Transoral Surgery Followed By Low-Dose or Standard-Dose Radiation Therapy With or Without Chemotherapy in Treating Patients With HPV Positive Stage III-IVA Oropharyngeal Cancer
Condition: Human Papilloma Virus Infection; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Oropharynx
MeSH terms: Papillomavirus Infections; Carcinoma; Carcinoma, Squamous Cell; Oropharyngeal Neoplasms; Papilloma
Intervention: Transoral surgery; intensity-modulated radiation therapy; cisplatin; carboplatin
Intervention description: Undergo transoral surgical resection; Undergo standard-dose or low-dose IMRT; Given IV; Given IV
Intervention MeSH terms: Cisplatin; Carboplatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 519.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: oropharynx cancer; HPV+

Summary:

      This randomized phase II trial studies how well transoral surgery followed by low-dose or
      standard-dose radiation therapy works in treating patients with human papilloma virus (HPV)
      positive stage III-IVA oropharyngeal cancer. Radiation therapy uses high-energy x-rays to
      kill tumor cells. Drugs used in chemotherapy work in different ways to stop the growth of
      tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation
      therapy with chemotherapy may kill any tumor cells that remain after surgery. It is not yet
      known how much extra treatment needs to be given after surgery.
    

Eligibility criteria:

        Inclusion Criteria:

        Registration to Surgery (Arm S)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Patients must have newly diagnosed, histologically or cytologically confirmed squamous
             cell carcinoma or undifferentiated carcinoma of the oropharynx; patients must have
             been determined to have resectable oropharyngeal disease; patients with primary tumor
             or nodal metastasis fixed to the carotid artery, skull base or cervical spine are not
             eligible

          -  Patients must have American Joint Committee on Cancer (AJCC) TNM tumor stage III, IV
             a, or IV b (with no evidence of distant metastases) as determined by imaging studies
             (performed < 30 days prior to pre-registration) and complete head and neck exam; the
             following imaging is required: computed tomography (CT) scan with IV contrast or
             magnetic resonance imaging (MRI)

          -  Patients must have biopsy-proven p16+ oropharynx cancer; the histologic evidence of
             invasive squamous cell carcinoma may have been obtained from the primary tumor or
             metastatic lymph node. It is required that patients have a positive p16 IHC (as
             surrogate for HPV) status from either the primary tumor or metastatic lymph node.

          -  Carcinoma of the oropharynx associated with HPV as determined by p16 protein
             expression using immunohistochemistry (IHC) performed by a Clinical Laboratory
             Improvement Amendments (CLIA) approved laboratory; using p16 antibody obtained from
             Roche mtm laboratories AG (CINtec, clone E6H4) is recommended

          -  Patients with a history of a curatively treated malignancy must be disease-free for at
             least two years except for carcinoma in situ of cervix and/or non-melanomatous skin
             cancer

          -  Patients with the following within the last 6 months prior to pre-registration must be
             evaluated by a cardiologist and/or neurologist prior to entry into the study

               -  Congestive heart failure > NYHA Class II

               -  Cerebrovascular accident (CVA)/transient ischaemic attack (TIA)

               -  Unstable angina

               -  Myocardial infarction

          -  Absolute neutrophil count >= 1,500/mm^3

          -  Platelets >= 100,000/mm^3

          -  Total bilirubin =< the upper limit of normal (ULN)

          -  Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula

        Registration/Randomization to Step2 - Arms A, B, C and D

          -  Histopathologic assessment of surgical pathology must include examination for
             perineural invasion (PNI) and lymphovascular invasion (LVI) and reported as absent or
             present; the absence or presence of extracapsular extension (ECE) requires gross and
             microscopic assessment and is defined to be:

               -  Absent (negative or nodal metastasis with smooth/rounded leading edge confined to
                  thickened capsule/pseudocapsule),

               -  Present - minimal (tumor extends =< 1 mm beyond the lymph node capsule), or

               -  Present - extensive (gross, tumor extends > 1 mm beyond the lymph node capsule
                  (includes soft tissue metastasis)

          -  Patient must be stratified/classified into one of the following risk categories (the
             highest risk feature assessed pathologically will determine the patient's
             category/treatment arm assignment):

               -  Low Risk: T1-T2, N0-N1 AND clear (≥ 3mm) margins, AND no ECE or PNI/LVI

               -  High Risk: Any of the following features: one or more positive margin(s) with any
                  T stage, OR "Extensive" (> 1mm) ECE, OR ≥ 5 metastatic lymph nodes (regardless of
                  primary tumor margin status)

               -  Intermediate Risk: Any of the following features: one or more "close" (< 3mm)
                  margin(s), OR "Minimal" (≤ 1mm) ECE, OR N2a (1 or more lymph node > 3cm in
                  diameter), OR N2b (2-4 lymph nodes positive, any diameter ≤ 6cm), OR with
                  perineural invasion or lymphovascular invasion.

               -  Unknown Risk: Patients found to have N2C or N3 disease on final pathologic
                  analysis are at unknown risk for recurrence, but are not candidates for
                  deintensified adjuvant therapy in this trial. These patients will be treated on
                  Arm C.

               -  Patients not categorized into the appropriate risk category will be considered
                  ineligible for the study

          -  Patient must be registered/randomized to Step 2 within a maximum of 7 weeks following
             surgery

          -  Women of childbearing potential and sexually active males are strongly advised to use
             an accepted and effective method of contraception

        Exclusion Criteria:

        Registration to Surgery (Arm S)

          -  Prior radiation above the clavicles

          -  Evidence of extensive or "matted/fixed" pathologic adenopathy on preoperative imaging

          -  Women must not be pregnant or breast-feeding due to the teratogenicity of
             chemotherapy; all females of childbearing potential must have a blood test or urine
             study within 2 weeks prior to registration to rule out pregnancy; a female of
             childbearing potential is any woman, regardless of sexual orientation or whether they
             have undergone tubal ligation, who meets the following criteria: has not undergone a
             hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for
             at least 24 consecutive months (i.e., has had menses at any time in the preceding 24
             consecutive months)

          -  Any intercurrent illness likely to interfere with protocol therapy or prevent surgical
             resection

          -  Uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled
             hypertension within 30 days prior to pre-registration