Head and Neck Cancer
Conditions
Keywords
stage III squamous cell carcinoma of the hypopharynx, stage IV squamous cell carcinoma of the hypopharynx, stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx, stage III squamous cell carcinoma of the larynx, stage IV squamous cell carcinoma of the larynx, stage III lymphoepithelioma of the oropharynx, stage IV lymphoepithelioma of the oropharynx
Brief summary
RATIONALE: Monoclonal antibodies such as cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as cisplatin and docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Cisplatin and docetaxel may make the tumor cells more sensitive to radiation therapy. Combining a monoclonal antibody with chemoradiotherapy and giving them after surgery may kill any remaining tumor cells. PURPOSE: This randomized phase II trial is studying adjuvant cetuximab given together with chemoradiotherapy using cisplatin to see how well it works compared to adjuvant cetuximab given together with chemoradiotherapy using docetaxel in treating patients with resected stage III or stage IV squamous cell carcinoma (cancer) or lymphoepithelioma of the head and neck.
Detailed description
OBJECTIVES: Primary * Compare disease-free survival of patients with resected stage III or IV squamous cell carcinoma or lymphoepithelioma of the head and neck treated with adjuvant cetuximab in combination with chemoradiotherapy comprising docetaxel vs cisplatin. Secondary * Compare the safety and efficacy of these regimens in these patients. * Compare locoregional control and overall survival rates in patients treated with these regimens. * Correlate epidermal growth factor receptor (total and phosphorylated), pMAPK, pAKT, Stat-3, Ki-67, cyclo-oxygenase-2, and cyclin B1 expression with outcome in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to Zubrod performance status (0 vs 1), risk category (positive margins vs high risk \[i.e., ≥ 2 positive nodes or extracapsular nodal extension\]) and use of intensity-modulated radiotherapy (no vs yes). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive cetuximab IV over 2 hours on day 1 (week 1). Patients then receive cetuximab IV over 1 hour and cisplatin IV over 1 hour before radiotherapy on days 8, 15, 22, 29, 36, and 43 (weeks 2-7). Patients undergo radiotherapy once daily, 5 days a week, beginning on day 8 for a total of 6 weeks (weeks 2-7). * Arm II: Patients receive cetuximab and undergo radiotherapy as in arm I. Patients also receive docetaxel IV over 30 minutes before radiotherapy on days 8, 15, 22, 29, 36, and 43 (weeks 2-7). Treatment in both arms continues in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years and then every 6 months for 4 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 230 patients (115 per treatment arm) will be accrued for this study within approximately 29 months.
Interventions
BIOLOGICALcetuximab
400 mg/m\^2 intravenously over 120 minutes on day 1 (week 1) followed by 250 mg/m\^2 intravenously over 60 minutes in weeks 2 through 7.
DRUGcisplatin
30 mg/m\^2 intravenously infused over over 60 minutes in weeks 2 through 7.
DRUGdocetaxel
15 mg/m\^2 intravenously infused over 30 minutes in weeks 2 through 7.
RADIATIONradiation therapy
60 Gy (2 Gy once a day, 5 times a week)
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
DISEASE CHARACTERISTICS: * Histologically confirmed squamous cell carcinoma of the head and neck meeting the following criteria: * Site of tumor origin in the oral cavity, oropharynx, larynx, or hypopharynx (excluding lip, nasopharynx, or sinuses) * Gross total resection must be completed within 7 weeks of randomization, with pathology demonstrating one or more of the following risk factors: * Histologic extracapsular nodal extension * Histologic involvement of ≥ 2 regional lymph nodes * Invasive cancer seen on microscopic evaluation of the resection margin, with no evidence of gross tumor residual. * Tonsillar cancer patients who undergo transoral excision of all gross tumor are eligible provided extracapsular nodal extension or involvement of ≥ 2 regional lymph nodes is histologically confirmed * American Joint Committee on Cancer (AJCC) pathological stage III or IV * No evidence of distant metastases * No synchronous or concurrent head and neck primary tumors PATIENT CHARACTERISTICS: Age * 18 and over Performance status * Zubrod 0-1 Life expectancy * Not specified Hematopoietic * Absolute neutrophil count ≥ 2,000/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin \> 8.0 g/dL Hepatic * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT), and alkaline phosphatase meeting 1 of the following parameters: * Alkaline phosphatase ≤ ULN AND AST or ALT ≤ 5 times ULN * Alkaline phosphatase ≤ 2.5 times ULN AND AST or ALT ≤ 1.5 times ULN * Alkaline phosphatase ≤ 5 times ULN AND AST or ALT ≤ ULN Renal * Creatinine ≤ 1.5 mg/dL Cardiovascular * No unstable angina * No uncontrolled hypertension * No myocardial infarction within the past 6 months (unless successfully treated with coronary artery bypass surgery or percutaneous transluminal coronary angioplasty) * No uncontrolled arrhythmia * No congestive heart failure * No more than 2 heart-related hospitalizations within the past year * No other active cardiac disease Pulmonary * No more than 2 hospitalizations for chronic obstructive pulmonary disease within the past year Neurologic * No pre-existing peripheral neuropathy ≥ grade 2 * No uncontrolled seizure disorder * No active neurological disease Other * No prior severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 * No other invasive malignancy within the past 3 years except nonmelanoma skin cancer * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 3 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy * No prior anti-epidermal growth factor receptor antibody therapy Chemotherapy * More than 3 years since prior cytotoxic chemotherapy Endocrine therapy * Not specified Radiotherapy * No prior head and neck radiotherapy Surgery * See Disease Characteristics Other * No prior tyrosine kinase inhibitor therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | From randomization to 2 years | Two-year rates are shown (Kaplan-Meier estimates). Disease-free survival is defined as the time from randomization to local, regional, or distant progression, second primary, or death (event) or last follow-up (censored). Response criteria as follows: No evidence of disease (NED): All patients must have no measurable tumor following surgery; Local-Regional Relapse: Recurrent cancer in the tumor bed and/or neck not clearly attributable to a second primary neoplasm; biopsy confirmation is necessary; Distant Relapse: Clear evidence of distant metastases (lung, bone, brain, etc.); Biopsy is recommended where possible. A solitary lung mass/nodule is considered a second primary neoplasm unless proven otherwise. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Tolerance | From start of treatment to end of treatment (protocol treatment lasts seven weeks). | Tolerability was defined as having received 90% of the radiation dose, 95% of the cetuximab loading dose, and at least 4 weeks of cetuximab and cisplatin or docetaxel at doses 95% of the protocol prescription. The percentage of patients determined to be tolerant of treatment are shown. |
| Frequency of Toxicity (Grade 5 and Acute Non-hematologic Grade 4) | From start of treatment to last follow-up. Analysis occurs at the time of the primary analysis. | Each regimen was monitored for excessive acute toxicity (defined as nonhematologic grade 4 toxicity within 90 days of the start of radiation or any grade 5 toxicity). The target rate was based on the observed rate from RTOG-9501/NCT00002670 of 15%. The unacceptable rate was \>30%. \[RTOG = Radiation Therapy Oncology Group\] |
| Overall Survival | From randomization to 2 years | Two-year rates are shown (Kaplan-Meier estimates). Overall survival is defined as the time from randomization to death (event) or last follow-up (censored). |
| Local-regional Control | From randomization to 2 years | Two-year rate is shown (cumulative incidence estimate). Local-regional failure is defined as the time from randomization to local-regional recurrence (event), death (competing risk), or last follow-up (censored). |
| Correlation of EGFR (Total and Phosphorylated) pMAPK, pAKT, Stat-3, KI-67, COX-2, and Cyclin B1 Expression With Local-regional Control, and Overall and Disease-free Survival | From randomization to two years | — |
| Frequency of Other Acute and Late Toxicity | From start of treatment to last follow-up. Analysis occurs at the time of the primary endpoint analysis. | Maximum grade toxicity that is definitely, probably, or possibly related to protocol treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RT + Cisplatin + Cetuximab Loading dose of cetuximab followed by radiation therapy with weekly cisplatin and cetuximab. | 97 |
| RT + Docetaxel + Cetuximab Loading dose of cetuximab followed by radiation therapy (RT) with weekly docetaxel and cetuximab. | 106 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | No protocol treatment | 2 | 0 |
| Overall Study | Protocol Violation | 15 | 11 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | RT + Cisplatin + Cetuximab | RT + Docetaxel + Cetuximab | Total |
|---|---|---|---|
| Age, Continuous | 57 years | 55 years | 56 years |
| Sex: Female, Male Female | 20 Participants | 32 Participants | 52 Participants |
| Sex: Female, Male Male | 77 Participants | 74 Participants | 151 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 97 / 97 | 105 / 106 |
| serious Total, serious adverse events | 42 / 97 | 56 / 106 |
Outcome results
Primary
Disease-free Survival
Two-year rates are shown (Kaplan-Meier estimates). Disease-free survival is defined as the time from randomization to local, regional, or distant progression, second primary, or death (event) or last follow-up (censored). Response criteria as follows: No evidence of disease (NED): All patients must have no measurable tumor following surgery; Local-Regional Relapse: Recurrent cancer in the tumor bed and/or neck not clearly attributable to a second primary neoplasm; biopsy confirmation is necessary; Distant Relapse: Clear evidence of distant metastases (lung, bone, brain, etc.); Biopsy is recommended where possible. A solitary lung mass/nodule is considered a second primary neoplasm unless proven otherwise.
Time frame: From randomization to 2 years
Population: Eligible patients who started protocol treatment and did not withdraw consent.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin + Cetuximab | Disease-free Survival | 57.3 percentage of participants |
| RT + Docetaxel + Cetuximab | Disease-free Survival | 65.9 percentage of participants |
Comparison: Using the method of Dixon and Simon, 104 analyzable patients per arm were needed to detect a ≥ 33 reduction in the hazard rate for disease-free survival compared to historical control data (the chemoradiation arm of study RTOG-9501/NCT00002670) with 80% power and one-sided log-rank test at the 0.05 level. Two-year rates were estimated by the Kaplan-Meier method. \[RTOG = Radiation Therapy Oncology Group\]p-value: 0.0595% CI: [0.54, 1.06]Log Rank
Comparison: Using the method of Dixon and Simon, 104 analyzable patients per arm were needed to detect a ≥ 33 reduction in the hazard rate for disease-free survival compared to historical control data (the chemoradiation arm of study RTOG-9501/NCT00002670) with 80% power and one-sided log-rank test at the 0.05 level. Two-year rates were estimated by the Kaplan-Meier method.p-value: 0.0195% CI: [0.5, 0.96]Log Rank
Secondary
Correlation of EGFR (Total and Phosphorylated) pMAPK, pAKT, Stat-3, KI-67, COX-2, and Cyclin B1 Expression With Local-regional Control, and Overall and Disease-free Survival
Time frame: From randomization to two years
Population: Effective and reliable assessment of nuclear expression of these receptors was not achieved and therefore no data was available for analysis.
Secondary
Frequency of Other Acute and Late Toxicity
Maximum grade toxicity that is definitely, probably, or possibly related to protocol treatment.
Time frame: From start of treatment to last follow-up. Analysis occurs at the time of the primary endpoint analysis.
Population: Eligible patients who started protocol treatment and did not withdraw consent
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RT + Cisplatin + Cetuximab | Frequency of Other Acute and Late Toxicity | Grade 2 | 10.3 percentage of participants |
| RT + Cisplatin + Cetuximab | Frequency of Other Acute and Late Toxicity | Grade 4 | 14.4 percentage of participants |
| RT + Cisplatin + Cetuximab | Frequency of Other Acute and Late Toxicity | Grade 1 | 1.0 percentage of participants |
| RT + Cisplatin + Cetuximab | Frequency of Other Acute and Late Toxicity | Grade 5 | 0.0 percentage of participants |
| RT + Cisplatin + Cetuximab | Frequency of Other Acute and Late Toxicity | Grade 3 | 74.2 percentage of participants |
| RT + Docetaxel + Cetuximab | Frequency of Other Acute and Late Toxicity | Grade 5 | 0.9 percentage of participants |
| RT + Docetaxel + Cetuximab | Frequency of Other Acute and Late Toxicity | Grade 1 | 0.0 percentage of participants |
| RT + Docetaxel + Cetuximab | Frequency of Other Acute and Late Toxicity | Grade 2 | 9.4 percentage of participants |
| RT + Docetaxel + Cetuximab | Frequency of Other Acute and Late Toxicity | Grade 3 | 73.6 percentage of participants |
| RT + Docetaxel + Cetuximab | Frequency of Other Acute and Late Toxicity | Grade 4 | 16.0 percentage of participants |
Secondary
Frequency of Toxicity (Grade 5 and Acute Non-hematologic Grade 4)
Each regimen was monitored for excessive acute toxicity (defined as nonhematologic grade 4 toxicity within 90 days of the start of radiation or any grade 5 toxicity). The target rate was based on the observed rate from RTOG-9501/NCT00002670 of 15%. The unacceptable rate was \>30%. \[RTOG = Radiation Therapy Oncology Group\]
Time frame: From start of treatment to last follow-up. Analysis occurs at the time of the primary analysis.
Population: Eligible patients who started protocol treatment and did not withdraw consent
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin + Cetuximab | Frequency of Toxicity (Grade 5 and Acute Non-hematologic Grade 4) | 9.3 percentage of participants |
| RT + Docetaxel + Cetuximab | Frequency of Toxicity (Grade 5 and Acute Non-hematologic Grade 4) | 12.3 percentage of participants |
Secondary
Local-regional Control
Two-year rate is shown (cumulative incidence estimate). Local-regional failure is defined as the time from randomization to local-regional recurrence (event), death (competing risk), or last follow-up (censored).
Time frame: From randomization to 2 years
Population: Eligible patients who started protocol treatment and did not withdraw consent.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin + Cetuximab | Local-regional Control | 19.8 percentage of participants |
| RT + Docetaxel + Cetuximab | Local-regional Control | 18.9 percentage of participants |
Comparison: Two-year failure rates were estimated by the cumulative incidence method. RTOG 0234 results were compared to historical control data (the chemoradiation arm of study RTOG-9501/NCT00002670) by 1-sided Gray's test. Hazard ratios were estimated by Cox model. \[RTOG = Radiation Therapy Oncology Group\]p-value: 0.6695% CI: [0.63, 1.76]Gray's test
Comparison: Two-year failure rates were estimated by the cumulative incidence method. RTOG 0234 results were compared to historical control data (the chemoradiation arm of study RTOG-9501/NCT00002670) by 1-sided Gray's test. Hazard ratios were estimated by Cox model.p-value: 0.8695% CI: [0.72, 1.87]Gray's test
Secondary
Overall Survival
Two-year rates are shown (Kaplan-Meier estimates). Overall survival is defined as the time from randomization to death (event) or last follow-up (censored).
Time frame: From randomization to 2 years
Population: Eligible patients who started protocol treatment and did not withdraw consent
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin + Cetuximab | Overall Survival | 68.8 percentage of participants |
| RT + Docetaxel + Cetuximab | Overall Survival | 79.2 percentage of participants |
Comparison: Two-year rates were estimated by the Kaplan-Meier method. RTOG 0234 results were compared to historical control data (the chemoradiation arm of study RTOG-9501/NCT00002670) by 1-sided log-rank test. Hazard ratios were estimated by Cox model. \[RTOG = Radiation Therapy Oncology Group\]p-value: 0.0495% CI: [0.5, 1.03]Log Rank
Comparison: Two-year rates were estimated by the Kaplan-Meier method. RTOG 0234 results were compared to historical control data (the chemoradiation arm of study RTOG-9501/NCT00002670) by 1-sided log-rank test. Hazard ratios were estimated by Cox model.p-value: 0.00195% CI: [0.39, 0.82]Log Rank
Secondary
Treatment Tolerance
Tolerability was defined as having received 90% of the radiation dose, 95% of the cetuximab loading dose, and at least 4 weeks of cetuximab and cisplatin or docetaxel at doses 95% of the protocol prescription. The percentage of patients determined to be tolerant of treatment are shown.
Time frame: From start of treatment to end of treatment (protocol treatment lasts seven weeks).
Population: Eligible patients who started protocol treatment and did not withdraw consent
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin + Cetuximab | Treatment Tolerance | 80.4 percentage of participants |
| RT + Docetaxel + Cetuximab | Treatment Tolerance | 84.9 percentage of participants |