Stage III Oropharyngeal Squamous Cell Carcinoma, Stage IVA Oropharyngeal Squamous Cell Carcinoma, Stage IVB Oropharyngeal Squamous Cell Carcinoma, Stage IVC Oropharyngeal Squamous Cell Carcinoma, Tongue Carcinoma
Conditions
Brief summary
This randomized phase II trial studies the side effects and how well modestly reduced-dose intensity-modulated radiation therapy (IMRT) with or without cisplatin works in treating patients with oropharyngeal cancer that has spread to other places in the body (advanced). Radiation therapy uses high energy x rays to kill tumor cells. Drugs used in chemotherapy, 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. It is not yet known whether IMRT is more effective with or without cisplatin in treating patients with oropharyngeal cancer.
Detailed description
PRIMARY OBJECTIVES: -To select the arm(s) achieving a 2-year progression-free survival rate of \>= 85% without unacceptable swallowing toxicity at 1 year. SECONDARY OBJECTIVES: * To determine patterns of failure (locoregional relapse versus distant) and survival -(overall and progression-free) at 6 months and 2 years. * To determine acute toxicity profiles at the end of radiation therapy and at 1 and 6 months. * To determine late toxicity profiles at 1 and 2 years. * To determine patient-reported swallowing outcomes at 6 months and 1 and 2 years. * To determine the predictive value of 12-14 week, post-treatment fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/computed tomography (CT) for locoregional control and progression free survival (PFS) at 2 years. * To determine the predictive value of blood and tissue biomarkers for disease outcomes at 2 years. * To determine swallowing recovery per videofluoroscopy imaging at 2 years. After completion of study treatment, patients are followed at 1 and 3 months then every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Interventions
DRUGCisplatin
40 mg/m2 IV (intravenously) weekly for 6 weeks
RADIATIONIMRT 6 weeks
Intensity-modulated radiation therapy (IMRT), 30 fractions over 6 weeks, 5 fractions per week, 2 Gray per fraction to total dose of 60 Gy
RADIATIONIMRT 5 weeks
Intensity-modulated radiation therapy (IMRT), 30 fractions over 5 weeks, 6 fractions per week, 2 Gray per fraction to total dose of 60 Gy
Sponsors
NRG Oncology
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Step 1: Registration: 1. Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) 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). 2. Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. 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. 3. Immunohistochemical staining for p16 must be performed on tissue, and this tissue must be submitted for central review. Fine needle aspiration (FNA) biopsy specimens may be used as the sole diagnostic tissue if formalin-fixed paraffin-embedded cell block material is available for p16 immunohistochemistry. FNA specimens prepared with adequate p16 testing in this manner are acceptable to submit for central review. If the p16 preparation is not adequate, additional specimens will be required to establish p16 status. Centers are encouraged to contact the pathology chairs for clarification. 4. Clinical stage T1-T2, N1-N2b or T3, N0-N2b (AJCC, 7th ed.) including no distant metastases based on the following diagnostic workup: * General history and physical examination within 56 days prior to registration; * Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 70 days prior to registration; * One of the following combinations of imaging is required within 56 days prior to registration: 1. A computed tomography (CT) scan of the neck (with contrast) and a chest CT scan (with or without contrast); 2. or an MRI of the neck (with contrast) and a chest CT scan (with or without contrast); 3. or a CT scan of neck (with contrast) and a PET/CT of neck and chest (with or without contrast); 4. or an MRI of the neck (with contrast) and a PET/CT of neck and chest (with or without contrast). Note: A CT scan of neck and/or a PET/CT performed for the purposes of radiation planning may serve as both staging and planning tools. 5. 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 = \[Frequency of smoking (number of cigarettes per day) × duration of cigarette smoking (years)\] / 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. 6. Zubrod Performance Status of 0-1 within 56 days prior to registration; 7. Age ≥ 18; 8. The trial is open to both genders; 9. Adequate hematologic function within 14 days prior to registration, defined as follows: * Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; * Platelets ≥ 100,000 cells/mm3; * Hemoglobin (Hgb) ≥ 8.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable. 10. Adequate renal function within 14 days prior to registration, defined as follows: • Serum creatinine (Cr) \< 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula: * CC male = \[(140 - age) x (wt in kg)\] / \[(Serum Cr mg/dl) x (72)\] * CC female = 0.85 x (CC male) 11. Adequate hepatic function within 14 days prior to registration defined as follows: * Bilirubin \< 2 mg/dl; * Aspartate transaminase (AST) or alanine transaminase (ALT) \< 3 x the upper limit of normal. 12. Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential; 13. Patients who are HIV positive but have no prior Acquired Immune Deficiency Syndrome (AIDS) -defining illness and have CD4 cells of at least 350/mm3 are eligible. HIV-positive patients must not have multi-drug resistant HIV infection or other concurrent AIDS-defining conditions. Patients must not be sero-positive for Hepatitis B (Hepatitis B surface antigen positive or anti-hepatitis B core antigen positive) or sero-positive for Hepatitis C (anti-Hepatitis C antibody positive). However, patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B). 14. The patient must provide study-specific informed consent prior to study entry, including consent for mandatory submission of tissue for required, central p16 review. 15. Patients who speak English (or read one of the languages for which a translation is available (see Section 10.2) must consent to complete the mandatory dysphagia-related patient reported instrument (MDADI). If the patient cannot understand spoken English and reads only languages not available in the MDADI translations, the patient can still participate in the trial, as this has been factored into the trial statistics. For all other patients, the MDADI is mandatory as it is included in the primary endpoint to be studied. Step 2: Randomization: 16. p16 positive by immunohistochemistry (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells), confirmed by central pathology review; (see Section 10.1 for details).
Exclusion criteria
Step 1: Registration: 1. 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; 2. Carcinoma of the neck of unknown primary site origin (even if p16 positive); 3. Radiographically matted nodes, defined as 3 abutting nodes with loss of the intervening fat plane; 4. Supraclavicular nodes, defined as nodes visualized on the same axial imaging slice as the clavicle; 5. Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the clavicles; 6. Gross total excision of both primary and nodal disease with curative intent; 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. 7. Patients with simultaneous primary cancers or separate bilateral primary tumor sites are excluded with the exception of patients with bilateral tonsil cancers; 8. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible); 9. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable; 10. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields; 11. 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; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol other than those requested in Section 3.2.10. * Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition with immune compromise greater than that noted in Inclusion Criterion 13; 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. 12. Pregnancy; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. 13. Prior allergic reaction to cisplatin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Alive Without Progression at Two Years (Progression-free Survival) | From randomization to 2 years | Progression is defined as local, regional, or distant disease progression or death due to any cause. Percentage is estimated using the binomial distribution. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Local-regional Failure | From randomization to 2 years | Local-regional failure is defined as local or regional progression, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown \> 20 weeks after the end of radiation therapy, death due to study cancer without documented progression, or death due to unknown causes without documented progression. Distant metastasis and death due to other causes are considered competing risks. Local-regional failure time is defined as time from randomization to the date of first progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method. |
| Percentage of Participants With Distant Metastasis | From randomization to 2 years | Distant metastasis is defined as distant progression. Local-regional failure and death due to any cause are considered competing risks. Distant metastasis time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method. |
| Percentage of Participants Alive | from randomization to 2 years | Overall survival time is defined as time from randomization to the date of death or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. |
| Percentage of Participants With Grade 3+ Adverse Events | End of radiation therapy (RT) (approximately 6 weeks for Arm 1 and 5 weeks for Arm 2), then 1 month, 6 months, 1 year, and two years after end of RT | Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. |
| Mean One-year Total MD Anderson Dysphagia Inventory (MDADI) Score (Patient-reported Swallowing Outcome) | One year post-RT. Radiation therapy (RT) ends at approximately 6 weeks for Arm 1 and 5 weeks for Arm 2 | The MDADI is a 20-item tool with each item scored as Strongly agree; Agree; No opinion; Disagree; or Strongly disagree. There is 1 global item (G1), 6 emotional subscale items (E2-E7), 5 functional subscale items (F1-F5), and 8 physical subscale items (P1-P8). For all items except E7 and F2, Strongly agree corresponds to a score of 1, Agree 2, No opinion 3, Disagree 4, and Strongly disagree 5. For E7 and F2, the scores are reversed; these 2 items are rescored to match the others before calculating summary scores. The composite (total) score is the mean of the 19 items (other than G1) X 20. Composite scores range from 20 to 100 with higher scores indicating less dysphagia. |
| Negative Predictive Value (NPV) of Post-treatment FDG-PET/CT Scan [Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computed Tomography (CT)] for Progression-free Survival and Local-regional Control at Two Years | 3 months (scan) and two years after the end of RT (approximately 6 weeks for Arm 1 and 5 weeks for Arm 2) | NPV is the percentage of participants alive and failure-free at 2 years among those with a negative post-treatment scan, as evaluated by central review. Negative scan determined as follows: primary site, right neck, left neck evaluated using a 5-point ordinal scale: 1-Definite complete metabolic response (CMR), 2-Likely CMR, 3-Likely inflammatory, 4-Likely residual metabolic disease (RMD), and 5-Definite RMD. 'Negative'= 1 or 2, 'Indeterminate'=3, 'Positive' = 4 or 5. 'Negative' for all three evaluation sites = overall score of 'Negative.' Progression (failure) is defined as local, regional, or distant disease progression (PR) or any death. Local-regional progression (failure) is defined as local or regional PR, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown \> 20 weeks post RT, death due to study cancer or unknown causes without documented PR. The protocol specified that both arms would be combined for analysis. |
| Percentage of Participants Positive for Human Papillomavirus (HPV) Deoxyribonucleic Acid (DNA) After Treatment (Detection Rate) | Between 2 weeks to 1 month after treatment completion (approximately 6 weeks). | Positive HPV DNA status is defined as 5 or more HPV DNA fragments per mL of blood plasma, assessed by tumor-tissue modified viral (TTMV) testing. |
| Change in Number of HPV DNA Fragments/mL (Copy Number) From Baseline to During Treatment (HPV DNA Rate Decline) | Baseline and during treatment (obtained after 20 Gy of radiotherapy and before 28 Gy, approximately between day 10 and 14) | Calculated as treatment value - baseline value. HPV DNA was assessed by tumor-tissue modified viral (TTMV) testing. |
| Correlation of Baseline Log HPV DNA Copy Number and Gross Tumor Volume (GTV) | Baseline | HPV DNA copy number is the number of HPV DNA fragments per mL of blood plasma, assessed by tumor-tissue modified viral (TTMV) testing. The natural logarithm of HPV DNA copy is used to determine correlation. GTV is the volume of the tumor determined by imaging used for treatment planning. The summary data of these two measures are reported separately in corresponding outcome measures. Correlation is measured by the Pearson correlation coefficient and ranges from -1 to +1, where ±1 indicates the strongest possible (negative or positive) correlation and 0 indicates no correlation. The study protocol indicates that participants are analyzed as a single group, treatment arms combined. |
| Natural Logarithm (ln) of Baseline HPV DNA Copy Number [for Purpose of Correlation] | Baseline | HPV DNA copy number is the number of HPV DNA fragments per mL of blood plasma, assessed by tumor-tissue modified viral (TTMV) testing. The natural logarithm of HPV DNA copy is used to determine correlation with gross tumor volume. Note that a natural log, by definition, has no units. The study protocol indicates that participants are analyzed as a single group, treatment arms combined. Correlation of Baseline Log HPV DNA Copy Number and Gross Tumor Volume (GTV) are reported in another outcome measure. |
| Gross Tumor Volume (GTV) [for Purpose of Correlation] | Baseline | GTV is the volume of the tumor determined by imaging used for radiation treatment planning. The study protocol indicates that participants are analyzed as a single group, treatment arms combined. Correlation of Baseline Log HPV DNA Copy Number and Gross Tumor Volume (GTV) are reported in another outcome measure. |
| HPV DNA Status by 2-year Local-regional Failure Status | From end of treatment (approximate 6 weeks) to 2 years | Local-regional failure is defined as local or regional progression, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown \> 20 weeks after the end of radiation therapy, death due to study cancer without documented progression, or death due to unknown causes without documented progression. Positive HPV DNA status is defined as 5 or more HPV DNA fragments per mL of blood plasma, assessed by tumor-tissue modified viral (TTMV) testing. |
| HPV DNA Status by 2-year Progression-free Survival Status | From end of treatment (approximate 6 weeks) to 2 years | Progression-free survival (PFS) failure is defined as local, regional, or distant disease progression or death due to any cause. Positive HPV DNA status is defined as 5 or more HPV DNA fragments per mL of blood plasma, assessed by tumor-tissue modified viral (TTMV) testing. |
Countries
Canada, Ireland, Saudi Arabia, United States
Contacts
PRINCIPAL_INVESTIGATORSue Yom
NRG Oncology
Participant flow
Pre-assignment details
After first step registration and prior to randomization, patients were tested for p16. Only patients with p16-positive tumors continued on to randomization. In total, 316 patients were enrolled and 308 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| IMRT 6 Weeks + Cisplatin Cisplatin: 40 mg/m2 IV (intravenously) weekly for 6 weeks
IMRT 6 weeks: Intensity-modulated radiation therapy (IMRT), 30 fractions over 6 weeks, 5 fractions per week, 2 Gray per fraction to total dose of 60 Gy | 157 |
| IMRT 5 Weeks IMRT 5 weeks: Intensity-modulated radiation therapy (IMRT), 30 fractions over 5 weeks, 6 fractions per week, 2 Gray per fraction to total dose of 60 Gy | 149 |
| Total | 306 |
Baseline characteristics
| Characteristic | IMRT 5 Weeks | Total | IMRT 6 Weeks + Cisplatin |
|---|---|---|---|
| Age, Customized ≤ 49 | 14 Participants | 42 Participants | 28 Participants |
| Age, Customized 50 - 59 | 60 Participants | 116 Participants | 56 Participants |
| Age, Customized 60 - 69 | 55 Participants | 101 Participants | 46 Participants |
| Age, Customized ≥ 70 | 20 Participants | 47 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 10 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 130 Participants | 273 Participants | 143 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 12 Participants | 23 Participants | 11 Participants |
| N stage, clinical N0 | 7 Participants | 13 Participants | 6 Participants |
| N stage, clinical N1 | 34 Participants | 62 Participants | 28 Participants |
| N stage, clinical N2a | 19 Participants | 43 Participants | 24 Participants |
| N stage, clinical N2b | 89 Participants | 188 Participants | 99 Participants |
| Primary tumor site Base of tongue | 58 Participants | 126 Participants | 68 Participants |
| Primary tumor site Oropharynx NOS (not otherwise specified) | 13 Participants | 17 Participants | 4 Participants |
| Primary tumor site Pharyngeal oropharynx | 0 Participants | 1 Participants | 1 Participants |
| Primary tumor site Posterior pharyngeal wall | 0 Participants | 1 Participants | 1 Participants |
| Primary tumor site Tonsillar fossa, tonsil | 78 Participants | 161 Participants | 83 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 16 Participants | 4 Participants |
| Race (NIH/OMB) White | 130 Participants | 281 Participants | 151 Participants |
| Radiation Therapy (RT) planning (as stratified) Bilateral | 102 Participants | 207 Participants | 105 Participants |
| Radiation Therapy (RT) planning (as stratified) Unilateral | 47 Participants | 99 Participants | 52 Participants |
| RT planning (per central review) Bilateral | 125 Participants | 261 Participants | 136 Participants |
| RT planning (per central review) Unilateral | 21 Participants | 37 Participants | 16 Participants |
| RT planning (per central review) Unknown | 3 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Female | 25 Participants | 49 Participants | 24 Participants |
| Sex: Female, Male Male | 124 Participants | 257 Participants | 133 Participants |
| Smoking history (pack years) 0 | 101 Participants | 213 Participants | 112 Participants |
| Smoking history (pack years) >0 - <5 | 32 Participants | 58 Participants | 26 Participants |
| Smoking history (pack years) 5 - 10 | 16 Participants | 35 Participants | 19 Participants |
| T stage, clinical T1 | 51 Participants | 115 Participants | 64 Participants |
| T stage, clinical T2 | 80 Participants | 147 Participants | 67 Participants |
| T stage, clinical T3 | 18 Participants | 44 Participants | 26 Participants |
| Zubrod performance status 0: Asymptomatic | 113 Participants | 245 Participants | 132 Participants |
| Zubrod performance status 1: Symptomatic but completely ambulatory | 36 Participants | 61 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 152 | 6 / 147 |
| other Total, other adverse events | 152 / 152 | 147 / 147 |
| serious Total, serious adverse events | 31 / 152 | 11 / 147 |
Outcome results
Primary
Percentage of Participants Alive Without Progression at Two Years (Progression-free Survival)
Progression is defined as local, regional, or distant disease progression or death due to any cause. Percentage is estimated using the binomial distribution.
Time frame: From randomization to 2 years
Population: Two-year data was available for 147/157 (Arm 1) and 145/149 (Arm 2) randomized and eligible participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants Alive Without Progression at Two Years (Progression-free Survival) | 90.5 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants Alive Without Progression at Two Years (Progression-free Survival) | 87.6 percentage of participants |
Comparison: Assuming a binomial distribution, 140 eligible patients per arm were required for 80% power and 1-sided type I error rate of 10% to test the null hypothesis of 2-year progression-free survival (PFS) rate ≤ 85% against the alternative hypothesis of \> 85% with a binomial test. The arms are not compared to each other; they are each tested separately against the null hypothesis.p-value: 0.04binomial
Comparison: Assuming a binomial distribution, 140 eligible patients per arm were required for 80% power and 1-sided type I error rate of 10% to test the null hypothesis of 2-year PFS rate ≤ 85% against the alternative hypothesis of \> 85% with a binomial test. The arms are not compared to each other; they are each tested separately against the null hypothesis.p-value: 0.23bionmial
Secondary
Change in Number of HPV DNA Fragments/mL (Copy Number) From Baseline to During Treatment (HPV DNA Rate Decline)
Calculated as treatment value - baseline value. HPV DNA was assessed by tumor-tissue modified viral (TTMV) testing.
Time frame: Baseline and during treatment (obtained after 20 Gy of radiotherapy and before 28 Gy, approximately between day 10 and 14)
Population: Eligible patients with baseline and during treatment HPV DNA values.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Change in Number of HPV DNA Fragments/mL (Copy Number) From Baseline to During Treatment (HPV DNA Rate Decline) | -1.06 fragments/mL |
| IMRT 5 Weeks (Arm 2) | Change in Number of HPV DNA Fragments/mL (Copy Number) From Baseline to During Treatment (HPV DNA Rate Decline) | -0.22 fragments/mL |
p-value: 0.03t-test, 2 sided
Secondary
Correlation of Baseline Log HPV DNA Copy Number and Gross Tumor Volume (GTV)
HPV DNA copy number is the number of HPV DNA fragments per mL of blood plasma, assessed by tumor-tissue modified viral (TTMV) testing. The natural logarithm of HPV DNA copy is used to determine correlation. GTV is the volume of the tumor determined by imaging used for treatment planning. The summary data of these two measures are reported separately in corresponding outcome measures. Correlation is measured by the Pearson correlation coefficient and ranges from -1 to +1, where ±1 indicates the strongest possible (negative or positive) correlation and 0 indicates no correlation. The study protocol indicates that participants are analyzed as a single group, treatment arms combined.
Time frame: Baseline
Population: Eligible participants with baseline HPV DNA value
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Correlation of Baseline Log HPV DNA Copy Number and Gross Tumor Volume (GTV) | 0.30 correlation coefficient |
Secondary
Gross Tumor Volume (GTV) [for Purpose of Correlation]
GTV is the volume of the tumor determined by imaging used for radiation treatment planning. The study protocol indicates that participants are analyzed as a single group, treatment arms combined. Correlation of Baseline Log HPV DNA Copy Number and Gross Tumor Volume (GTV) are reported in another outcome measure.
Time frame: Baseline
Population: Eligible participants with baseline HPV DNA value
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Gross Tumor Volume (GTV) [for Purpose of Correlation] | 25.7 mL |
Secondary
HPV DNA Status by 2-year Local-regional Failure Status
Local-regional failure is defined as local or regional progression, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown \> 20 weeks after the end of radiation therapy, death due to study cancer without documented progression, or death due to unknown causes without documented progression. Positive HPV DNA status is defined as 5 or more HPV DNA fragments per mL of blood plasma, assessed by tumor-tissue modified viral (TTMV) testing.
Time frame: From end of treatment (approximate 6 weeks) to 2 years
Population: Eligible participants with post-treatment HPV DNA value and two-year local-regional failure data (i.e. not censored)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | HPV DNA Status by 2-year Local-regional Failure Status | HPV DNA Negative | 114 Participants |
| IMRT 6 Weeks + Cisplatin (Arm 1) | HPV DNA Status by 2-year Local-regional Failure Status | HPV DNA Positive | 6 Participants |
| IMRT 5 Weeks (Arm 2) | HPV DNA Status by 2-year Local-regional Failure Status | HPV DNA Negative | 6 Participants |
| IMRT 5 Weeks (Arm 2) | HPV DNA Status by 2-year Local-regional Failure Status | HPV DNA Positive | 2 Participants |
p-value: 0.08Fisher Exact
Secondary
HPV DNA Status by 2-year Progression-free Survival Status
Progression-free survival (PFS) failure is defined as local, regional, or distant disease progression or death due to any cause. Positive HPV DNA status is defined as 5 or more HPV DNA fragments per mL of blood plasma, assessed by tumor-tissue modified viral (TTMV) testing.
Time frame: From end of treatment (approximate 6 weeks) to 2 years
Population: Eligible participants with post-treatment HPV DNA value and two-year progression-free survival data (i.e. not censored)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | HPV DNA Status by 2-year Progression-free Survival Status | HPV DNA Negative | 112 Participants |
| IMRT 6 Weeks + Cisplatin (Arm 1) | HPV DNA Status by 2-year Progression-free Survival Status | HPV DNA Positive | 5 Participants |
| IMRT 5 Weeks (Arm 2) | HPV DNA Status by 2-year Progression-free Survival Status | HPV DNA Negative | 8 Participants |
| IMRT 5 Weeks (Arm 2) | HPV DNA Status by 2-year Progression-free Survival Status | HPV DNA Positive | 3 Participants |
p-value: 0.02Fisher Exact
Secondary
Mean One-year Total MD Anderson Dysphagia Inventory (MDADI) Score (Patient-reported Swallowing Outcome)
The MDADI is a 20-item tool with each item scored as Strongly agree; Agree; No opinion; Disagree; or Strongly disagree. There is 1 global item (G1), 6 emotional subscale items (E2-E7), 5 functional subscale items (F1-F5), and 8 physical subscale items (P1-P8). For all items except E7 and F2, Strongly agree corresponds to a score of 1, Agree 2, No opinion 3, Disagree 4, and Strongly disagree 5. For E7 and F2, the scores are reversed; these 2 items are rescored to match the others before calculating summary scores. The composite (total) score is the mean of the 19 items (other than G1) X 20. Composite scores range from 20 to 100 with higher scores indicating less dysphagia.
Time frame: One year post-RT. Radiation therapy (RT) ends at approximately 6 weeks for Arm 1 and 5 weeks for Arm 2
Population: Randomized and eligible participants. Questionnaires were not completed by all participants. 121 Arm 1 and 106 Arm 2 participants had one year post-RT data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Mean One-year Total MD Anderson Dysphagia Inventory (MDADI) Score (Patient-reported Swallowing Outcome) | 85.3 score on a scale |
| IMRT 5 Weeks (Arm 2) | Mean One-year Total MD Anderson Dysphagia Inventory (MDADI) Score (Patient-reported Swallowing Outcome) | 81.8 score on a scale |
Secondary
Natural Logarithm (ln) of Baseline HPV DNA Copy Number [for Purpose of Correlation]
HPV DNA copy number is the number of HPV DNA fragments per mL of blood plasma, assessed by tumor-tissue modified viral (TTMV) testing. The natural logarithm of HPV DNA copy is used to determine correlation with gross tumor volume. Note that a natural log, by definition, has no units. The study protocol indicates that participants are analyzed as a single group, treatment arms combined. Correlation of Baseline Log HPV DNA Copy Number and Gross Tumor Volume (GTV) are reported in another outcome measure.
Time frame: Baseline
Population: Eligible participants with baseline HPV DNA value
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Natural Logarithm (ln) of Baseline HPV DNA Copy Number [for Purpose of Correlation] | 5.3 ln fragments per mL |
Secondary
Negative Predictive Value (NPV) of Post-treatment FDG-PET/CT Scan [Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computed Tomography (CT)] for Progression-free Survival and Local-regional Control at Two Years
NPV is the percentage of participants alive and failure-free at 2 years among those with a negative post-treatment scan, as evaluated by central review. Negative scan determined as follows: primary site, right neck, left neck evaluated using a 5-point ordinal scale: 1-Definite complete metabolic response (CMR), 2-Likely CMR, 3-Likely inflammatory, 4-Likely residual metabolic disease (RMD), and 5-Definite RMD. 'Negative'= 1 or 2, 'Indeterminate'=3, 'Positive' = 4 or 5. 'Negative' for all three evaluation sites = overall score of 'Negative.' Progression (failure) is defined as local, regional, or distant disease progression (PR) or any death. Local-regional progression (failure) is defined as local or regional PR, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown \> 20 weeks post RT, death due to study cancer or unknown causes without documented PR. The protocol specified that both arms would be combined for analysis.
Time frame: 3 months (scan) and two years after the end of RT (approximately 6 weeks for Arm 1 and 5 weeks for Arm 2)
Population: Randomized and eligible participants with negative post-treatment PET
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Negative Predictive Value (NPV) of Post-treatment FDG-PET/CT Scan [Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computed Tomography (CT)] for Progression-free Survival and Local-regional Control at Two Years | Progression-free Survival | 92.0 percentage of participants |
| IMRT 6 Weeks + Cisplatin (Arm 1) | Negative Predictive Value (NPV) of Post-treatment FDG-PET/CT Scan [Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computed Tomography (CT)] for Progression-free Survival and Local-regional Control at Two Years | Local-regional failure | 94.5 percentage of participants |
Comparison: Progression-free survival: The null hypothesis of negative predictive value ≤ 90% was tested against the alternative of \> 90% with a 1-sided binomial test at the 0.10 level.p-value: 0.3binomial test
Comparison: Local-regional control: The null hypothesis of negative predictive value ≤ 90% was tested against the alternative of \> 90% with a 1-sided binomial test at the 0.10 level.p-value: 0.07binomial test
Secondary
Percentage of Participants Alive
Overall survival time is defined as time from randomization to the date of death or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.
Time frame: from randomization to 2 years
Population: Randomized and eligible participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants Alive | Six months | 99.3 percentage of participants |
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants Alive | Two years | 96.7 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants Alive | Six months | 98.0 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants Alive | Two years | 97.3 percentage of participants |
p-value: 0.9395% CI: [0.31, 2.95]Log Rank
Secondary
Percentage of Participants Positive for Human Papillomavirus (HPV) Deoxyribonucleic Acid (DNA) After Treatment (Detection Rate)
Positive HPV DNA status is defined as 5 or more HPV DNA fragments per mL of blood plasma, assessed by tumor-tissue modified viral (TTMV) testing.
Time frame: Between 2 weeks to 1 month after treatment completion (approximately 6 weeks).
Population: Eligible participants with post-treatment HPV DNA value
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants Positive for Human Papillomavirus (HPV) Deoxyribonucleic Acid (DNA) After Treatment (Detection Rate) | 3.3 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants Positive for Human Papillomavirus (HPV) Deoxyribonucleic Acid (DNA) After Treatment (Detection Rate) | 8.7 percentage of participants |
p-value: 0.28Fisher Exact
Secondary
Percentage of Participants With Distant Metastasis
Distant metastasis is defined as distant progression. Local-regional failure and death due to any cause are considered competing risks. Distant metastasis time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method.
Time frame: From randomization to 2 years
Population: Randomized and eligible participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants With Distant Metastasis | Six months | 0 percentage of participants |
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants With Distant Metastasis | Two years | 4.0 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants With Distant Metastasis | Six months | 0 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants With Distant Metastasis | Two years | 2.1 percentage of participants |
p-value: 0.5895% CI: [0.4, 5.08]Log Rank
Secondary
Percentage of Participants With Grade 3+ Adverse Events
Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.
Time frame: End of radiation therapy (RT) (approximately 6 weeks for Arm 1 and 5 weeks for Arm 2), then 1 month, 6 months, 1 year, and two years after end of RT
Population: Randomized and eligible participants who started study treatment. Adverse event data was not available for all participants at each time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants With Grade 3+ Adverse Events | End of RT | 73.7 percentage of participants |
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants With Grade 3+ Adverse Events | 6 months post-RT | 17.9 percentage of participants |
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants With Grade 3+ Adverse Events | 2 years post-RT | 8.6 percentage of participants |
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants With Grade 3+ Adverse Events | 1 year post-RT | 14.0 percentage of participants |
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants With Grade 3+ Adverse Events | 1 month post-RT | 36.1 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants With Grade 3+ Adverse Events | 1 year post-RT | 9.0 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants With Grade 3+ Adverse Events | End of RT | 46.3 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants With Grade 3+ Adverse Events | 1 month post-RT | 28.2 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants With Grade 3+ Adverse Events | 6 months post-RT | 11.1 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants With Grade 3+ Adverse Events | 2 years post-RT | 7.4 percentage of participants |
Comparison: End of RTp-value: <0.0001Fisher Exact
Comparison: One month after end of RTp-value: 0.17Fisher Exact
Comparison: Six months after end of RTp-value: 0.16Fisher Exact
Comparison: One year after end of RTp-value: 0.26Fisher Exact
Comparison: Two years after the end of RTp-value: 0.82Fisher Exact
Secondary
Percentage of Participants With Local-regional Failure
Local-regional failure is defined as local or regional progression, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown \> 20 weeks after the end of radiation therapy, death due to study cancer without documented progression, or death due to unknown causes without documented progression. Distant metastasis and death due to other causes are considered competing risks. Local-regional failure time is defined as time from randomization to the date of first progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method.
Time frame: From randomization to 2 years
Population: Randomized and eligible participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants With Local-regional Failure | Six months | 0.7 percentage of participants |
| IMRT 6 Weeks + Cisplatin (Arm 1) | Percentage of Participants With Local-regional Failure | Two years | 3.3 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants With Local-regional Failure | Six months | 2.0 percentage of participants |
| IMRT 5 Weeks (Arm 2) | Percentage of Participants With Local-regional Failure | Two years | 9.5 percentage of participants |
p-value: 0.0295% CI: [0.17, 0.9]Log Rank