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

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

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.

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.

Inclusion Criteria:

1. 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).

2. Patients must be positive for p16, determined by central review prior to randomization.

3. 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.

4. 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:

     1. A computerized tomography (CT) scan of the neck (with contrast) and a chest CT scan (with or without contrast);
     2. or a magnetic resonance imaging (MRI) scan of the neck (with contrast) and a chest CT scan (with or without contrast);
     3. or a CT scan of neck (with contrast) and a positron emission tomography (PET)/CT of neck and chest (with or without contrast);
     4. 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.

5. Zubrod Performance Status 0-1 within 2 weeks prior to registration

6. Age ≥ 18;

7. 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.

8. 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;

9. 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)

10. Patients must provide their smoking history (for stratification) via the computer-assisted self interview (CASI) head and neck risk factor survey tool.

11. Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential;

12. 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.

13. 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.

14. 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:

1. 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.

2. Stage T1-2, N0-1;

3. Distant metastasis or adenopathy below the clavicles;

4. 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.

5. Simultaneous primaries or bilateral tumors;

6. 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);

7. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable;

8. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;

9. 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.

10. 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.

11. Prior allergic reaction to cisplatin or cetuximab;

12. Prior cetuximab or other anti-EGFR therapy.