Adaptive Treatment De-escalation in Favorable Risk HPV-Positive Oropharyngeal Carcinoma

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of squamous cellcarcinoma of the oropharynx, which include the sites tonsil, base of tongue, softpalate, or posterior oropharyngeal wall. Histologic variants will be included (papillary squamous cell carcinoma and basaloid squamous cell carcinoma). Cytologicdiagnosis from a cervical lymph node is sufficient in the presence of clinicalevidence of a primary tumor in the oropharynx.

• Patient's tissue must be positive for p16 by immunohistochemical staining (>70%staining). Fine needle aspiration (FNA) biopsy specimens may be used as the solediagnostic tissue if formalin-fixed paraffin-embedded cell block material isavailable for p16 immunohistochemistry.

• Patients must have detectable circulating plasma HPV DNA at baseline

• Clinical stage T1-T2, N1-N2b or T3, N1-N2b (AJCC 7th Edition) with no distantmetastases based on the following diagnostic workup:

• Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or directprocedure) within 8 weeks prior to registration.

• One of the following combinations of imaging is required within 8 weeks ofregistration:

1. Or a CT scan of the neck (with contrast) and a PET/CT of neck and chest (withor without contrast);

2. Or an MRI of the neck (with contrast) and a PET/CT of neck and chest (with orwithout contrast)

3. Note: A CT scan of the neck and/or a PET/CT performed for the purposes ofradiation planning may serve as both staging and planning tools.

• Patients must provide their personal smoking history prior to registration. Patientscannot have a cumulative personal smoking history that exceeds 10 pack-years.

1. Number of pack-years = [Frequency of smoking (number of cigarettes per day) xduration of cigarette smoking (years)] / 20

2. Note: Twenty cigarettes is considered equivalent to one pack. Cigar and pipetobacco consumption is not included in calculating lifetime pack-years.

• Zubrod Performance Status of 0-1 within 8 weeks prior to registration;

• Adequate hematologic function within 2 weeks prior to registration, defined asfollows:

Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 8.0 g/dl; Note: the use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.

• Adequate renal function within 2 weeks prior to registration, defined as follows: a.Serum creatinine ≤ mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24hour collection or estimated by Cockcorft-Gault formula: i.CCr male = [(140 - age) x (wt in kg)] [(Serum Cr mg/dl) x (72)] ii.CCr female = 0.85 x (CrCl male)

• Negative serum pregnancy test within 14 days prior to registration for women ofchildbearing potential;

• Patients who are HIV positive but who have no prior AIDS-defining illness and haveCD4 cells of at least 350/mm3 are eligible. HIV-positive patients must not havemulti-drug resistant HIV infection or other concurrent AIDS-defining conditions.Patients must not be sero-positive for Hepatitis B (Hepatitis B surface antigenpositive or anti-hepatitis B core antigen positive) or sero-positive for Hepatitis C (anti-Hepatitis C antibody positive). However, patients who are immune to hepatitisB (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunizedagainst hepatitis B).

• The patient must provide study-specific informed consent prior to study entry.

Exclusion Criteria:

• Cancers considered to be from an oral cavity site (oral tongue, floor of mouth,alveolar ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even ifp16 positive;

• Carcinoma of the neck of unknown primary site origin (even if p16 positive);

• 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 andradiographically evident disease.

• Simultaneous primary cancers or separate bilateral primary tumor sites;

• Prior invasive malignancy malignancy (except non-melanomatous skin cancer) unlessdisease free for a minimum of 1095 days (3 years) (for example, carcinoma in situ ofthe breast, oral cavity, or cervix are all permissible);

• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for adifferent cancer is allowable;

• Prior radiotherapy to the region of the study cancer that would result in overlap ofradiation therapy fields;

• Severe, active co-morbidity defined as follows:

1. Unstable angina and/or congestive heart failure requiring hospitalizationwithin the last 6 months;

2. Transmural myocardial infarction within the last 6 months;

3. Acute bacterial or fungal infection intravenous antibiotics at the time ofregistration;

4. Chronic obstructive pulmonary disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy within 30 days ofregistration;

5. Hepatic insufficiency resulting in clinical jaundice and/or coagulationdefects; note, however, that laboratory tests for liver function andcoagulation parameters are not required for entry into this protocol other thanthose listed in 4.1.10.

6. Acquired immune deficiency syndrome (AIDS) based upon the current CDCdefinition with immune compromise greater than that noted in section 4.1.12;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 becausethe treatments involved in this protocol may be significantlyimmunosuppressive. Protocol-specific requirements may also excludeimmune-compromised patients.

• Pregnancy; this exclusion is necessary because the treatment in this study may besignificantly teratogenic

• Prior allergic reaction to cisplatin.

• Exclusion Criteria for MRI: Normal MRI exclusion criteria will apply, includingthose on the following list. A standard MRI safety form will be used to identifypotential conditions warranting exclusion.

• Electrical implants such as cardiac pacemakers or perfusion pumps

• Ferromagnetic implants such as aneurysm clips, surgical clips, prostheses,artificial heart, valves with steel parts, metal fragments, shrapnel, bullets,tattoos near the eye, or steel implants

• Ferromagnetic objects such as jewelry or metal clips in clothing

• Claustrophobia

• History of seizures

• Diabetes a.In addition, patients with GFR < 15 ml/min/1.73m2 or who are on dialysiswill not have DCE-MRI scan. These patients will have conventional anatomical MRIwithout contrast and DW-MRI,