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 larynx, stage IV squamous cell carcinoma of the larynx, stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx
Brief summary
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Cisplatin may also make tumor cells more sensitive to radiation therapy. 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. Giving radiation therapy and cisplatin together with cetuximab may kill more tumor cells. It is not yet known whether radiation therapy and cisplatin are more effective with or without cetuximab in treating head and neck cancer. PURPOSE: This randomized phase III trial is studying radiation therapy, cisplatin, and cetuximab to see how well they work compared to radiation therapy and cisplatin in treating patients with stage III or stage IV head and neck cancer.
Detailed description
OBJECTIVES: Primary * Evaluate whether the addition of cetuximab to a concurrent radiation-cisplatin regimen will improve progression-free survival in patients with stage III or IV squamous cell carcinoma of the oropharynx, hypopharynx, or larynx. Secondary * Determine the impact of the addition of cetuximab to a concurrent radiation-cisplatin regimen on overall survival, local-regional control, acute and late toxic effects, quality of life, and health utilities in these patients. * Correlate the expression of epidermal growth factor receptor (EGFR) and its down-stream molecules with outcome in patients participating in this component of the trial. * Correlate pre-treatment positron emission tomography (PET) scan findings with progression-free survival, overall survival, and local-regional control in patients participating in this component of the trial. * Correlate post-treatment PET scan findings with nodal response and nodal relapse in patients participating in this component of the trial. OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified according to primary site (larynx vs non-larynx), nodal stage (N0 vs N1, N2a, N2b vs N2c, N3), Zubrod performance status (0 vs 1), use of intensity modulated radiotherapy (IMRT) (no vs yes), and pre-treatment PET/CT scan (no vs yes). Patients are randomized to 1 of 2 treatment arms. NOTE: \*A neck dissection is optional for patients with multiple lymph nodes or lymph nodes \> 3 cm in diameter who achieve a complete clinical and radiographic response in the neck. Quality of life is assessed at baseline, once during the last 2 weeks of treatment, at 3 and 12 months from the start of treatment, and then annually for 4 years. After completion of study treatment, patients are followed periodically for 5 years and then annually thereafter.
Interventions
DRUGcetuximab
Cetuximab 400 mg/m\^2 IV loading dose 5-7 days before start of radiation therapy, then 250 mg/m\^2 IV weekly for 7 weeks
DRUGcisplatin
Cisplatin 100 mg/m\^2 IV on days 1 and 22
RADIATIONAccelerated Fractionation by Concomitant Boost
3DCRT 54 Gy in 30 1.8 Gy fractions over 6 weeks with boost 18 Gy in 12 1.5 Gy fractions for last 12 days, for a total of 72 Gy in 42 fractions over 6 weeks
RADIATIONIntensity-modulated radiation therapy
70 Gy in 35 2.0 Gy fractions over 6 weeks with 6 fractions per week (on Saturday or as second daily fraction) in 5 of the 6 weeks.
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
* Pathologically (histologically or cytologically) proven (from primary lesion and/or lymph nodes) diagnosis of squamous cell carcinoma of the oropharynx, hypopharynx, or larynx; * Selected stage III or IV disease (T2N2-3M0, T3-4 any N M0); Note: Patients with T1, any N, or T2N1 tumors are not eligible. * Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: * History/physical examination within 4 weeks prior to registration, including assessment of weight and weight loss in past 6 months and an examination by a Medical Oncologist; * Chest x-ray (or Chest CT scan or PET/CT scan) within 6 weeks prior to registration; * CT scan or MRI of the head and neck (of the primary tumor and neck nodes) or PET/CT scan within 6 weeks prior to registration; see Section 6.11 for details of PET scans. Note: A PET/CT can only be used instead of a CT scan or MRI if the CT is a high quality scan with contrast. * Left ejection fraction determined by echocardiogram and/or multiple gated acquisition (MUGA) technique within 12 weeks of registration; * Zubrod Performance Status 0-1; * Age \> 18; * Adequate bone marrow function, defined as follows: * Absolute neutrophil count (ANC) \> 1,800 cells/mm3 based upon CBC/differential obtained within 2 weeks prior to registration on study; * Platelets \> 100,000 cells/mm3 based upon complete blood count (CBC)/differential obtained within 2 weeks prior to registration on study; * Hemoglobin \> 8.0 g/dl based upon CBC/differential obtained within 2 weeks prior to registration on study (Note: The use of transfusion or other intervention to achieve Hgb \> 8.0 g/dl is acceptable.) * Adequate hepatic function, defined as follows: * Bilirubin \< 1.5 mg/dl within 2 weeks prior to registration on study; For patients with Gilbert's disease as the sole cause of elevated bilirubin, please contact the PI, Dr. Ang. * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \< 2x the upper limit of normal within 2 weeks prior to registration on study; * Adequate renal function, defined as follows: * Serum creatinine \< 1.5 mg/dl within 2 weeks prior to registration * 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 = \[(140 - age) x (wt in kg)\]/\[(Serum Cr mg/dl) x (72)\] CCr female = 0.85 x (CrCl male) * Pregnancy test within 2 weeks prior to registration for women of childbearing potential; * Women of childbearing potential and male participants must agree to use a medically effective means of birth control throughout their participation in the treatment phase of the study (until at least 60 days following the last study treatment); * Patient must sign study specific informed consent prior to study entry.
Exclusion criteria
* Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; * Patients with simultaneous primaries or bilateral tumors are excluded. * Gross total excision (e.g., by tonsillectomy) of the primary tumor; however, partial removal of the tumor to alleviate an impending airway obstruction does not make the patient ineligible. * Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable; * Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields; * Primary site of tumor of oral cavity, nasopharynx, sinuses, or salivary glands; * Initial surgical treatment, excluding diagnostic biopsy of the primary site or nodal sampling of neck disease; radical or modified neck dissection is not permitted. * Severe, active co-morbidity, defined as follows: * Current uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction; * Left Ventricular Ejection Fraction \< 45%; * Transmural myocardial infarction within the last 6 months; * 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; * Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that 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. * Any uncontrolled condition, which in the opinion of the investigator, would interfere in the safe and timely completion of study procedures; * CTCAE, v. 3.0 grade 3-4 electrolyte abnormalities: * Calcium \< 7 mg/dl or \> 12.5 mg/dl; * Glucose \< 40 mg/dl or \> 250 mg/dl; * Magnesium \< 0.9 mg/dl or \> 3 mg/dl; * Potassium \< 3 mmol/L or \> 6 mmol/L; * Sodium \< 130 mmol/L or \> 155 mmol/L * Pregnant or lactating women 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 the study drug(s) involved in this protocol; * Prior therapy that specifically and directly targets the EGFR pathway; * Prior severe infusion reaction to a monoclonal antibody.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) (3-year Rate Reported) | From randomization until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.) | Progression-free survival (PFS) is defined as time from randomization to date of local, regional, or distant disease progression, or death from any cause. Patients last known to be alive without progression are censored at the date of last contact. Three-year rates were estimated by the Kaplan-Meier method. Local or regional progression is 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. Distant progression is defined as clear evidence of distant metastases. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Local-regional Failure (LRF) (3-year Rate Reported) | From randomization until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.) | Local-regional failure is defined as time from randomization to date of failure (local or regional progression), or distant disease progression, or death from any cause. Patients last known to be alive without progression are censored at the date of last contact. Distant disease progression is considered a competing risk. Local or regional progression is 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. Distant progression is defined as clear evidence of distant metastases. Three-year rates were estimated by the cumulative incidence method. |
| Rate of Mucositis Toxicity ≥ Grade 3 | From start of treatment until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.) | Grade 3 or higher Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 radiation mucositis definitely, probably, or possibly related to protocol treatment. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. |
| Rate of Other Toxicity ≥ Grade 3 (Not Mucositis) | From start of treatment until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.) | Grade 3 or higher Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 other than radiation mucositis definitely, probably, or possibly related to protocol treatment. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. |
| Rate of Patients Who Tolerated Treatment | From start of treatment to end of treatment (6-7 weeks) | A patient was considered to have tolerated treatment if radiation therapy was scored as per protocol or with acceptable variation, they received 2 cycles of cisplatin, and for arm 2, they received the initial dose of cetuximab and at least 5 weekly doses of cetuximab . |
| Rate of Deaths ≤ 30 Days After Discontinuation of Protocol Treatment | From start of treatment to 30 days after the end of treatment | Patients who died during treatment or within 30 days after the end of treatment |
| Overall Survival (OS) (3-year Rate Reported) | From randomization until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.) | Overall survival is defined as time from randomization to date of death from any cause. Patients last known to be alive are censored at the date of last contact. Three-year rates were estimated by the Kaplan-Meier method. |
| Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | 3 months and 12 months | The PSS-HN is a clinician rated instrument consisting of assessment of three functions (subscales): Normalcy of Diet, Eating in Public, and Understandability of Speech. The interviewer rates the patient on each scale based on the patient's responses to targeted questions. Scores on each subscale range from 0-100, with higher scores indicating better performance. It has been demonstrated to be reliable and valid in head and neck cancer patients.The site research nurse or clinical research associate (CRA) will determine the score on each of the subscales by performing a clinical evaluation and unstructured interview format. The PSS-HN takes approximately 5 minutes to complete. |
| Quality of Life as Measured by Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-HN) at 12 Months | Baseline and 12 months | The Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN) is a 10-item self-report instrument designed to measure multidimensional quality of life in patients with head and neck cancer. It is to be administered with the FACT-General. There are 5 responses options, with 0=Not a lot and 4=Very much. All items are added together to obtain a total score which ranges from 0-40. Certain items must be reversed before it is added by subtracting the response from 4. It requires at least 50% of the items to be completed while the overall response rate of the FACT-HN including the FACT-G must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicated better QOL. Change from baseline to 12 months (12 months - baseline) is reported. |
| Correlation of Expression of Epidermal Growth Factor Receptor (EGFR) With PFS, OS, and LRF | From randomization until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.) | EGFR expression is categorized as high (\>/=80%) and low (\<80%) in order to compare outcome by favorable and unfavorable risk group, per protocol. Times are measured from randomization. Overall survival is defined as time from randomization to date of death from any cause. PFS is time to loco-regional progression (LRP), distant disease progression (DDP), or death. LRF is time to LRP, DDP, or death, with DDP considered a competing risk. Patients last known to be alive without event are censored at the date of last contact. LRP is 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. DDP is defined as clear evidence of distant metastases. Three-year LRF rates were estimated by the cumulative incidence method. Three-year PFS and OS rates were estimated by the Kaplan-Meier method. |
| Correlation of Pre-treatment Positron Emission Tomography (PET)/CT Maximum Standardized Uptake Value (SUVmax) With PFS, OS, and LRF | From randomization until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.) | SUVmax is categorized as high (\>median) and low (\</=median). All times are measured from randomization. Overall survival is defined as time from randomization to date of death from any cause. PFS is time to loco-regional failure (LRP), distant disease progression (DDP), or death. LRF is time to LRP, DDP, or death, with DDP considered a competing risk. Patients last known to be alive without event are censored at the date of last contact. LRP is 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. DDP is defined as clear evidence of distant metastases. Three-year LRF rates were estimated by the cumulative incidence method. Three-year PFS and OS rates were estimated by the Kaplan-Meier method. |
| 2-year Nodal Relapse Rates in Clinical N2-3 Patients by Post-treatment PET/CT Finding and Nodal Response | From randomization to 2 years | Patients are grouped by the combination of clinical nodal response status and the post-treatment PET/CT finding (negative or positive). Nodal relapse rate is calculated for each group by the cumulative incidence method. Relapse is defined as reappearance of tumor after complete response. If possible, relapse should be confirmed by biopsy. |
| Quality of Life as Measured by European Quality of Life Questionnaire (EQ-5D) | 3 months and 12 months | The EQ-5D is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 3 problem levels (1-none, 2-moderate, 3-extreme). Health states are defined by the combination of the leveled responses to the 5 dimensions, generating 243 health states to which unconsciousness and death are added. The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm 10-point interval scale. Worst imaginable health state is scored as 0 at the bottom of the scale, and best imaginable health state is scored as 100 at the top. Both the 5-item index score and the VAS score are transformed into a utility score between 0 (worst health state) and 1 (best health state). |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RT + Cisplatin Radiation therapy (RT) as accelerated fractionation by concomitant boost (AFX-CB) or intensity-modulated radiation therapy (IMRT) plus cisplatin | 447 |
| RT + Cisplatin + Cetuximab Radiation therapy (RT) as accelerated fractionation by concomitant boost (AFX-CB) or intensity-modulated radiation therapy (IMRT) plus cisplatin plus cetuximab | 444 |
| Total | 891 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol Violation | 22 | 25 |
Baseline characteristics
| Characteristic | RT + Cisplatin | Total | RT + Cisplatin + Cetuximab |
|---|---|---|---|
| Age, Continuous | 57 years | 57 years | 58 years |
| Sex: Female, Male Female | 60 Participants | 105 Participants | 45 Participants |
| Sex: Female, Male Male | 387 Participants | 786 Participants | 399 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 442 / 447 | 433 / 444 |
| serious Total, serious adverse events | 208 / 447 | 237 / 444 |
Outcome results
Primary
Progression-free Survival (PFS) (3-year Rate Reported)
Progression-free survival (PFS) is defined as time from randomization to date of local, regional, or distant disease progression, or death from any cause. Patients last known to be alive without progression are censored at the date of last contact. Three-year rates were estimated by the Kaplan-Meier method. Local or regional progression is 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. Distant progression is defined as clear evidence of distant metastases.
Time frame: From randomization until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.)
Population: Randomized eligible patients with follow-up data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin | Progression-free Survival (PFS) (3-year Rate Reported) | 61.2 percentage of participants |
| RT + Cisplatin + Cetuximab | Progression-free Survival (PFS) (3-year Rate Reported) | 58.9 percentage of participants |
Comparison: A total of 945 patients were required (900 analyzable) to test for a 25% reduction in the hazard associated with progression-free survival with 84% statistical power using a one-sided log-rank test at the 0.025 significance level (0.0238 after 3 interim analyses).p-value: 0.7695% CI: [0.88, 1.32]Log Rank
Secondary
2-year Nodal Relapse Rates in Clinical N2-3 Patients by Post-treatment PET/CT Finding and Nodal Response
Patients are grouped by the combination of clinical nodal response status and the post-treatment PET/CT finding (negative or positive). Nodal relapse rate is calculated for each group by the cumulative incidence method. Relapse is defined as reappearance of tumor after complete response. If possible, relapse should be confirmed by biopsy.
Time frame: From randomization to 2 years
Population: Randomized eligible N2-3 patients with follow-up and PET data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin | 2-year Nodal Relapse Rates in Clinical N2-3 Patients by Post-treatment PET/CT Finding and Nodal Response | 3.9 percentage of participants |
| RT + Cisplatin + Cetuximab | 2-year Nodal Relapse Rates in Clinical N2-3 Patients by Post-treatment PET/CT Finding and Nodal Response | 33.3 percentage of participants |
| Clinical CR + Positive PET | 2-year Nodal Relapse Rates in Clinical N2-3 Patients by Post-treatment PET/CT Finding and Nodal Response | 16.7 percentage of participants |
| No Clinical CR + Positive PET | 2-year Nodal Relapse Rates in Clinical N2-3 Patients by Post-treatment PET/CT Finding and Nodal Response | 11.1 percentage of participants |
Secondary
Correlation of Expression of Epidermal Growth Factor Receptor (EGFR) With PFS, OS, and LRF
EGFR expression is categorized as high (\>/=80%) and low (\<80%) in order to compare outcome by favorable and unfavorable risk group, per protocol. Times are measured from randomization. Overall survival is defined as time from randomization to date of death from any cause. PFS is time to loco-regional progression (LRP), distant disease progression (DDP), or death. LRF is time to LRP, DDP, or death, with DDP considered a competing risk. Patients last known to be alive without event are censored at the date of last contact. LRP is 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. DDP is defined as clear evidence of distant metastases. Three-year LRF rates were estimated by the cumulative incidence method. Three-year PFS and OS rates were estimated by the Kaplan-Meier method.
Time frame: From randomization until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.)
Population: Randomized eligible patients with follow-up and EGFR data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RT + Cisplatin | Correlation of Expression of Epidermal Growth Factor Receptor (EGFR) With PFS, OS, and LRF | Progression-free survival (PFS) | 63.5 percentage of participants |
| RT + Cisplatin | Correlation of Expression of Epidermal Growth Factor Receptor (EGFR) With PFS, OS, and LRF | Overall survival (OS) | 76.7 percentage of participants |
| RT + Cisplatin | Correlation of Expression of Epidermal Growth Factor Receptor (EGFR) With PFS, OS, and LRF | Loco-regional failure (LRF) | 21.7 percentage of participants |
| RT + Cisplatin + Cetuximab | Correlation of Expression of Epidermal Growth Factor Receptor (EGFR) With PFS, OS, and LRF | Progression-free survival (PFS) | 60.3 percentage of participants |
| RT + Cisplatin + Cetuximab | Correlation of Expression of Epidermal Growth Factor Receptor (EGFR) With PFS, OS, and LRF | Overall survival (OS) | 75.0 percentage of participants |
| RT + Cisplatin + Cetuximab | Correlation of Expression of Epidermal Growth Factor Receptor (EGFR) With PFS, OS, and LRF | Loco-regional failure (LRF) | 19.2 percentage of participants |
Comparison: Progression-free survival is compared between favorable risk and unfavorable risk groups.p-value: 0.695% CI: [0.79, 1.51]Log Rank
Comparison: Overall survival is compared between favorable risk and unfavorable risk groups.p-value: 0.3795% CI: [0.81, 1.76]Log Rank
Comparison: Local-regional failurep-value: 0.7695% CI: [0.6, 1.46]Log Rank
Secondary
Correlation of Pre-treatment Positron Emission Tomography (PET)/CT Maximum Standardized Uptake Value (SUVmax) With PFS, OS, and LRF
SUVmax is categorized as high (\>median) and low (\</=median). All times are measured from randomization. Overall survival is defined as time from randomization to date of death from any cause. PFS is time to loco-regional failure (LRP), distant disease progression (DDP), or death. LRF is time to LRP, DDP, or death, with DDP considered a competing risk. Patients last known to be alive without event are censored at the date of last contact. LRP is 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. DDP is defined as clear evidence of distant metastases. Three-year LRF rates were estimated by the cumulative incidence method. Three-year PFS and OS rates were estimated by the Kaplan-Meier method.
Time frame: From randomization until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.)
Population: Randomized eligible N2-3 patients with follow-up and PET data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RT + Cisplatin | Correlation of Pre-treatment Positron Emission Tomography (PET)/CT Maximum Standardized Uptake Value (SUVmax) With PFS, OS, and LRF | Progression-free Survival (PFS) | 55.9 percentage of participants |
| RT + Cisplatin | Correlation of Pre-treatment Positron Emission Tomography (PET)/CT Maximum Standardized Uptake Value (SUVmax) With PFS, OS, and LRF | Overall Survival (OS) | 85.3 percentage of participants |
| RT + Cisplatin | Correlation of Pre-treatment Positron Emission Tomography (PET)/CT Maximum Standardized Uptake Value (SUVmax) With PFS, OS, and LRF | Loco-regional failure (LRF) | 32.4 percentage of participants |
| RT + Cisplatin + Cetuximab | Correlation of Pre-treatment Positron Emission Tomography (PET)/CT Maximum Standardized Uptake Value (SUVmax) With PFS, OS, and LRF | Progression-free Survival (PFS) | 85.3 percentage of participants |
| RT + Cisplatin + Cetuximab | Correlation of Pre-treatment Positron Emission Tomography (PET)/CT Maximum Standardized Uptake Value (SUVmax) With PFS, OS, and LRF | Overall Survival (OS) | 91.2 percentage of participants |
| RT + Cisplatin + Cetuximab | Correlation of Pre-treatment Positron Emission Tomography (PET)/CT Maximum Standardized Uptake Value (SUVmax) With PFS, OS, and LRF | Loco-regional failure (LRF) | 11.8 percentage of participants |
Comparison: Progression-free survival is compared between low and high SUVmax groups.p-value: 0.0195% CI: [0.12, 0.75]Log Rank
Comparison: Overall survival (OS) is compared between low and high SUVmax groups.p-value: 0.195% CI: [0.12, 1.2]Log Rank
Comparison: Loco-regional control (LRC) is compared between low and high SUVmax groups.p-value: 0.0495% CI: [0.1, 0.97]Log Rank
Secondary
Local-regional Failure (LRF) (3-year Rate Reported)
Local-regional failure is defined as time from randomization to date of failure (local or regional progression), or distant disease progression, or death from any cause. Patients last known to be alive without progression are censored at the date of last contact. Distant disease progression is considered a competing risk. Local or regional progression is 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. Distant progression is defined as clear evidence of distant metastases. Three-year rates were estimated by the cumulative incidence method.
Time frame: From randomization until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.)
Population: Randomized eligible patients with follow-up data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin | Local-regional Failure (LRF) (3-year Rate Reported) | 19.9 percentage of participants |
| RT + Cisplatin + Cetuximab | Local-regional Failure (LRF) (3-year Rate Reported) | 25.9 percentage of participants |
p-value: 0.9795% CI: [0.99, 1.7]Log Rank
Secondary
Overall Survival (OS) (3-year Rate Reported)
Overall survival is defined as time from randomization to date of death from any cause. Patients last known to be alive are censored at the date of last contact. Three-year rates were estimated by the Kaplan-Meier method.
Time frame: From randomization until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.)
Population: Randomized eligible patients with follow-up data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin | Overall Survival (OS) (3-year Rate Reported) | 72.9 percentage of participants |
| RT + Cisplatin + Cetuximab | Overall Survival (OS) (3-year Rate Reported) | 75.8 percentage of participants |
Comparison: Arms were compared using a one-sided log-rank test at the 0.025 significance level.p-value: 0.3295% CI: [0.74, 1.21]Log Rank
Secondary
Quality of Life as Measured by Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-HN) at 12 Months
The Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN) is a 10-item self-report instrument designed to measure multidimensional quality of life in patients with head and neck cancer. It is to be administered with the FACT-General. There are 5 responses options, with 0=Not a lot and 4=Very much. All items are added together to obtain a total score which ranges from 0-40. Certain items must be reversed before it is added by subtracting the response from 4. It requires at least 50% of the items to be completed while the overall response rate of the FACT-HN including the FACT-G must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicated better QOL. Change from baseline to 12 months (12 months - baseline) is reported.
Time frame: Baseline and 12 months
Population: Randomized eligible patients with baseline and 12-month FACT-HN data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RT + Cisplatin | Quality of Life as Measured by Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-HN) at 12 Months | -0.41 units on a scale | Standard Deviation 18.9 |
| RT + Cisplatin + Cetuximab | Quality of Life as Measured by Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-HN) at 12 Months | -5.11 units on a scale | Standard Deviation 22.5 |
p-value: 0.016t-test, 2 sided
Secondary
Quality of Life as Measured by European Quality of Life Questionnaire (EQ-5D)
The EQ-5D is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 3 problem levels (1-none, 2-moderate, 3-extreme). Health states are defined by the combination of the leveled responses to the 5 dimensions, generating 243 health states to which unconsciousness and death are added. The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm 10-point interval scale. Worst imaginable health state is scored as 0 at the bottom of the scale, and best imaginable health state is scored as 100 at the top. Both the 5-item index score and the VAS score are transformed into a utility score between 0 (worst health state) and 1 (best health state).
Time frame: 3 months and 12 months
Population: Randomized eligible patients with EQ-5D data at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RT + Cisplatin | Quality of Life as Measured by European Quality of Life Questionnaire (EQ-5D) | EQ-5D 3 months | 0.78 units on a scale | Standard Deviation 0.18 |
| RT + Cisplatin | Quality of Life as Measured by European Quality of Life Questionnaire (EQ-5D) | EQ-5D 12 months | 0.84 units on a scale | Standard Deviation 0.17 |
| RT + Cisplatin + Cetuximab | Quality of Life as Measured by European Quality of Life Questionnaire (EQ-5D) | EQ-5D 3 months | 0.77 units on a scale | Standard Deviation 0.15 |
| RT + Cisplatin + Cetuximab | Quality of Life as Measured by European Quality of Life Questionnaire (EQ-5D) | EQ-5D 12 months | 0.84 units on a scale | Standard Deviation 0.16 |
Comparison: 3 monthsp-value: 0.74Kolmogorov-Smirnov
Comparison: 12 monthsp-value: 0.99Kolmogorov-Smirnov
Secondary
Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50
The PSS-HN is a clinician rated instrument consisting of assessment of three functions (subscales): Normalcy of Diet, Eating in Public, and Understandability of Speech. The interviewer rates the patient on each scale based on the patient's responses to targeted questions. Scores on each subscale range from 0-100, with higher scores indicating better performance. It has been demonstrated to be reliable and valid in head and neck cancer patients.The site research nurse or clinical research associate (CRA) will determine the score on each of the subscales by performing a clinical evaluation and unstructured interview format. The PSS-HN takes approximately 5 minutes to complete.
Time frame: 3 months and 12 months
Population: Randomized eligible patients with PSS-HN data at the given time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RT + Cisplatin | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Normalcy of Diet 3 months | 0.80 proportion of participants |
| RT + Cisplatin | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Normalcy of Diet 12 months | 0.37 proportion of participants |
| RT + Cisplatin | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Public Eating 3 months | 0.62 proportion of participants |
| RT + Cisplatin | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Public Eating 12 months | 0.18 proportion of participants |
| RT + Cisplatin | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Understandability of Speech 3 months | 0.09 proportion of participants |
| RT + Cisplatin | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Understandability of Speech 12 months | 0.05 proportion of participants |
| RT + Cisplatin + Cetuximab | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Understandability of Speech 3 months | 0.08 proportion of participants |
| RT + Cisplatin + Cetuximab | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Normalcy of Diet 3 months | 0.85 proportion of participants |
| RT + Cisplatin + Cetuximab | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Public Eating 12 months | 0.23 proportion of participants |
| RT + Cisplatin + Cetuximab | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Normalcy of Diet 12 months | 0.37 proportion of participants |
| RT + Cisplatin + Cetuximab | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Understandability of Speech 12 months | 0.04 proportion of participants |
| RT + Cisplatin + Cetuximab | Quality of Life as Measured by Proportion of Patients With Performance Status Scale for Head and Neck Cancer (PSS-HN) Scores ≤ 50 | Public Eating 3 months | 0.63 proportion of participants |
Comparison: Diet 3-monthp-value: 0.13Chi-squared
Comparison: Diet 12-monthp-value: 0.87Chi-squared
Comparison: Eating 3-monthp-value: 0.39Chi-squared
Comparison: Eating 12-monthp-value: 0.16Chi-squared
Comparison: Speech 3-monthp-value: 0.81Chi-squared
Comparison: Speech 12-monthp-value: 0.67Chi-squared
Secondary
Rate of Deaths ≤ 30 Days After Discontinuation of Protocol Treatment
Patients who died during treatment or within 30 days after the end of treatment
Time frame: From start of treatment to 30 days after the end of treatment
Population: Randomized eligible patients with follow-up data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin | Rate of Deaths ≤ 30 Days After Discontinuation of Protocol Treatment | 1.8 percentage of participants |
| RT + Cisplatin + Cetuximab | Rate of Deaths ≤ 30 Days After Discontinuation of Protocol Treatment | 2.0 percentage of participants |
Secondary
Rate of Mucositis Toxicity ≥ Grade 3
Grade 3 or higher Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 radiation mucositis definitely, probably, or possibly related to protocol treatment. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time frame: From start of treatment until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.)
Population: Randomized eligible patients with follow-up data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin | Rate of Mucositis Toxicity ≥ Grade 3 | 33.3 percentage of participants |
| RT + Cisplatin + Cetuximab | Rate of Mucositis Toxicity ≥ Grade 3 | 43.2 percentage of participants |
Secondary
Rate of Other Toxicity ≥ Grade 3 (Not Mucositis)
Grade 3 or higher Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 other than radiation mucositis definitely, probably, or possibly related to protocol treatment. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time frame: From start of treatment until 434 failures have occurred, approximately 5 years from start of study. (Patients are followed until death or study termination, whichever occurs first.)
Population: Randomized eligible patients with follow-up data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin | Rate of Other Toxicity ≥ Grade 3 (Not Mucositis) | 89.3 percentage of participants |
| RT + Cisplatin + Cetuximab | Rate of Other Toxicity ≥ Grade 3 (Not Mucositis) | 91.9 percentage of participants |
Secondary
Rate of Patients Who Tolerated Treatment
A patient was considered to have tolerated treatment if radiation therapy was scored as per protocol or with acceptable variation, they received 2 cycles of cisplatin, and for arm 2, they received the initial dose of cetuximab and at least 5 weekly doses of cetuximab .
Time frame: From start of treatment to end of treatment (6-7 weeks)
Population: Randomized eligible patients with follow-up data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RT + Cisplatin | Rate of Patients Who Tolerated Treatment | 84.8 percentage of participants |
| RT + Cisplatin + Cetuximab | Rate of Patients Who Tolerated Treatment | 70.7 percentage of participants |