Radiation Therapy and Cisplatin With or Without Cetuximab in Treating Patients With Stage III or Stage IV Head and Neck Cancer

Phase 3

Completed

Conditions: Head and Neck Cancer

Interventions: Drug: cisplatin
Drug: cetuximab
Radiation: Accelerated Fractionation by Concomitant Boost
Radiation: Intensity-modulated radiation therapy

Registration Number: NCT00265941

Lead Sponsor: Radiation Therapy Oncology Group

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 940

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RT + cisplatin	Accelerated Fractionation by Concomitant Boost	Radiation therapy (RT) as accelerated fractionation by concomitant boost (AFX-CB) or intensity-modulated radiation therapy (IMRT) plus cisplatin
RT + cisplatin	Intensity-modulated radiation therapy	Radiation therapy (RT) as accelerated fractionation by concomitant boost (AFX-CB) or intensity-modulated radiation therapy (IMRT) plus cisplatin
RT + cisplatin + cetuximab	Accelerated Fractionation by Concomitant Boost	Radiation therapy (RT) as accelerated fractionation by concomitant boost (AFX-CB) or intensity-modulated radiation therapy (IMRT) plus cisplatin plus cetuximab
RT + cisplatin + cetuximab	Intensity-modulated radiation therapy	Radiation therapy (RT) as accelerated fractionation by concomitant boost (AFX-CB) or intensity-modulated radiation therapy (IMRT) plus cisplatin plus cetuximab
RT + cisplatin	cisplatin	Radiation therapy (RT) as accelerated fractionation by concomitant boost (AFX-CB) or intensity-modulated radiation therapy (IMRT) plus cisplatin
RT + cisplatin + cetuximab	cetuximab	Radiation therapy (RT) as accelerated fractionation by concomitant boost (AFX-CB) or intensity-modulated radiation therapy (IMRT) plus cisplatin plus cetuximab
RT + cisplatin + cetuximab	cisplatin	Radiation therapy (RT) as accelerated fractionation by concomitant boost (AFX-CB) or intensity-modulated radiation therapy (IMRT) plus cisplatin plus cetuximab

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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
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).
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.
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.
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.

Trial Locations

Locations (369): Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
🇺🇸
Birmingham, Alabama, United States
Providence Cancer Center
🇺🇸
Anchorage, Alaska, United States
Mayo Clinic Scottsdale
🇺🇸
Scottsdale, Arizona, United States
Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
Auburn Radiation Oncology
🇺🇸
Auburn, California, United States
Alta Bates Summit Comprehensive Cancer Center
🇺🇸
Berkeley, California, United States
Peninsula Medical Center
🇺🇸
Burlingame, California, United States
Radiation Oncology Centers - Cameron Park
🇺🇸
Cameron Park, California, United States
Mercy Cancer Center at Mercy San Juan Medical Center
🇺🇸
Carmichael, California, United States
East Bay Radiation Oncology Center
🇺🇸
Castro Valley, California, United States
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Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
🇺🇸Birmingham, Alabama, United States