PRIMARY OBJECTIVES:
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)
SECONDARY OBJECTIVES:
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.
EXPLORATORY OBJECTIVES:
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.
OUTLINE:
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.
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
[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
registration:
- 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
registration:
- 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
alone
- Zubrod performance status of 0-1 within 14 days prior to registration
- 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
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)
- 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
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
