Radiation Therapy With Cisplatin or Cetuximab in Treating Patients With Oropharyngeal Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase III Trial of Radiotherapy Plus Cetuximab Versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer

Conditions
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Head and Neck Cancer, Precancerous Condition

Intervention / Treatment
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* Biological: cetuximab
* Drug: cisplatin
* Radiation: IMRT


Participation Criteria
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Eligibility Criteria
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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); or an MRI of the neck (with contrast) and a PET/CT of neck and chest (with or without contrast). Note: A CT scan of neck and/or a PET/CT performed for radiation planning and read by a radiologist may serve as both staging and planning tools. Zubrod Performance Status 0-1 within 2 weeks prior to registration Age ≥ 18; Complete blood count (CBC)/differential obtained within 2 weeks prior to registration on study, with adequate bone marrow function, defined as follows: Absolute neutrophil count (ANC) > 1,500 cells/mm3; Platelets > 100,000 cells/mm3; Hemoglobin (Hgb) > 8.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb > 8.0 g/dl is acceptable. Adequate hepatic function, defined as follows: Bilirubin < 2 mg/dl within 2 weeks prior to registration; Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x the upper limit of normal within 2 weeks prior to registration; Adequate renal function, defined as follows: • Serum creatinine < 1.5 mg/dl within 2 weeks prior to registration or creatinine clearance (CCr) ≥ 50 ml/min within 2 weeks prior to registration determined by 24-hour collection or estimated by Cockcroft-Gault formula: CCr male = [(140 - age) x (wt in kg)] [(Serum Cr mg/dl) x (72)] CCr female = 0.85 x (CCr male) Patients must provide their smoking history (for stratification) via the computer-assisted self interview (CASI) head and neck risk factor survey tool. Negative serum 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 and until at least 60 days following the last study treatment. Patients who are human immunodeficiency virus (HIV) positive but have no prior acquired immune deficiency syndrome (AIDS) -defining illness and have CD4 cells of at least 350/mm3 are eligible. Patient HIV status must be known prior to registration. Patients must not be sero-positive for Hepatitis B (Hepatitis B surface antigen positive or anti-hepatitis B core antigen positive) or sero-positive for Hepatitis C (anti-Hepatitis C antibody positive). However, patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B). HIV-positive patients must not have multi-drug resistant HIV infection or other concurrent AIDS-defining conditions. Patient must provide study specific informed consent prior to study entry, including consent for mandatory submission of tissue for required, central p16 review and consent to participate in the computer-assisted self interview (CASI) survey questions regarding smoking history. 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; 9.2 Transmural myocardial infarction within the last 6 months; 9.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; 9.4 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration; 9.5 Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol. 9.6 Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition with immune compromise greater than that noted in Section 3.1.13; 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. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. Prior allergic reaction to cisplatin or cetuximab; Prior cetuximab or other anti-EGFR therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IMRT + Cisplatin<br>Intensity-modulated radiotherapy (IMRT) with concurrent cisplatin | Drug: cisplatin<br>* 100 mg/m2 IV on days 1 and 22 of IMRT<br>Radiation: IMRT<br>* 35 fractions over 6 weeks, 6 fractions per week, 2 Gray per fraction to total dose of 70 Gy.<br>* Other names: intensity-modulated radiation therapy;|
| Active Comparator: IMRT + Cetuximab<br>Intensity-modulated radiotherapy (IMRT) with concurrent cetuximab | Biological: cetuximab<br>* 400 mg/m2 IV 5-7 days before IMRT then 250 mg/m2 IV weekly for 7 weeks<br>Radiation: IMRT<br>* 35 fractions over 6 weeks, 6 fractions per week, 2 Gray per fraction to total dose of 70 Gy.<br>* Other names: intensity-modulated radiation therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | An event for progression-free survival is local, regional, or distant disease progression or death due to any cause. Progression-free survival time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is the distribution of progression-free survival times, for which the hazard ratio is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure. | 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 | Failure for local-regional failure endpoint was defined as local or regional progression, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown > 20 weeks after the end of radiation therapy, death due to study cancer without documented progression, or death due to unknown causes without documented progression; distant metastasis and death due to other causes were considered competing risks. Local-regional failure time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method. The protocol endpoint is the distribution of local-regional failure times, for which the hazard ratio is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure. | 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 | Failure for distant metastasis endpoint was defined as distant progression; local-regional failure and death due to any cause were considered competing risks. Distant metastasis time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method. The protocol endpoint is the distribution of distant metastasis times, for which the hazard ratio is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure. | 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 | Failure for second primary endpoint was defined as reporting of a new primary cancer; death due to any cause was considered a competing risk. Second primary time is defined as time from randomization to the date of second primary or last known follow-up (censored). Rates are estimated by the cumulative incidence method. The protocol endpoint is the distribution of second primary cancer times, for which the hazard ratio is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure. | 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 | The first event type for progression-free survival is counted for each participant. Possible first progression events are local, regional, or distant progression, any combination of these, or death. The frequency table of these events is also referred to as Pattern of 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. | 
| Percentage of Participants Experiencing Early Death | Early death is defined as death due to adverse event or within 30 days of treatment completion. | 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 | Acute adverse events (AE) are defined as occurring within 180 days from the end of treatment. Treatment-related means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE | 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 | Acute adverse events (AE) are defined as occurring within 180 days from the end of treatment. Treatment-related means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE | 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 | Acute adverse events (AE) are defined as occurring within 180 days from the end of treatment. Treatment-related means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE | 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 | Acute adverse events (AE) are defined as occurring within 180 days from the end of treatment. Treatment-related means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE | 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 | Late adverse events (AE) are defined as > 180 days from end of treatment. Treatment-related means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE | 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 | Late adverse events (AE) are defined as > 180 days from end of treatment. Treatment-related means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE | 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 | Late adverse events (AE) are defined as > 180 days from end of treatment. Treatment-related means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE | 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 at Baseline, End of Treatment, 3, 6, and 12 Months From End of Treatment. |  | From randomization to 1 year after end of treatment. | 
| EORTC QLQ-H&N35 at Baseline, End of Treatment, 3, 6, and 12 Months From End of Treatment. |  | From randomization to 1 year after end of treatment. | 
| 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 | This study utilized a dental effects health scale from 0 (normal) to 4 (life-threatening dental condition). The percentage of participants with a value of 0 or 1 is reported: 0 = Normal: Edentulous, with no gingival disease; 1 = Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated. Ten year data is not yet available. | Before treatment | 
| Percentage of Patients With Normal/Good Dental Health: 1 Year After End of Treatment | This study utilized a dental effects health scale from 0 (normal) to 4 (life-threatening dental condition). The percentage of participants with a value of 0 or 1 is reported: 0 = Normal: Edentulous, with no gingival disease; 1 = Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated. | 1 year after end of treatment (approximately 13.5 months) | 
| Percentage of Patients With Normal/Good Dental Health: 2 Years After End of Treatment | This study utilized a dental effects health scale from 0 (normal) to 4 (life-threatening dental condition). The percentage of participants with a value of 0 or 1 is reported: 0 = Normal: Edentulous, with no gingival disease; 1 = Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated. | 2 years after end of treatment (approximately 25.5 months) | 
| Percentage of Patients With Normal/Good Dental Health: 5 Years After End of Treatment | This study utilized a dental effects health scale from 0 (normal) to 4 (life-threatening dental condition). The percentage of participants with a value of 0 or 1 is reported: 0 = Normal: Edentulous, with no gingival disease; 1 = Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated. | 5 years after end of treatment (approximately 61.5 months) | 
| Percentage of Patients With Normal/Good Dental Health: 10 Years After End of Treatment | his study utilized a dental effects health scale from 0 (normal) to 4 (life-threatening dental condition). The percentage of participants with a value of 0 or 1 is reported: 0 = Normal: Edentulous, with no gingival disease; 1 = Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated. | 10 years after end of treatment (approximately 121.5 months) | 
| Hearing Quality of Life Outcomes as Measured by the Hearing Handicap Inventory for Adults (HHIA-S) at Baseline, End of Treatment and at 3, 6, and 12 Months From End of Treatment. |  | From randomization to 1 year after end of treatment. | 
| Behavioral Risk Assessment Survey (BRASS) at Baseline. |  | Prior to randomization. | 
| Translational Research Analysis |  | From randomization to date of death or last follow-up. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx, human papilloma virus infection