complete blood count (CBC)/differential obtained within 4 weeks prior to registration on study, with adequate bone marrow function defined as follows: * Absolute granulocyte count (AGC) ≥ 1,500 cells/mm3; * Platelets ≥ 100,000 cells/mm3; * Hemoglobin (Hgb) ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥8.0 g/dl is acceptable). * Adequate hepatic function, defined as follows: * Total bilirubin \< 2 x institutional upper limit of normal (ULN) within 2 weeks prior to registration; * aspartate aminotransferase (AST) or alanine transaminase (ALT) \< 3 x institutional ULN within 2 weeks prior to registration. * Adequate renal function, defined as follows: * Serum creatinine (Scr) \< 2 x institutional ULN within 2 weeks prior to registration or; creatinine clearance (CCr) ≥ 50 ml/min within 2 weeks prior to registration determined by 24-hour collection or estimated by Cockcroft-Gault formula: CCr male = \[(140 - age) x (weight in kg)\] /\[(SCr mg/dl) x (72)\] CCr female = 0.85 x (CCr male) * Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential; * The following assessments are required within 2 weeks prior to the start of registration: Na, K, Cl, glucose, Ca, Mg, and albumin. Note: Patients with an initial magnesium \< 0.5 mmol/L (1.2 mg/dl) may receive corrective magnesium supplementation but should continue to receive either prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (e.g., magnesium oxide) at the investigator's discretion. * Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control; * Patients must provide study specific informed consent prior to study entry, including consent for mandatory tissue submission for EGFR and for oropharyngeal patients, HPV analyses. Conditions for Patient Ineligibility * Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; noninvasive cancers (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) are permitted even if diagnosed and treated \< 3 years ago. Patients with simultaneous primaries or bilateral tumors are excluded, with the exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0 resected differentiated thyroid carcinoma, who are eligible. * Per the operative and/or pathology report, positive margin(s) \[defined as tumor present at the cut or inked edge of the tumor\], nodal extracapsular extension, and/or gross residual disease after surgery; Note: Patients whose tumors had focally positive margins in the main specimen but negative margins from re-excised samples in the region of the positive margin are eligible. * Prior systemic chemotherapy or anti-EGF therapy for the study cancer; note: prior chemotherapy or anti-EGF therapy for a different cancer is allowable. * Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields; * Severe, active co-morbidity, defined as follows: * Unstable angina and/or congestive heart failure requiring hospitalization within 6 months prior to registration; * Transmural myocardial infarction within 6 months prior to registration; * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; * Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; * Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to require oxygen therapy within 1 year prior to registration; * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol. * Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note: HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients. * Grade 3-4 electrolyte abnormalities (CTCAE v4): * Serum calcium (ionized or adjusted for albumin) \< 7 mg/dl (1.75 mmol/L) or \>12.5 mg/dl (\> 3.1 mmol/L) despite intervention to normalize levels; * Glucose \< 40 mg/dl (\< 2.2 mmol/L) or \> 250 mg/dl (\> 14mmol/L); * Magnesium \< 0.9 mg/dl (\< 0.4 mmol/L) or \> 3 mg/dl (\> 1.23 mmol/L) despite intervention to normalize levels; * Potassium \< 3.0 mmol/L or \> 6 mmol/L despite intervention to normalize levels; * Sodium \< 130 mmol/L or \> 155 mmol/L despite intervention to normalize levels. * Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. * Prior allergic reaction to cetuximab.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Alive (Overall Survival) | From randomization to date of death or last follow-up. Maximum follow-up at time of analysis was 12.1 years. | Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Analysis occurred after all participants had potentially been on study for at least 5 years. The distributions of survival times are compared, which is reported in the statistical analysis results. Five-year rates are provided. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥ Grade 3 Acute Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | From start of radiation therapy to 90 days | Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Adverse events (AEs) assessed to be definitely, probably, or possibly related to protocol treatment were included. If relationship was missing, it was assumed to be definitely, probably, or possibly related to protocol treatment. Acute adverse events are those occurring within 90 days of the start of radiation therapy. |
| Percentage of Participants With Other ≥ Grade 3 Adverse Events Related to Protocol Treatment | From start of radiation therapy to 90 days. | Adverse events other than dysphagia, dermatitis radiation, and rash acneiform. Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Adverse events (AEs) assessed to be definitely, probably, or possibly related to protocol treatment were included. If relationship was missing, it was assumed to be definitely, probably, or possibly related to protocol treatment. Acute adverse events are those occurring within 90 days of the start of radiation therapy. |
| Percentage of Participants With ≥ Grade 3 Late Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | From 91 days after start of radiation therapy to date of last reported follow-up. Maximum follow-up at time of analysis was 12.1 years. | Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Adverse events assessed to be definitely, probably, or possibly related to protocol treatment were included. If relationship was missing, it was assumed to be definitely, probably, or possibly related to protocol treatment. Late adverse events are those occurring after days from the start of radiation therapy. |
| Percentage of Participants With Other ≥ Grade 3 Late Adverse Events Related to Protocol Treatment | From 91 days after start of radiation therapy to date of last reported follow-up. Maximum follow-up at time of analysis was 12.1 years. | Adverse events other than dysphagia, dermatitis radiation, and rash acneiform. Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Adverse events (AEs) assessed to be definitely, probably, or possibly related to protocol treatment were included. If relationship was missing, it was assumed to be definitely, probably, or possibly related to protocol treatment. Late adverse events are those occurring after days from the start of radiation therapy. |
| Disease-free Survival | From randomization to date of LRR, DM, death or last known follow-up, whichever occurred first. Maximum follow-up at time of analysis was 12.1 years. | Disease is defined as local-regional progression/recurrence (LRR) or distant metastasis (DM). LRR is defined as recurrent cancer in the tumor bed and/or neck not clearly attributable to a second primary neoplasm; both imaging and biopsy confirmation are strongly recommended. DM is defined as clear evidence of distant metastases; biopsy is recommended where possible. Disease-free survival time is defined as time from randomization to the date of first disease, death, or last known follow-up (censored), whichever occurred first. Disease-free survival rates are estimated using the Kaplan-Meier method. Analysis occurred after all participants had potentially been on study for at least 5 years. The distributions of disease-free survival times are compared, which is reported in the statistical analysis results. Five-year rates are provided. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Alive (Overall Survival) by Ethnicity | From randomization to date of death or last follow-up. Maximum follow-up at time of analysis was 12.1 years. | NIH-required analysis. Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Analysis occurred after all participants had potentially been on study for at least 5 years. The distributions of survival times are compared, which is reported in the statistical analysis results. Five-year rates are provided. |
| Xerostomia as Measured by University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) at Baseline and at 3, 12, and 24 Months | From randomization to 2 years. | — |
| Percentage of Participants Alive (Overall Survival) by Race | From randomization to date of death or last follow-up. Maximum follow-up at time of analysis was 12.1 years. | NIH-required analysis. Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Analysis occurred after all participants had potentially been on study for at least 5 years. The distributions of survival times are compared, which is reported in the statistical analysis results. Five-year rates are provided. |
| Swallowing as Measured by the Normalcy of Diet Subscale of the Performance Status Scale for Head and Neck Cancer (PSS-HN) at Baseline and at 3, 12, and 24 Months | From randomization to 2 years. | — |
| Skin Toxicity as Measured by the Dermatology Life Quality Index (DLQI) at Baseline and at 3, 12, and 24 Months | From randomization to 2 years. | — |
| Quality of Life as Measured by Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN) and EuroQol (EQ-5D) at Baseline and at 3, 12, and 24 Months | From randomization to 2 years. | — |
| Loco-regional Control | From randomization to date of failure (local or regional progression or distant progression or death) or last follow-up. Analysis occurs at the same time as the primary outcome. | — |
| Percentage of Participants Alive (Overall Survival) by Sex | From randomization to date of death or last follow-up. Maximum follow-up at time of analysis was 12.1 years. | Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Analysis occurred after all participants had potentially been on study for at least 5 years. The distributions of survival times are compared, which is reported in the statistical analysis results. Five-year rates are provided. |
Countries
Canada, China, Saudi Arabia, United States
Participant flow
Pre-assignment details
After trial registration, tissue slides from the tumor specimen were sent to the NRG Oncology biorepository for immunohistochemical analysis of epidermal growth factor receptor (EGFR) expression and (for oropharynx cancer) p16, a surrogate biomarker for human papillomavirus (HPV) positivity. From 702 registered participants, 627 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| IMRT Radiation therapy: 60 Gy intensity-modulated radiotherapy (IMRT), 2 Gy/day in 30 fractions (5 days a week for 6 weeks). | 287 |
| IMRT Plus Cetuximab Radiation therapy (RT): 60 Gy IMRT, 2 Gy/day in 30 fractions (5 days a week for 6 weeks).
Cetuximab: 400 mg/m\^2 intravenously (IV) at least 5 days prior to IMRT; 250 mg/m\^2 IV once a week for 6 weeks during RT and continuing 4 weeks after RT. | 290 |
| Total | 577 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 27 | 23 |
Baseline characteristics
| Characteristic | IMRT | IMRT Plus Cetuximab | Total |
|---|---|---|---|
| Age, Continuous | 57 years | 57.5 years | 57 years |
| Age, Customized ≤ 49 years | 62 Participants | 71 Participants | 133 Participants |
| Age, Customized 50 - 59 years | 111 Participants | 95 Participants | 206 Participants |
| Age, Customized 60 - 69 years | 91 Participants | 101 Participants | 192 Participants |
| Age, Customized ≥ 70 years | 23 Participants | 23 Participants | 46 Participants |
| Close margins of resection (centrally reviewed) Indeterminate | 1 Participants | 4 Participants | 5 Participants |
| Close margins of resection (centrally reviewed) No | 39 Participants | 33 Participants | 72 Participants |
| Close margins of resection (centrally reviewed) Unknown | 21 Participants | 30 Participants | 51 Participants |
| Close margins of resection (centrally reviewed) Yes | 226 Participants | 223 Participants | 449 Participants |
| EGFR expression High (≥ 80% of cells positive) | 246 Participants | 242 Participants | 488 Participants |
| EGFR expression Low (< 80% of cells positive) | 38 Participants | 44 Participants | 82 Participants |
| EGFR expression Not evaluable | 3 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 16 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 256 Participants | 268 Participants | 524 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 6 Participants | 15 Participants |
| Lymph node > 3cm or multiple lymph nodes (centrally reviewed) Indeterminate | 2 Participants | 0 Participants | 2 Participants |
| Lymph node > 3cm or multiple lymph nodes (centrally reviewed) No | 160 Participants | 155 Participants | 315 Participants |
| Lymph node > 3cm or multiple lymph nodes (centrally reviewed) Unknown | 6 Participants | 14 Participants | 20 Participants |
| Lymph node > 3cm or multiple lymph nodes (centrally reviewed) Yes | 119 Participants | 121 Participants | 240 Participants |
| Lymphovascular invasion (centrally reviewed) Indeterminate | 5 Participants | 5 Participants | 10 Participants |
| Lymphovascular invasion (centrally reviewed) No | 196 Participants | 179 Participants | 375 Participants |
| Lymphovascular invasion (centrally reviewed) Unknown | 13 Participants | 23 Participants | 36 Participants |
| Lymphovascular invasion (centrally reviewed) Yes | 73 Participants | 83 Participants | 156 Participants |
| Number of intermediate risk factors (centrally reviewed) 1 | 36 Participants | 46 Participants | 82 Participants |
| Number of intermediate risk factors (centrally reviewed) 2 | 121 Participants | 105 Participants | 226 Participants |
| Number of intermediate risk factors (centrally reviewed) 3 | 92 Participants | 92 Participants | 184 Participants |
| Number of intermediate risk factors (centrally reviewed) 4 | 30 Participants | 37 Participants | 67 Participants |
| Number of intermediate risk factors (centrally reviewed) 5 | 8 Participants | 9 Participants | 17 Participants |
| Number of intermediate risk factors (centrally reviewed) 6 | 0 Participants | 1 Participants | 1 Participants |
| Pathologic AJCC stage Stage III (T3, N0, M0; T1-3, N1, M0) | 63 Participants | 71 Participants | 134 Participants |
| Pathologic AJCC stage Stage II (T2, N0, M0) | 33 Participants | 38 Participants | 71 Participants |
| Pathologic AJCC stage Stage I (T1, N0, M0) | 7 Participants | 6 Participants | 13 Participants |
| Pathologic AJCC stage Stage IV (T4a, N0-2, M0; any T, N2, M0; T4b, any N, M0; any T, N3, M0; any T, Any N, M1) | 182 Participants | 171 Participants | 353 Participants |
| Pathologic AJCC stage Unknown | 2 Participants | 4 Participants | 6 Participants |
| Pathologic N stage N0 | 101 Participants | 105 Participants | 206 Participants |
| Pathologic N stage N1 | 56 Participants | 62 Participants | 118 Participants |
| Pathologic N stage N2a | 15 Participants | 13 Participants | 28 Participants |
| Pathologic N stage N2b | 88 Participants | 99 Participants | 187 Participants |
| Pathologic N stage N2c | 23 Participants | 6 Participants | 29 Participants |
| Pathologic N stage NX | 4 Participants | 5 Participants | 9 Participants |
| Pathologic T stage T1 | 54 Participants | 55 Participants | 109 Participants |
| Pathologic T stage T2 | 120 Participants | 116 Participants | 236 Participants |
| Pathologic T stage T3 | 42 Participants | 51 Participants | 93 Participants |
| Pathologic T stage T4a | 71 Participants | 68 Participants | 139 Participants |
| Perineural invasion (centrally reviewed) Indeterminate | 2 Participants | 0 Participants | 2 Participants |
| Perineural invasion (centrally reviewed) No | 161 Participants | 148 Participants | 309 Participants |
| Perineural invasion (centrally reviewed) Unknown | 10 Participants | 21 Participants | 31 Participants |
| Perineural invasion (centrally reviewed) Yes | 114 Participants | 121 Participants | 235 Participants |
| Primary site Larynx | 44 Participants | 38 Participants | 82 Participants |
| Primary site Oral cavity | 183 Participants | 184 Participants | 367 Participants |
| Primary site Oropharynx, p16-negative | 6 Participants | 8 Participants | 14 Participants |
| Primary site Oropharynx, p16-positive | 50 Participants | 55 Participants | 105 Participants |
| Primary site Oropharynx, p16 unknown | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 12 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 21 Participants | 42 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 6 Participants | 12 Participants |
| Race (NIH/OMB) White | 249 Participants | 249 Participants | 498 Participants |
| Sex: Female, Male Female | 83 Participants | 90 Participants | 173 Participants |
| Sex: Female, Male Male | 204 Participants | 200 Participants | 404 Participants |
| Smoking history Current | 21 Participants | 18 Participants | 39 Participants |
| Smoking history Former | 173 Participants | 160 Participants | 333 Participants |
| Smoking history Never | 92 Participants | 110 Participants | 202 Participants |
| Smoking history Unknown | 1 Participants | 2 Participants | 3 Participants |
| Smoking history: pack-years ≤ 10 | 139 Participants | 152 Participants | 291 Participants |
| Smoking history: pack-years > 10 | 112 Participants | 107 Participants | 219 Participants |
| T2 oral cavity with >5mm depth of invasion (centrally reviewed) No | 203 Participants | 207 Participants | 410 Participants |
| T2 oral cavity with >5mm depth of invasion (centrally reviewed) Unknown | 12 Participants | 9 Participants | 21 Participants |
| T2 oral cavity with >5mm depth of invasion (centrally reviewed) Yes | 72 Participants | 74 Participants | 146 Participants |
| T3 or microscopic T4a (centrally reviewed) No | 175 Participants | 179 Participants | 354 Participants |
| T3 or microscopic T4a (centrally reviewed) Unknown | 2 Participants | 2 Participants | 4 Participants |
| T3 or microscopic T4a (centrally reviewed) Yes | 110 Participants | 109 Participants | 219 Participants |
| Type of radiation therapy IMRT+ image-guided radiation therapy (IGRT) | 153 Participants | 128 Participants | 281 Participants |
| Type of radiation therapy Intensity-modulated radiation therapy (IMRT) | 129 Participants | 146 Participants | 275 Participants |
| Type of radiation therapy None | 5 Participants | 16 Participants | 21 Participants |
| Zubrod performance status 0 | 134 Participants | 152 Participants | 286 Participants |
| Zubrod performance status 1 | 153 Participants | 138 Participants | 291 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 97 / 287 | 87 / 290 |
| other Total, other adverse events | 278 / 282 | 275 / 276 |
| serious Total, serious adverse events | 50 / 282 | 83 / 276 |
Outcome results
Primary
Percentage of Participants Alive (Overall Survival)
Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Analysis occurred after all participants had potentially been on study for at least 5 years. The distributions of survival times are compared, which is reported in the statistical analysis results. Five-year rates are provided.
Time frame: From randomization to date of death or last follow-up. Maximum follow-up at time of analysis was 12.1 years.
Population: Randomized eligible participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT | Percentage of Participants Alive (Overall Survival) | 68.7 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) | 76.5 percentage of participants |
Comparison: This trial was designed to detect a hazard ratio (HR) of 0.74 with 80% statistical power and overall one-sided alpha of 0.025 (372 deaths) using a stratified log-rank test, assuming a control arm 3-year survival rate of 60.1%. The amended protocol based on ≥ 5 years potential follow-up projected 169 events, providing 55%, 66%, and 79% power to detect HRs of 0.71, 0.68, and 0.64, respectively, using the original one-sided alpha of 0.0183 the final analysis.p-value: 0.074795% CI: [0.6, 1.08]Log Rank
Secondary
Disease-free Survival
Disease is defined as local-regional progression/recurrence (LRR) or distant metastasis (DM). LRR is defined as recurrent cancer in the tumor bed and/or neck not clearly attributable to a second primary neoplasm; both imaging and biopsy confirmation are strongly recommended. DM is defined as clear evidence of distant metastases; biopsy is recommended where possible. Disease-free survival time is defined as time from randomization to the date of first disease, death, or last known follow-up (censored), whichever occurred first. Disease-free survival rates are estimated using the Kaplan-Meier method. Analysis occurred after all participants had potentially been on study for at least 5 years. The distributions of disease-free survival times are compared, which is reported in the statistical analysis results. Five-year rates are provided.
Time frame: From randomization to date of LRR, DM, death or last known follow-up, whichever occurred first. Maximum follow-up at time of analysis was 12.1 years.
Population: Randomized eligible participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT | Disease-free Survival | 63.6 percentage of participants |
| IMRT Plus Cetuximab | Disease-free Survival | 71.7 percentage of participants |
p-value: 0.016895% CI: [0.57, 0.98]Log Rank
Secondary
Percentage of Participants With ≥ Grade 3 Acute Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment
Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Adverse events (AEs) assessed to be definitely, probably, or possibly related to protocol treatment were included. If relationship was missing, it was assumed to be definitely, probably, or possibly related to protocol treatment. Acute adverse events are those occurring within 90 days of the start of radiation therapy.
Time frame: From start of radiation therapy to 90 days
Population: Randomized eligible participants who started protocol treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT | Percentage of Participants With ≥ Grade 3 Acute Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dysphagia | 13.1 percentage of participants |
| IMRT | Percentage of Participants With ≥ Grade 3 Acute Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dry mouth (xerostomia) | 3.5 percentage of participants |
| IMRT | Percentage of Participants With ≥ Grade 3 Acute Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dermatitis radiation | 6.4 percentage of participants |
| IMRT | Percentage of Participants With ≥ Grade 3 Acute Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Rash acneiform | 0.0 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants With ≥ Grade 3 Acute Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Rash acneiform | 13.4 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants With ≥ Grade 3 Acute Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dysphagia | 21.7 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants With ≥ Grade 3 Acute Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dermatitis radiation | 17.0 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants With ≥ Grade 3 Acute Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dry mouth (xerostomia) | 1.8 percentage of participants |
Comparison: Dysphagiap-value: 0.0075Fisher Exact
Comparison: Dry mouthp-value: 0.2955Fisher Exact
Comparison: Dermatitis radiationp-value: 0.0001Fisher Exact
Comparison: Rach acneiformp-value: <0.0001Fisher Exact
Secondary
Percentage of Participants With ≥ Grade 3 Late Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment
Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Adverse events assessed to be definitely, probably, or possibly related to protocol treatment were included. If relationship was missing, it was assumed to be definitely, probably, or possibly related to protocol treatment. Late adverse events are those occurring after days from the start of radiation therapy.
Time frame: From 91 days after start of radiation therapy to date of last reported follow-up. Maximum follow-up at time of analysis was 12.1 years.
Population: Randomized eligible participants who started protocol treatment and had follow-up data at or after day 91 from start of radiation therapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT | Percentage of Participants With ≥ Grade 3 Late Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dysphagia | 8.6 percentage of participants |
| IMRT | Percentage of Participants With ≥ Grade 3 Late Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dry mouth (xerostomia) | 3.2 percentage of participants |
| IMRT | Percentage of Participants With ≥ Grade 3 Late Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dermatitis radiation | 1.4 percentage of participants |
| IMRT | Percentage of Participants With ≥ Grade 3 Late Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Rash acneiform | 0.0 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants With ≥ Grade 3 Late Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Rash acneiform | 1.5 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants With ≥ Grade 3 Late Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dysphagia | 12.3 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants With ≥ Grade 3 Late Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dermatitis radiation | 2.2 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants With ≥ Grade 3 Late Dysphagia, Dry Mouth, or Skin Toxicity Related to Protocol Treatment | Dry mouth (xerostomia) | 1.5 percentage of participants |
Comparison: Dysphagiap-value: 0.1641Fisher Exact
Comparison: Dry mouthp-value: 0.2623Fisher Exact
Comparison: Dermatitis radiationp-value: 0.5378Fisher Exact
Comparison: Rash acneiformp-value: 0.057Fisher Exact
Secondary
Percentage of Participants With Other ≥ Grade 3 Adverse Events Related to Protocol Treatment
Adverse events other than dysphagia, dermatitis radiation, and rash acneiform. Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Adverse events (AEs) assessed to be definitely, probably, or possibly related to protocol treatment were included. If relationship was missing, it was assumed to be definitely, probably, or possibly related to protocol treatment. Acute adverse events are those occurring within 90 days of the start of radiation therapy.
Time frame: From start of radiation therapy to 90 days.
Population: Randomized eligible participants who started protocol treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT | Percentage of Participants With Other ≥ Grade 3 Adverse Events Related to Protocol Treatment | 33.0 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants With Other ≥ Grade 3 Adverse Events Related to Protocol Treatment | 64.1 percentage of participants |
p-value: <0.0001Fisher Exact
Secondary
Percentage of Participants With Other ≥ Grade 3 Late Adverse Events Related to Protocol Treatment
Adverse events other than dysphagia, dermatitis radiation, and rash acneiform. Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Adverse events (AEs) assessed to be definitely, probably, or possibly related to protocol treatment were included. If relationship was missing, it was assumed to be definitely, probably, or possibly related to protocol treatment. Late adverse events are those occurring after days from the start of radiation therapy.
Time frame: From 91 days after start of radiation therapy to date of last reported follow-up. Maximum follow-up at time of analysis was 12.1 years.
Population: Randomized eligible participants who started protocol treatment and had follow-up data at or after day 91 from start of radiation therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT | Percentage of Participants With Other ≥ Grade 3 Late Adverse Events Related to Protocol Treatment | 20.8 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants With Other ≥ Grade 3 Late Adverse Events Related to Protocol Treatment | 26.1 percentage of participants |
p-value: 0.1575Fisher Exact
Other Pre-specified
Loco-regional Control
Time frame: From randomization to date of failure (local or regional progression or distant progression or death) or last follow-up. Analysis occurs at the same time as the primary outcome.
Other Pre-specified
Percentage of Participants Alive (Overall Survival) by Ethnicity
NIH-required analysis. Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Analysis occurred after all participants had potentially been on study for at least 5 years. The distributions of survival times are compared, which is reported in the statistical analysis results. Five-year rates are provided.
Time frame: From randomization to date of death or last follow-up. Maximum follow-up at time of analysis was 12.1 years.
Population: Randomized eligible participants. Data were stratified by ethnicity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT | Percentage of Participants Alive (Overall Survival) by Ethnicity | Hispanic or Latino | 81.8 percentage of participants |
| IMRT | Percentage of Participants Alive (Overall Survival) by Ethnicity | Not Hispanic or Latino | 66.9 percentage of participants |
| IMRT | Percentage of Participants Alive (Overall Survival) by Ethnicity | Unknown or Not Reported | 88.9 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) by Ethnicity | Hispanic or Latino | 80.0 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) by Ethnicity | Not Hispanic or Latino | 76.2 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) by Ethnicity | Unknown or Not Reported | 83.3 percentage of participants |
Other Pre-specified
Percentage of Participants Alive (Overall Survival) by Race
NIH-required analysis. Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Analysis occurred after all participants had potentially been on study for at least 5 years. The distributions of survival times are compared, which is reported in the statistical analysis results. Five-year rates are provided.
Time frame: From randomization to date of death or last follow-up. Maximum follow-up at time of analysis was 12.1 years.
Population: Randomized eligible participants. Data were stratified by race.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT | Percentage of Participants Alive (Overall Survival) by Race | Unknown for Not Reported | 83.3 percentage of participants |
| IMRT | Percentage of Participants Alive (Overall Survival) by Race | Asian | 53.6 percentage of participants |
| IMRT | Percentage of Participants Alive (Overall Survival) by Race | Native Hawaiian or Other Pacific Islander | 0 percentage of participants |
| IMRT | Percentage of Participants Alive (Overall Survival) by Race | Black or African American | 57.9 percentage of participants |
| IMRT | Percentage of Participants Alive (Overall Survival) by Race | White | 70.1 percentage of participants |
| IMRT | Percentage of Participants Alive (Overall Survival) by Race | More than one race | 50.0 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) by Race | American Indian or Alaska Native | 0 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) by Race | Black or African American | 69.6 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) by Race | Asian | 91.7 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) by Race | Unknown for Not Reported | 80.0 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) by Race | White | 76.8 percentage of participants |
Other Pre-specified
Percentage of Participants Alive (Overall Survival) by Sex
Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Analysis occurred after all participants had potentially been on study for at least 5 years. The distributions of survival times are compared, which is reported in the statistical analysis results. Five-year rates are provided.
Time frame: From randomization to date of death or last follow-up. Maximum follow-up at time of analysis was 12.1 years.
Population: Randomized eligible participants. Data were stratified by sex.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT | Percentage of Participants Alive (Overall Survival) by Sex | Female | 75.3 percentage of participants |
| IMRT | Percentage of Participants Alive (Overall Survival) by Sex | Male | 65.9 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) by Sex | Female | 72.1 percentage of participants |
| IMRT Plus Cetuximab | Percentage of Participants Alive (Overall Survival) by Sex | Male | 78.5 percentage of participants |
Other Pre-specified
Quality of Life as Measured by Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN) and EuroQol (EQ-5D) at Baseline and at 3, 12, and 24 Months
Time frame: From randomization to 2 years.
Other Pre-specified
Skin Toxicity as Measured by the Dermatology Life Quality Index (DLQI) at Baseline and at 3, 12, and 24 Months
Time frame: From randomization to 2 years.
Other Pre-specified
Swallowing as Measured by the Normalcy of Diet Subscale of the Performance Status Scale for Head and Neck Cancer (PSS-HN) at Baseline and at 3, 12, and 24 Months
Time frame: From randomization to 2 years.
Other Pre-specified
Xerostomia as Measured by University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) at Baseline and at 3, 12, and 24 Months
Time frame: From randomization to 2 years.