Phase III Trial of Radiotherapy Plus Cetuximab Versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer
Overview
- Phase
- Phase 3
- Intervention
- cisplatin
- Conditions
- Head and Neck Cancer
- Sponsor
- Radiation Therapy Oncology Group
- Enrollment
- 987
- Locations
- 369
- Primary Endpoint
- Overall Survival
- Status
- Completed
- Last Updated
- 3 months ago
Overview
Brief Summary
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. 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. 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 with cisplatin or cetuximab in treating oropharyngeal cancer.
PURPOSE: This phase III trial is studying radiation therapy with cisplatin or cetuximab to see how well it works in treating patients with oropharyngeal cancer.
Detailed Description
OBJECTIVES: Primary * To determine whether substitution of cisplatin with cetuximab will result in comparable 5-year overall survival. Secondary * To monitor and compare progression-free survival for "safety". * To compare patterns of failure (locoregional vs distant). * To compare acute toxicity profiles (and overall toxicity burden). * To compare overall quality of life (QOL) short-term (\< 6 months) and long-term (1 year). * To compare QOL Swallowing Domains short-term and long-term. * To compare clinician-reported versus patient-reported CTCAE toxicity events. * To explore differences in the cost effectiveness of cetuximab as compared to cisplatin. * To explore differences in work status and time to return to work. * To compare patient-reported changes in hearing. * To compare CTCAE v. 4 late toxicity at 1, 2, and 5 years. * To evaluate the effect of tobacco exposure (and other exposures) as measured by standardized computer-assisted self interview (CASI) on overall survival and progression-free survival. * To pilot CASI collection of patient reported outcomes in a cooperative group setting. * To determine whether specific molecular profiles are associated with overall or progression-free survival. * To investigate associations between changes in serum biomarkers or human papilloma virus (HPV)-specific cellular immune responses measured at baseline and three months with overall or progression-free survival. OUTLINE: This is a multicenter study. Patients are stratified according to T stage (T1-2 vs T 3-4), N stage (N0-2a vs N2b-3), Zubrod performance status (0 vs 1), and smoking history (≤ 10 pack-years vs \> 10 pack-years). Patients are randomized to 1 of 2 treatment arms. Patients may complete quality-of-life questionnaires and risk factors for head and neck cancer surveys at baseline, periodically during study, and at follow-up for 1 year. After completion of study therapy, patients are followed up at 1-3 months, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls).
- •Patients must be positive for p16, determined by central review prior to randomization.
- •Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving ≤ 4 nodes are permitted and considered as non-therapeutic nodal excisions. Fine needle aspirations of the neck are insufficient due to limited tissue for retrospective central review. Biopsy specimens from the primary or nodes measuring at least 3-5 mm are required.
- •Clinical stage T1-2, N2a-N3 or T3-4, any N (AJCC, 7th ed.; see Appendix III), including no distant metastases, based upon the following minimum diagnostic workup:
- •General history and physical examination by a radiation oncologist and medical oncologist within 8 weeks prior to registration;
- •Examination by an ear, nose, and throat (ENT) or head and neck surgeon, including laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 8 weeks prior to registration;
- •One of the following combinations of imaging is required within 8 weeks prior to registration:
- •A computerized tomography (CT) scan of the neck (with contrast) and a chest CT scan (with or without contrast);
- •or a magnetic resonance imaging (MRI) scan of the neck (with contrast) and a chest CT scan (with or without contrast);
- •or a CT scan of neck (with contrast) and a positron emission tomography (PET)/CT of neck and chest (with or without contrast);
Exclusion Criteria
- •Cancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip), nasopharynx, hypopharynx, or larynx, even if p16 positive, are excluded. Carcinoma of the neck of unknown primary site origin (even if p16 positive) are excluded from participation.
- •Stage T1-2, N0-1;
- •Distant metastasis or adenopathy below the clavicles;
- •Gross total excision of both primary and nodal disease; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease.
- •Simultaneous primaries or bilateral tumors;
- •Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible);
- •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;
- •Severe, active co-morbidity, defined as follows:
- •9.1 Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months;
Arms & Interventions
IMRT + Cisplatin
Intensity-modulated radiotherapy (IMRT) with concurrent cisplatin
Intervention: cisplatin
IMRT + Cisplatin
Intensity-modulated radiotherapy (IMRT) with concurrent cisplatin
Intervention: IMRT
IMRT + Cetuximab
Intensity-modulated radiotherapy (IMRT) with concurrent cetuximab
Intervention: cetuximab
IMRT + Cetuximab
Intensity-modulated radiotherapy (IMRT) with concurrent cetuximab
Intervention: IMRT
Outcomes
Primary Outcomes
Overall Survival
Time Frame: From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.
An event for overall survival is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is hazard ratio, which is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.
Secondary Outcomes
- Progression-free Survival(From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.)
- Time to Local-regional Failure(From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.)
- Time to Distant Metastasis(From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.)
- Time to Secondary Primary Cancer(From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.)
- Distribution of First Progression Events(From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.)
- Percentage of Participants Experiencing Early Death(From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.)
- Percentage of Participants With Acute Grade 3-4 Treatment-related Adverse Events: During Treatment(From start of treatment to end of treatment, approximately 6 weeks)
- Percentage of Participants With Acute Grade 3-4 Treatment-related Adverse Events: 1 Month After End of Study Treatment(From start of treatment to approximately 2.5 months (1 month after the end of treatment))
- Percentage of Participants With Acute Grade 3-4 Treatment-related Adverse Events: 3 Months After the End of Study Treatment(From start of treatment to approximately 4.5 months (3 months after the end of treatment))
- Percentage of Participants With Acute Grade 3-4 Treatment-related Adverse Events: 6 Months After the End of Study Treatment(From start of treatment to approximately 7.5 months (6 months after the end of treatment))
- Percentage of Participants With Late Grade 3-4 Treatment-related Adverse Events: 1 Year After the End of Study Treatment(From start of treatment to approximately 13.5 months (one year after the end of treatment))
- Percentage of Participants With Late Grade 3-4 Treatment-related Adverse Events: 2 Years After the End of Study Treatment(From 180 days after end of treatment to two years after end of treatment.)
- Percentage of Participants With Late Grade 3-4 Treatment-related Adverse Events: 5 Years After the End of Study Treatment(From start of treatment to approximately 61.5 months (five years after the end of treatment))
- Percentage of Participants With a Feeding Tube at 1 Year(From randomization to 1 year.)
- EORTC QLQ-C30 Global Health Status Score Change From Baseline at End of Treatment(Baseline and end of treatment (6-7 weeks))
- EORTC QLQ-C30 Global Health Status Score Change From Baseline at 3 Months From End of Treatment(Baseline and 3 months from end of treatment. Treatment lasts 6-7 weeks.)
- EORTC QLQ-C30 Global Health Status Score Change From Baseline at 6 Months From End of Treatment(Baseline and 6 months from end of treatment. Treatment lasts 6-7 weeks.)
- EORTC QLQ-C30 Global Health Status Score Change From Baseline at 12 Months From End of Treatment(Baseline and 12 months from end of treatment. Treatment lasts 6-7 weeks)
- EORTC QLQ-H&N35 Swallowing Score Change From Baseline at End of Treatment(Baseline and end of treatment (6-7 weeks))
- EORTC QLQ-H&N35 Swallowing Score Change From Baseline at 3 Months From End of Treatment.(Baseline and 3 months from end of treatment. Treatment lasts 6-7 weeks.)
- EORTC QLQ-H&N35 Swallowing Score Change From Baseline at 6 Months From End of Treatment.(Baseline and 6 months from end of treatment. Treatment lasts 6-7 weeks.)
- EORTC QLQ-H&N35 Swallowing Score Change From Baseline at 12 Months From End of Treatment.(Baseline and 12 months from end of treatment. Treatment lasts 6-7 weeks.)
- Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events for Head and Neck (PRO-CTCAE H&N) at Baseline, End of Treatment, 3, 6, and 12 Months From End of Treatment.(From randomization to 1 year after end of treatment.)
- EuroQol Five Dimension Scale (EQ-5D) at Baseline, End of Treatment, 3, 6, and 12 Months From End of Treatment.(From randomization to 1 year after end of treatment.)
- Work Status Questionnaire at Baseline, End of Treatment, 3, 6, and 12 Months.(From randomization to 1 year after end of treatment.)
- Percentage of Patients With Normal/Good Dental Health: Pretreatment(Before treatment)
- Percentage of Patients With Normal/Good Dental Health: 1 Year After End of Treatment(1 year after end of treatment (approximately 13.5 months))
- Percentage of Patients With Normal/Good Dental Health: 2 Years After End of Treatment(2 years after end of treatment (approximately 25.5 months))
- Percentage of Patients With Normal/Good Dental Health: 5 Years After End of Treatment(5 years after end of treatment (approximately 61.5 months))
- Percentage of Patients With Normal/Good Dental Health: 10 Years After End of Treatment(10 years after end of treatment (approximately 121.5 months))
- Number of Participants by HHIA-S Category at Baseline(Baseline)
- Number of Participants by HHIA-S Category at End of Treatment(End of treatment (6-7 weeks))
- Number of Participants by HHIA-S Category at 3 Months After End of Treatment(3 months after end of treatment. Treatment lasts 6-7 weeks.)
- Number of Participants by HHIA-S Category at 6 Months After End of Treatment(6 months after end of treatment. Treatment lasts 6-7 weeks.)
- Number of Participants by HHIA-S Category at 12 Months After End of Treatment(12 months after end of treatment. Treatment lasts 6-7 weeks.)
- Overall Survival by KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) Variant Status(From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 214 deaths were reported. Median follow-up at time of analysis was 8.3 years.)
- Progression-free Survival by KRAS Variant Status(From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 214 deaths were reported. Median follow-up at time of analysis was 8.3 years.)
- Overall Survival by Treatment Arm Within KRAS Variant Status Group(From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 214 deaths were reported. Median follow-up at time of analysis was 8.3 years.)
- Progression-free Survival Within KRAS Variant Status(From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 214 deaths were reported. Median follow-up at time of analysis was 8.3 years.)