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

  • End date
    Feb 28, 2025
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 21 October 2022
ct scan
measurable disease
squamous cell carcinoma
bilateral oophorectomy
cigarette smoking
neutrophil count
tumor cells
primary tumor
chemotherapy regimen
follicle stimulating hormone
chemotherapy drugs
head and neck cancer
human papillomavirus
pet/ct scan
fine needle aspiration
oropharyngeal cancer
neck cancer
administration intravenous
intensity-modulated radiation therapy
hepatitis b virus surface antigen
neck dissection
pet-ct scan
hepatitis c virus ribonucleic acid


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.



I. To demonstrate non-inferiority in terms of progression-free survival (PFS) of concurrent reduced-dose radiation therapy (RT) with cisplatin or concurrent reduced-dose radiation therapy with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase II) II. To demonstrate co-primary endpoints of non-inferiority of PFS and superiority of quality of life (QOL) as measured by the MD Anderson Dysphagia Inventory (MDADI) of concurrent reduced-dose radiation with cisplatin or concurrent reduced-dose radiation with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase III)


I. To compare patterns of failure (local and regional relapse versus distant) and overall survival between each experimental arm and the control arm.

II. To assess long term PFS, overall survival, and toxicity between each experimental arm and the control arm.

III. To determine acute and late toxicity profiles as measured by the Common Terminology Criteria for Adverse Events (CTCAE).

IV. To explore the symptomatic adverse events (AEs) for tolerability of each treatment arm as measured by the Patient-Reported Outcomes (PRO)-CTCAE.

V. To compare changes in patient-reported outcomes (Hearing Handicap Inventory for Adults-Screening [HHIA-S], European Organization for Research and Treatment of Cancer [EORTC]-Quality of Life Questionnaire [QLQ]30) between each experimental arm and the control arm.

VI. To assess the association of fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) at baseline with locoregional control and PFS.

VII. To estimate the negative predictive value of the 12-14 weeks post-radiation therapy (RT) FDG-PET/CT in terms of locoregional control rates and PFS rates at 1 and 2 years.


I. To collect blood and tissue specimens for future translation research. II. To optimize radiotherapy treatment plan quality assurance methodology for radiotherapy planning and imaging.

III. To compare changes in patient-reported outcomes (European Quality of Life Five Dimension Five Level Scale [EQ-5D-5L]) between each experimental arm and the control arm.

IV. To collect Modified Barium Swallow (MBS) data for future review and analysis.


PHASE II: Patients are randomized to 1 of 3 arms.

ARM I: Patients undergo intensity modulated radiation therapy (IMRT) or image-guided radiation therapy (IGRT) over 6 fractions per week and receive cisplatin intravenously (IV) over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo reduced dose IMRT or IGRT once daily (QD) over 5 fractions per week and receive cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM III: Beginning 1 week prior to radiation, patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity.

PHASE III: Patients are randomized to Arm I, Arm II, and/or Arm III.

After completion of study treatment, patients are followed up at 12-14 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Condition Basaloid Squamous Cell Carcinoma, Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Oropharyngeal Squamous Cell Carcinoma, Papillary Squamous Cell Carcinoma, Pathologic Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Squamous Cell Carcinoma
Treatment questionnaire administration, cisplatin, quality-of-life assessment, Nivolumab, intensity-modulated radiation therapy, Image Guided Radiation Therapy
Clinical Study IdentifierNCT03952585
SponsorNational Cancer Institute (NCI)
Last Modified on21 October 2022


Yes No Not Sure

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 clarification
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
Clinical stage T1-2, N1, M0 (American Joint Committee on Cancer [AJCC], 8th edition
General history and physical examination within 56 days prior to registration
[ed.]) or T3, N0-N1, M0 (AJCC, 8th ed.) including no distant metastases based
Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) within 70 days prior to registration
on the following diagnostic workup
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
Number of pack-years = [Frequency of smoking (number of cigarettes per day) x duration of cigarette smoking (years)] / 20
Patients must provide their personal smoking history prior to registration. The
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 alone
lifetime cumulative history cannot exceed 10 pack-years. The following formula
Zubrod performance status of 0-1 within 14 days prior to registration
Absolute neutrophil count >= 1,500/mcL (within 14 days prior to registration)
is used to calculate the pack-years during the periods of smoking in the
Platelets >= 100,000/mcL (within 14 days prior to registration)
patient's life; the cumulative total of the number of pack-years during each
period of active smoking is the lifetime cumulative history
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 acceptable)
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)
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
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
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
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
For women of childbearing potential (WOCBP), negative serum or urine pregnancy test
within 24 hours prior to registration
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

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 p16-positive)
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 cartilage
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 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
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 registration
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 disease
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
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