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

Squamous Cell Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT03952585
• Other study ID #: NCI-2019-03015
• Secondary ID: NCI-2019-03015NR
• Status: Suspended
• Phase: Phase 2/Phase 3
• Start date: October 9, 2019
• Est. completion date: February 28, 2025

Study information

• Verified date: May 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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) (Arm 2 [concurrent reduced-dose RT with cisplatin] was dropped after interim futility analysis in phase II.) II. To demonstrate non-inferiority in terms of progression-free survival (PFS) of concurrent reduced-dose radiation therapy (RT) with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase II) III. 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) (Arm 2 [concurrent reduced-dose RT with cisplatin] was dropped after interim futility analysis in phase II.) IV. 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 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 the experimental arm and the control arm.

II. To assess long term PFS, overall survival, and toxicity between the 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 the 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 the 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. Patients receive fludeoxyglucose F-18 (FDG) and undergo positron emission tomography (PET)/computed tomography (CT) or CT during screening and during follow up, and undergo magnetic resonance imaging (MRI) during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.

ARM II (CLOSED TO ACCRUAL 03-FEB-2023): 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. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.

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. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.

PHASE III: Patients are randomized to Arm I 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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 590
• Est. completion date: February 28, 2025
• Est. primary completion date: February 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

• 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 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

• 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 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

Related Conditions & MeSH terms

• Basaloid Squamous Cell Carcinoma
• Carcinoma
• Carcinoma, Squamous Cell
• Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
• Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
• Oropharyngeal Neoplasms
• 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
• Squamous Cell Carcinoma of Head and Neck

Intervention

Procedure:
• Biopsy
Undergo tissue biopsy
• Biospecimen Collection
Undergo blood sample collection

Drug:
• Cisplatin
Given IV

Procedure:
• Computed Tomography
Undergo CT

Other:
• Fludeoxyglucose F-18
Receive FDG

Radiation:
• Image Guided Radiation Therapy
Undergo IGRT
• Intensity-Modulated Radiation Therapy
Undergo IMRT

Procedure:
• Magnetic Resonance Imaging
Undergo MRI

Biological:
• Nivolumab
Given IV

Procedure:
• Positron Emission Tomography
Undergo PET

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
United States	Hawaii Cancer Care - Westridge	'Aiea	Hawaii
United States	Pali Momi Medical Center	'Aiea	Hawaii
United States	Summa Health System - Akron Campus	Akron	Ohio
United States	New Mexico Oncology Hematology Consultants	Albuquerque	New Mexico
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	UPMC Altoona	Altoona	Pennsylvania
United States	The Don and Sybil Harrington Cancer Center	Amarillo	Texas
United States	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	Kaiser Permanente-Deer Valley Medical Center	Antioch	California
United States	Ascension Saint Elizabeth Hospital	Appleton	Wisconsin
United States	PCR Oncology	Arroyo Grande	California
United States	Duluth Clinic Ashland	Ashland	Wisconsin
United States	Northwest Wisconsin Cancer Center	Ashland	Wisconsin
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Grady Health System	Atlanta	Georgia
United States	Sutter Auburn Faith Hospital	Auburn	California
United States	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California
United States	Rocky Mountain Regional VA Medical Center	Aurora	Colorado
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	UH Seidman Cancer Center at UH Avon Health Center	Avon	Ohio
United States	AIS Cancer Center at San Joaquin Community Hospital	Bakersfield	California
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Summa Health System - Barberton Campus	Barberton	Ohio
United States	Advocate Good Shepherd Hospital	Barrington	Illinois
United States	MaineHealth Coastal Cancer Treatment Center	Bath	Maine
United States	Louisiana Hematology Oncology Associates LLC	Baton Rouge	Louisiana
United States	LSU Health Baton Rouge-North Clinic	Baton Rouge	Louisiana
United States	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana
United States	Our Lady of the Lake Physician Group	Baton Rouge	Louisiana
United States	McLaren Cancer Institute-Bay City	Bay City	Michigan
United States	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania
United States	UM Upper Chesapeake Medical Center	Bel Air	Maryland
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Tower Cancer Research Foundation	Beverly Hills	California
United States	MaineHealth/SMHC Cancer Care and Blood Disorders-Biddeford	Biddeford	Maine
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Boston Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado
United States	Bozeman Health Deaconess Hospital	Bozeman	Montana
United States	Essentia Health Saint Joseph's Medical Center	Brainerd	Minnesota
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Trinity Health Medical Center - Brighton	Brighton	Michigan
United States	Ascension Southeast Wisconsin Hospital - Elmbrook Campus	Brookfield	Wisconsin
United States	Henry Ford Cancer Institute-Downriver	Brownstown	Michigan
United States	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Sutter Cancer Centers Radiation Oncology Services-Cameron Park	Cameron Park	California
United States	Sands Cancer Center	Canandaigua	New York
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Trinity Health Medical Center - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Carlisle Regional Cancer Center	Carlisle	Pennsylvania
United States	IU Health North Hospital	Carmel	Indiana
United States	Caro Cancer Center	Caro	Michigan
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Chambersburg Hospital	Chambersburg	Pennsylvania
United States	Geauga Hospital	Chardon	Ohio
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Atrium Health Pineville/LCI-Pineville	Charlotte	North Carolina
United States	Atrium Health University City/LCI-University	Charlotte	North Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Levine Cancer Institute-Ballantyne	Charlotte	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	Chelsea Hospital	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Advocate Illinois Masonic Medical Center	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Ascension Calumet Hospital	Chilton	Wisconsin
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon
United States	McLaren Cancer Institute-Clarkston	Clarkston	Michigan
United States	Wake Forest University at Clemmons	Clemmons	North Carolina
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Mission Cancer and Blood - West Des Moines	Clive	Iowa
United States	Memorial Hospital North	Colorado Springs	Colorado
United States	Rocky Mountain Cancer Centers-Penrose	Colorado Springs	Colorado
United States	UCHealth Memorial Hospital Central	Colorado Springs	Colorado
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Atrium Health Cabarrus/LCI-Concord	Concord	North Carolina
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	UM Sylvester Comprehensive Cancer Center at Coral Springs	Coral Springs	Florida
United States	Greater Regional Medical Center	Creston	Iowa
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	AMG Crystal Lake - Oncology	Crystal Lake	Illinois
United States	Noyes Memorial Hospital/Myers Cancer Center	Dansville	New York
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Henry Ford Medical Center-Fairlane	Dearborn	Michigan
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Essentia Health - Deer River Clinic	Deer River	Minnesota
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Porter Adventist Hospital	Denver	Colorado
United States	Broadlawns Medical Center	Des Moines	Iowa
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Henry Ford Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Advocate Good Samaritan Hospital	Downers Grove	Illinois
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Kaiser Permanente Dublin	Dublin	California
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Fox Chase Cancer Center - East Norriton Hospital Outpatient Center	East Norriton	Pennsylvania
United States	HSHS Sacred Heart Hospital	Eau Claire	Wisconsin
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Advocate Sherman Hospital	Elgin	Illinois
United States	UC San Diego Health System - Encinitas	Encinitas	California
United States	Ephrata Cancer Center	Ephrata	Pennsylvania
United States	UPMC Hillman Cancer Center Erie	Erie	Pennsylvania
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Inova Fair Oaks Hospital	Fairfax	Virginia
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Farmington Health Center	Farmington	Utah
United States	Parkland Health Center - Farmington	Farmington	Missouri
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	UPMC Cancer Center at UPMC Horizon	Farrell	Pennsylvania
United States	McLaren Cancer Institute-Flint	Flint	Michigan
United States	Singh and Arora Hematology Oncology PC	Flint	Michigan
United States	Cancer Care and Hematology-Fort Collins	Fort Collins	Colorado
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Ascension Saint Francis - Reiman Cancer Center	Franklin	Wisconsin
United States	Ascension Southeast Wisconsin Hospital - Franklin	Franklin	Wisconsin
United States	Kaiser Permanente-Fremont	Fremont	California
United States	Fresno Cancer Center	Fresno	California
United States	Kaiser Permanente-Fresno	Fresno	California
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	Fox Chase Cancer Center Buckingham	Furlong	Pennsylvania
United States	Gibbs Cancer Center-Gaffney	Gaffney	South Carolina
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Western Illinois Cancer Treatment Center	Galesburg	Illinois
United States	CaroMont Regional Medical Center	Gastonia	North Carolina
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Tidelands Georgetown Memorial Hospital	Georgetown	South Carolina
United States	Aurora Health Care Germantown Health Center	Germantown	Wisconsin
United States	The West Clinic - Wolf River	Germantown	Tennessee
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	Aurora Cancer Care-Grafton	Grafton	Wisconsin
United States	Corewell Health Grand Rapids Hospitals - Butterworth Hospital	Grand Rapids	Michigan
United States	Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	UCHealth Greeley Hospital	Greeley	Colorado
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	East Carolina University	Greenville	North Carolina
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Saint Francis Hospital	Greenville	South Carolina
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	UPMC Pinnacle Cancer Center/Community Osteopathic Campus	Harrisburg	Pennsylvania
United States	Hartford Hospital	Hartford	Connecticut
United States	Essentia Health-Hayward Clinic	Hayward	Wisconsin
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Essentia Health Hibbing Clinic	Hibbing	Minnesota
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii
United States	Hawaii Cancer Care Inc-Liliha	Honolulu	Hawaii
United States	Kaiser Permanente Moanalua Medical Center	Honolulu	Hawaii
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Kuakini Medical Center	Honolulu	Hawaii
United States	Queen's Cancer Cenrer - POB I	Honolulu	Hawaii
United States	Queen's Cancer Center - Kuakini	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	The Cancer Center of Hawaii-Liliha	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Novant Health Cancer Institute - Huntersville	Huntersville	North Carolina
United States	Novant Health Presbyterian Medical Center Huntersville	Huntersville	North Carolina
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Sidney and Lois Eskenazi Hospital	Indianapolis	Indiana
United States	City of Hope at Irvine Lennar	Irvine	California
United States	University of Wisconsin Carbone Cancer Center - Johnson Creek	Johnson Creek	Wisconsin
United States	UPMC-Johnstown/John P. Murtha Regional Cancer Center	Johnstown	Pennsylvania
United States	Freeman Health System	Joplin	Missouri
United States	Jupiter Medical Center	Jupiter	Florida
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	CHI Health Good Samaritan	Kearney	Nebraska
United States	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin
United States	Novant Health Cancer Institute - Kernersville	Kernersville	North Carolina
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	University of Tennessee - Knoxville	Knoxville	Tennessee
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	City of Hope Antelope Valley	Lancaster	California
United States	Karmanos Cancer Institute at McLaren Greater Lansing	Lansing	Michigan
United States	Mid-Michigan Physicians-Lansing	Lansing	Michigan
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	McLaren Cancer Institute-Lapeer Region	Lapeer	Michigan
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Lewistown Hospital	Lewistown	Pennsylvania
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Wilcox Memorial Hospital and Kauai Medical Clinic	Lihue	Hawaii
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Logan Regional Hospital	Logan	Utah
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Los Angeles General Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Jewish Hospital	Louisville	Kentucky
United States	Norton Brownsboro Hospital and Medical Campus	Louisville	Kentucky
United States	Norton Hospital Pavilion and Medical Campus	Louisville	Kentucky
United States	The James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky
United States	Medical Center of the Rockies	Loveland	Colorado
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	Cleveland Clinic Cancer Center Mansfield	Mansfield	Ohio
United States	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin
United States	Saint Mary's Oncology/Hematology Associates of Marlette	Marlette	Michigan
United States	Fremont - Rideout Cancer Center	Marysville	California
United States	Novant Health Cancer Institute - Matthews	Matthews	North Carolina
United States	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio
United States	Loyola University Medical Center	Maywood	Illinois
United States	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania
United States	UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion	Mechanicsburg	Pennsylvania
United States	Summa Health Medina Medical Center	Medina	Ohio
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	Ascension Columbia Saint Mary's Hospital Ozaukee	Mequon	Wisconsin
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	East Jefferson General Hospital	Metairie	Louisiana
United States	Miami Cancer Institute	Miami	Florida
United States	UM Sylvester Comprehensive Cancer Center at Kendall	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	UH Seidman Cancer Center at Southwest General Hospital	Middleburg Heights	Ohio
United States	Ascension Columbia Saint Mary's Hospital - Milwaukee	Milwaukee	Wisconsin
United States	Ascension Saint Francis Hospital	Milwaukee	Wisconsin
United States	Ascension Southeast Wisconsin Hospital - Saint Joseph Campus	Milwaukee	Wisconsin
United States	Aurora Cancer Care-Milwaukee	Milwaukee	Wisconsin
United States	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin
United States	Aurora Sinai Medical Center	Milwaukee	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Kaiser Permanente-Modesto	Modesto	California
United States	Atrium Health Union/LCI-Union	Monroe	North Carolina
United States	Forbes Hospital	Monroeville	Pennsylvania
United States	UPMC Cancer Center - Monroeville	Monroeville	Pennsylvania
United States	UPMC Hillman Cancer Center in Coraopolis	Moon	Pennsylvania
United States	Novant Health Cancer Institute - Mooresville	Mooresville	North Carolina
United States	Novant Health Cancer Institute - Mount Airy	Mount Airy	North Carolina
United States	McLaren Cancer Institute-Macomb	Mount Clemens	Michigan
United States	Palo Alto Medical Foundation-Camino Division	Mountain View	California
United States	Intermountain Medical Center	Murray	Utah
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Corewell Health Lakeland Hospitals - Niles Hospital	Niles	Michigan
United States	University of Kansas Cancer Center at North Kansas City Hospital	North Kansas City	Missouri
United States	Henry Ford Medical Center-Columbus	Novi	Michigan
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	Kaiser Permanente-Oakland	Oakland	California
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Olathe Health Cancer Center	Olathe	Kansas
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	Orlando Health Cancer Institute	Orlando	Florida
United States	Ascension Mercy Hospital	Oshkosh	Wisconsin
United States	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin
United States	Upstate Cancer Center at Oswego	Oswego	New York
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	Parker Adventist Hospital	Parker	Colorado
United States	University Hospitals Parma Medical Center	Parma	Ohio
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Mercy Health Perrysburg Cancer Center	Perrysburg	Ohio
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	McLaren Cancer Institute-Northern Michigan	Petoskey	Michigan
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Jefferson Torresdale Hospital	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	FirstHealth of the Carolinas-Moore Regional Hospital	Pinehurst	North Carolina
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Magee Womens Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Saint Clair Hospital Cancer Center	Pittsburgh	Pennsylvania
United States	UPMC-Saint Margaret	Pittsburgh	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	McLaren-Port Huron	Port Huron	Michigan
United States	Kaiser Permanente Northwest	Portland	Oregon
United States	Maine Medical Center-Bramhall Campus	Portland	Maine
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Naval Medical Center - Portsmouth	Portsmouth	Virginia
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Ascension All Saints Hospital	Racine	Wisconsin
United States	Aurora Cancer Care-Racine	Racine	Wisconsin
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	University Hospitals Portage Medical Center	Ravenna	Ohio
United States	Kaiser Permanente- Marshall Medical Offices	Redwood City	California
United States	Renown Regional Medical Center	Reno	Nevada
United States	Valley Medical Center	Renton	Washington
United States	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin
United States	Kaiser Permanente-Richmond	Richmond	California
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Riverton Hospital	Riverton	Utah
United States	Highland Hospital	Rochester	New York
United States	University of Rochester	Rochester	New York
United States	Levine Cancer Institute-Rock Hill	Rock Hill	South Carolina
United States	Rock Hill Radiation Therapy Center	Rock Hill	South Carolina
United States	UW Health Carbone Cancer Center Rockford	Rockford	Illinois
United States	Penobscot Bay Medical Center	Rockport	Maine
United States	Rohnert Park Cancer Center	Rohnert Park	California
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Kaiser Permanente-Roseville	Roseville	California
United States	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California
United States	Sutter Roseville Medical Center	Roseville	California
United States	The Permanente Medical Group-Roseville Radiation Oncology	Roseville	California
United States	Kaiser Permanente Downtown Commons	Sacramento	California
United States	Kaiser Permanente-South Sacramento	Sacramento	California
United States	South Sacramento Cancer Center	Sacramento	California
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan
United States	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Saint George Regional Medical Center	Saint George	Utah
United States	Dartmouth Cancer Center - North	Saint Johnsbury	Vermont
United States	Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Corewell Health Lakeland Hospitals - Saint Joseph Hospital	Saint Joseph	Michigan
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Salina Regional Health Center	Salina	Kansas
United States	Novant Health Cancer Institute - Rowan	Salisbury	North Carolina
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	LDS Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah
United States	Naval Medical Center -San Diego	San Diego	California
United States	UC San Diego Medical Center - Hillcrest	San Diego	California
United States	Kaiser Permanente-San Francisco	San Francisco	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Kaiser Permanente-Santa Teresa-San Jose	San Jose	California
United States	Stanford Cancer Center South Bay	San Jose	California
United States	Kaiser Permanente San Leandro	San Leandro	California
United States	Pacific Central Coast Health Center-San Luis Obispo	San Luis Obispo	California
United States	Kaiser San Rafael-Gallinas	San Rafael	California
United States	Essentia Health Sandstone	Sandstone	Minnesota
United States	North Coast Cancer Care	Sandusky	Ohio
United States	MaineHealth Cancer Care Center of York County	Sanford	Maine
United States	MaineHealth/SMHC Cancer Care and Blood Disorders-Sanford	Sanford	Maine
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Kaiser Permanente-Santa Rosa	Santa Rosa	California
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	Swedish Medical Center-Ballard Campus	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania
United States	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin
United States	Henry Ford Macomb Health Center - Shelby Township	Shelby	Michigan
United States	Memorial Hospital East	Shiloh	Illinois
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	City of Hope South Pasadena	South Pasadena	California
United States	Maine Medical Partners - South Portland	South Portland	Maine
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	Kaiser Permanente-South San Francisco	South San Francisco	California
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Essentia Health-Spooner Clinic	Spooner	Wisconsin
United States	Memorial Medical Center	Springfield	Illinois
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Novant Health Cancer Institute - Statesville	Statesville	North Carolina
United States	Wake Forest Baptist Health - Hematology Oncology - Statesville	Statesville	North Carolina
United States	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Kaiser Permanente-Stockton	Stockton	California
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Cleveland Clinic Cancer Center Strongsville	Strongsville	Ohio
United States	Aurora Medical Center in Summit	Summit	Wisconsin
United States	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California
United States	Essentia Health Saint Mary's Hospital - Superior	Superior	Wisconsin
United States	Novant Cancer Institute Radiation Oncology - Supply	Supply	North Carolina
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	SUNY Upstate Medical Center-Community Campus	Syracuse	New York
United States	Moffitt Cancer Center	Tampa	Florida
United States	Moffitt Cancer Center - McKinley Campus	Tampa	Florida
United States	Moffitt Cancer Center-International Plaza	Tampa	Florida
United States	Ascension Saint Joseph Hospital	Tawas City	Michigan
United States	Novant Health Cancer Institute - Thomasville	Thomasville	North Carolina
United States	Mercy Health - Saint Anne Hospital	Toledo	Ohio
United States	Mercy Health - Saint Vincent Hospital	Toledo	Ohio
United States	Mercy Health Sylvania Radiation Oncology Center	Toledo	Ohio
United States	Community Medical Center	Toms River	New Jersey
United States	University of Kansas Health System Saint Francis Campus	Topeka	Kansas
United States	City of Hope South Bay	Torrance	California
United States	Torrance Memorial Medical Center	Torrance	California
United States	Torrance Memorial Physician Network - Cancer Care	Torrance	California
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	Vince Lombardi Cancer Clinic-Two Rivers	Two Rivers	Wisconsin
United States	MGC Hematology Oncology-Union	Union	South Carolina
United States	UPMC Uniontown Hospital Radiation Oncology	Uniontown	Pennsylvania
United States	City of Hope Upland	Upland	California
United States	Kaiser Permanente Medical Center-Vacaville	Vacaville	California
United States	Kaiser Permanente-Vallejo	Vallejo	California
United States	Upstate Cancer Center at Verona	Verona	New York
United States	Essentia Health Virginia Clinic	Virginia	Minnesota
United States	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington
United States	Kaiser Permanente-Walnut Creek	Walnut Creek	California
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	UPMC Washington Hospital Radiation Oncology	Washington	Pennsylvania
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Ascension Medical Group Southeast Wisconsin - Mayfair Road	Wauwatosa	Wisconsin
United States	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin
United States	Wilmot Cancer Institute at Webster	Webster	New York
United States	Moffitt Cancer Center at Wesley Chapel	Wesley Chapel	Florida
United States	Aurora West Allis Medical Center	West Allis	Wisconsin
United States	Froedtert West Bend Hospital/Kraemer Cancer Center	West Bend	Wisconsin
United States	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan
United States	Saint Mary's Oncology/Hematology Associates of West Branch	West Branch	Michigan
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Methodist West Hospital	West Des Moines	Iowa
United States	Reading Hospital	West Reading	Pennsylvania
United States	UH Seidman Cancer Center at Saint John Medical Center	Westlake	Ohio
United States	UHHS-Westlake Medical Center	Westlake	Ohio
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Wexford Health and Wellness Pavilion	Wexford	Pennsylvania
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Novant Health Cancer Institute - Wilkesboro	Wilkesboro	North Carolina
United States	Wake Forest Baptist Health - Wilkes Medical Center	Wilkesboro	North Carolina
United States	Divine Providence Hospital	Williamsport	Pennsylvania
United States	Asplundh Cancer Pavilion	Willow Grove	Pennsylvania
United States	Novant Health Cancer Institute Radiation Oncology - Wilmington	Wilmington	North Carolina
United States	Novant Health New Hanover Regional Medical Center	Wilmington	North Carolina
United States	Novant Health Forsyth Medical Center	Winston-Salem	North Carolina
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio
United States	University of Michigan Health - West	Wyoming	Michigan
United States	UPMC Memorial	York	Pennsylvania
United States	WellSpan Health-York Cancer Center	York	Pennsylvania
United States	WellSpan Health-York Hospital	York	Pennsylvania
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of life	Measured by EuroQol-5 Dimensional- 5 Level (EQ-5D-5L).	Baseline up to 24 months from end of RT
Other	Swallowing physiology	Measured by a Modified Barium Swallow (MBS) test. The proportion of aspiration for each arm will be estimated assuming a binomial distribution and between arm comparison will be performed using a Fisher's exact test.	Up to 6 years
Other	Locoregional control for patients with post-RT FDG-PET/CT	Locoregional control rates will be compared between negative and positive/undetermined patients. Cox proportional hazards models will be used to determine whether there are differences between these two groups, while adjusting for treatment arm and other covariates (cause-specific Cox models for locoregional failure).	At 12-14 weeks post-RT
Other	PFS for patients with post-RT FDG-PET/CT	PFS rates will be compared between negative and positive/undetermined patients. Cox proportional hazards models will be used to determine whether there are differences between these two groups, while adjusting for treatment arm and other covariates (cause-specific Cox models for locoregional failure).	At 12-14 weeks post-RT
Primary	Progression-free survival (PFS) (Phase II)	Will be estimated for all treatment arms using the Kaplan-Meier method (1958). The primary phase IIR endpoint will be tested using a confidence interval (CI) approach.	Up to 6 years
Primary	PFS (Phase III)	Will be estimated for all treatment arms using the Kaplan-Meier method (1958). The co-primary phase III endpoint will be tested using a confidence interval (CI) approach.	Up to 6 years
Primary	Quality of life	Measured by the MD Anderson Dysphagia Inventory (MDADI) global quality of life (QOL) score. Will be compared between arms using a two-sample independent t-test at a one-sided significance level of 0.05 for each experimental arm comparison. MDADI global score and change from baseline will be summarized using mean and standard deviation at each time point for each arm.	Baseline up to 6 years
Secondary	Locoregional failure	The cumulative incidence estimator will be used to estimate time to event distributions for locoregional failure between arm differences tested using cause-specific log-rank test.	From the time of randomization to the date of failure, date of precluding event, or last known follow-up date, assessed up to 6 years
Secondary	Distant failure		Up to 6 years
Secondary	Overall survival	Will be estimated using the Kaplan-Meier method and treatment arms compared using the log-rank test (Kaplan 1958).	From the date of randomization to the date of death or last known follow-up date, with patients alive at the last known follow-up time treated as censored, assessed up to 6 years
Secondary	Incidence of adverse events	Measured by the Common Terminology Criteria for Adverse Events (CTCAE). Adverse events (AEs) will be graded using CTCAE version (v)5.0. Counts of all AEs by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm. The number of patients with at least 1 grade 3 or higher AE will be compared between the treatment arms. A comparison between treatment arms of grade 3 and higher AEs related to treatment will also be tested. A comparison of grade 3 and higher events will be compared between treatment arms. All comparisons will be tested using a Chi-Square test, or Fisher's exact test if cell frequencies are < 5, with a significance level of 0.05.	Up to 6 years
Secondary	Hearing	Measured as Hearing Handicap Inventory for Adults-Screening (HHIA-S).	Baseline up to 24 months from end of radiation therapy (RT)
Secondary	Quality of life	Measured by the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire (QLQ)30.	Baseline up to 24 months from end of RT
Secondary	Fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) locoregional control	Will be associated with PFS.	Up to 6 years
Secondary	Negative predictive value of post-RT FDG-PET/CT for locoregional control	The negative predictive value of FDG-PET/CT for locoregional control will be estimated using binomial proportions and confidence intervals based on normal approximation.	At 1 and 2 years
Secondary	Negative predictive value of post-RT FDG-PET/CT for PFS	The negative predictive value of FDG-PET/CT PFS will be estimated using binomial proportions and confidence intervals based on normal approximation.	At 1 and 2 years
Secondary	Incidence of adverse events	Measured using Patient-Reported Outcomes (PRO)-CTCAE. For each symptom, counts and frequencies will be provided for the worst score experienced by the patient by treatment arm. The proportion of patients with scores >= 1 and >= 3 will be compared between groups using a Chi-square test, or Fisher's exact test if cell frequencies are < 5, using a significance level of 0.05. Analysis of changes in patient reported outcomes over time will analyzed by fitting generalized estimating equations (GEE) models using a logit link (dichotomizing the symptom scores as 0 vs. > 1 and 0-2 vs. 3-4) with time of assessment, treatment arm, and treatment-by-time interaction terms in the model.	Up to 6 years