De-intensified Radiation Therapy With Chemotherapy (Cisplatin) or Immunotherapy (Nivolumab) in Treating Patients With Early-Stage, HPV-Positive, Non-Smoking Associated Oropharyngeal Cancer


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Trial ID: NCT03952585


This phase II/III trial studies how well a reduced dose of radiation therapy works with nivolumab compared to cisplatin in treating patients with human papillomavirus (HPV)-positive oropharyngeal cancer that is early in its growth and may not have spread to other parts of the body (early-stage), and is not associated with smoking. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial is being done to see if a reduced dose of radiation therapy and nivolumab works as well as standard dose radiation therapy and cisplatin in treating patients with oropharyngeal cancer.

Official Title

A Randomized Phase II/III Trial of De-Intensified Radiation Therapy for Patients With Early-Stage, P16-Positive, Non-Smoking Associated Oropharyngeal Cancer

Stanford Investigator(s)

Beth Beadle
Beth Beadle

Professor of Radiation Oncology (Radiation Therapy)

Quynh-Thu Le, MD
Quynh-Thu Le, MD

Katharine Dexter McCormick and Stanley McCormick Memorial Professor and Professor, by courtesy, of Otolaryngology - Head & Neck Surgery (OHNS)


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 but not neuroendocrine phenotype) of the oropharynx
   (tonsil, base of tongue, soft palate, or oropharyngeal walls); cytologic diagnosis
   from a cervical lymph node is sufficient in the presence of clinical evidence of a
   primary tumor in the oropharynx. Clinical evidence should be documented, may consist
   of palpation, imaging, or endoscopic evaluation, and should be sufficient to estimate
   the size of the primary (for T stage)

   - Patients must have clinically or radiographically evident measurable disease at the
   primary site or at nodal stations. Simple 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

   - P16-positive based on local site immunohistochemical tissue staining (defined as
   greater than 70% strong diffuse nuclear or nuclear and cytoplasmic staining of tumor
   cells). Fine needle aspiration (FNA) biopsy specimens may be used as the sole
   diagnostic tissue. Centers are encouraged to contact the pathology chair for

      - Note: Institutions must screen patients, whose tumors must be p16-positive by
      immunohistochemistry (IHC) in order to be eligible for the trial using a Clinical
      Laboratory Improvement Amendments (CLIA)-certified laboratory. A rigorous
      laboratory accreditation process similar to the United States (U.S.) CLIA
      certification, such as the provincial accreditation status offered by the Ontario
      Laboratory Accreditation (OLA) Program in Canada, the College of American
      Pathologists (CAP), or an equivalent accreditation in other countries, is
      acceptable. The p16-positive results must be reported on the pathology report
      being submitted

      - Note: If p16 result is equivocal, positive HPV deoxyribonucleic acid (DNA) test
      of tumor specimen is acceptable and fulfills the eligibility criteria

   - Clinical stage T1-2, N1, M0 (American Joint Committee on Cancer [AJCC], 8th edition
   [ed.]) or T3, N0-N1, M0 (AJCC, 8th ed.) including no distant metastases based on the
   following diagnostic workup:

      - General history and physical examination within 56 days prior to registration;

      - Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable)
      within 70 days prior to registration;

      - One of the following imaging studies is required within 56 days prior to

         - FDG-PET/CT of the neck and chest (with or without contrast); FDG-PET/CT scan
         is strongly preferred and highly recommended to be used for eligibility OR

         - Chest CT (with or without contrast)

      - One of the following imaging studies is required within 28 days prior to

         - A diagnostic CT scan of neck (with contrast and of diagnostic quality) OR

         - An magnetic resonance imaging (MRI) of the neck (with contrast and of
         diagnostic quality)

         - Note: A diagnostic quality CT or MRI with contrast or FDG-PET/CT scan of
         neck performed for the purposes of radiation planning may serve as both
         staging and planning tools

   - Patients must provide their personal smoking history prior to registration. The
   lifetime cumulative history cannot exceed 10 pack-years. The following formula is used
   to calculate the pack-years during the periods of smoking in the patient's life; the
   cumulative total of the number of pack-years during each period of active smoking is
   the lifetime cumulative history

      - Number of pack-years = [Frequency of smoking (number of cigarettes per day) x
      duration of cigarette smoking (years)] / 20

      - Note: Twenty cigarettes is considered equivalent to one pack. The effect of
      non-cigarette tobacco products on the survival of patients with p16-positive
      oropharyngeal cancers is undefined. While there are reportedly increased risks of
      head and neck cancer associated with sustained heavy cigar and pipe use (Wyss
      2013), such sustained use of non-cigarette products is unusual and does not
      appear to convey added risk with synchronous cigarette smoking. Cigar and pipe
      tobacco consumption is therefore not included in calculating the lifetime
      pack-years. Marijuana consumption is likewise not considered in this calculation.
      There is no clear scientific evidence regarding the role of chewing
      tobacco-containing products in this disease, although this is possibly more
      concerning given the proximity of the oral cavity and oropharynx. In any case,
      investigators are discouraged from enrolling patients with a history of very
      sustained use (such as several years or more) of non-cigarette tobacco products

   - Zubrod performance status of 0-1 within 14 days prior to registration

   - Age >= 18

   - Absolute neutrophil count >= 1,500/mcL (within 14 days prior to registration)

   - Platelets >= 100,000/mcL (within 14 days prior to registration)

   - Hemoglobin >= 8.0 g/dL (within 14 days prior to registration) (Note: use of
   transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dL is

   - Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 14 days
   prior to registration)

   - Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) or
   alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x
   institutional ULN (within 14 days prior to registration)

   - Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using
   the Cockcroft-Gault formula) (within 14 days prior to registration)

   - Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
   therapy with undetectable viral load within 6 months are eligible for this trial

   - For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
   load must be undetectable on suppressive therapy, if indicated

      - Note: Known positive test for hepatitis B virus surface antigen (HBV sAg)
      indicating acute or chronic infection would make the patient ineligible unless
      the viral load becomes undetectable on suppressive therapy. Patients who are
      immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible
      (e.g. patients immunized against hepatitis B)

   - Patients with a history of hepatitis C virus (HCV) infection must have been treated
   and cured. For patients with HCV infection who are currently on treatment for the
   hepatitis, they are eligible if they have an undetectable HCV viral load.

      - Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA)
      indicating acute or chronic infection would make the patient ineligible unless
      the viral load becomes undetectable on suppressive therapy

   - For women of childbearing potential (WOCBP), negative serum or urine pregnancy test
   within 24 hours prior to registration

      - Women of childbearing potential (WOCBP) is defined as any female who has
      experienced menarche and who has not undergone surgical sterilization
      (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause
      is defined clinically as 12 months of amenorrhea in a woman over 45 in the
      absence of other biological or physiological causes. In addition, women under the
      age of 55 must have a documented serum follicle stimulating hormone (FSH) level
      less than 40 mIU/mL

   - Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP
   must be willing to use an adequate method of contraception during and after treatment

   - The patient or a legally authorized representative must provide study-specific
   informed consent prior to study entry

   - Only English, Spanish, or French speaking patients are eligible to participate as
   these are the only languages for which the mandatory dysphagia-related patient
   reported instrument (MDADI) is available

Exclusion Criteria:

   - Clinical stages T0; T4; T1-2, N0; or any N2 (AJCC, 8th ed)

   - Recurrent disease

   - Definitive clinical or radiologic evidence of metastatic disease or adenopathy below
   the clavicles

   - Cancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar
   ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if
   p16-positive, or histologies of adenosquamous, verrucous, or spindle cell carcinomas

   - Carcinoma of the neck of unknown primary site origin (T0 is ineligible, even if

   - Radiographically matted nodes, defined as 3 abutting nodes with loss of the
   intervening fat plane

   - Supraclavicular nodes, defined as nodes centered below the level of the cricoid

   - 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. In other words, to participate in this protocol, the
   patient must have clinically or radiographically evident gross disease for which
   disease response can be assessed

   - Patients with simultaneous primary cancers or separate bilateral primary tumor sites
   are excluded with the exception of patients with bilateral tonsil cancers

   - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
   for a minimum of 1095 days (3 years) (of note, the exclusion applies only for invasive
   cancers such that carcinoma in situ of the breast, oral cavity, or cervix are all

   - 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

   - Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or
   any other antibody or drug specifically targeting T-cell co-stimulation or immune
   checkpoint pathways

   - History of severe hypersensitivity reaction to any monoclonal antibody.

   - Severe, active co-morbidity defined as follows:

      - Unstable angina and/or congestive heart failure requiring hospitalization within
      the last 6 months

      - Transmural myocardial infarction within the last 6 months

      - Acute bacterial or fungal infection requiring intravenous antibiotics at the time
      of registration

      - Chronic obstructive pulmonary disease exacerbation or other respiratory illness
      requiring hospitalization or precluding study therapy within 30 days of

      - Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

      - Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease
      Control and Prevention (CDC) definition with immune compromise greater than that
      noted; 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

      - Condition requiring systemic treatment with either corticosteroids (> 10 mg daily
      prednisone equivalents) or other immunosuppressive medications within 14 days of
      registration. Inhaled or topical steroids and adrenal replacement doses < 10 mg
      daily prednisone equivalents are permitted in the absence of active autoimmune

      - Patients with active autoimmune disease requiring systemic treatment (i.e.
      disease modifying agents, corticosteroids, or immunosuppressive drugs) should be
      excluded. These include but are not limited to patients with a history of immune
      related neurologic disease, multiple sclerosis, autoimmune (demyelinating)
      neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune
      disease such as systemic lupus erythematosus (SLE), rheumatoid arthritis,
      connective tissue diseases, scleroderma, inflammatory bowel disease (IBD),
      Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic
      epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome
      should be excluded because of the risk of recurrence or exacerbation of disease

      - Note: Patients are permitted to enroll if they have vitiligo, type I diabetes
      mellitus, residual hypothyroidism due to autoimmune condition only requiring
      hormone replacement, psoriasis not requiring systemic treatment, or conditions
      not expected to recur in the absence of an external trigger (precipitating event)

   - Patients who are pregnant, nursing, or expecting to conceive or father children

   - Prior allergic reaction to cisplatin


drug: Cisplatin

radiation: Image Guided Radiation Therapy

radiation: Intensity-Modulated Radiation Therapy

biological: Nivolumab

other: Quality-of-Life Assessment

other: Questionnaire Administration

procedure: Biopsy

procedure: Biospecimen Collection

procedure: Computed Tomography

other: Fludeoxyglucose F-18

procedure: Magnetic Resonance Imaging

procedure: Positron Emission Tomography


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Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Martina Steffen

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