Squamous Cell Carcinomas
Conditions
Keywords
Reduced radiotherapy, Randomization, Phase III, Reduced radiation therapy, head and neck, oropharynx, unknown primary (cervical lymph nodes), nasopharynx primary, HPV, p16
Brief summary
This trial aims to directly compare a reduced radiation dose to the standard of care in HPVOPC for non-inferiority, thus allowing for direct comparison of outcomes between the two groups. The study hypothesis is that LRC and PFS at 3 years for reduced dose CRT are non-inferior to standard dose CRT.
Detailed description
This is a randomized Phase III study comparing two doses of definitive radiation therapy given with induction and concurrent chemotherapy in HPV-positive oropharynx, unknown primary or nasopharynx cancer. Eligible, consented and registered patients will receive three cycles of Docetaxel Cisplatin and 5-FU (TPF) induction chemotherapy. After 3 cycles, the patients will be assessed for clinical, radiographic and pathologic response to TPF. Patients with a clinical or radiographic CR or PR will be randomized on the second phase of this study, where patients will undergo a 2:1 randomization to reduced (5600 cGy) or standard (7000 cGy) dose radiotherapy with weekly Carboplatin. Patients not meeting the response criteria will be treated with standard dose CRT. Patients not completing 3 cycles TPF for reasons of toxicity, progressive disease, choice, or other medical necessity will be treated with standard dose CRT or surgery depending on their primary site and overall medical condition and followed for survival. Toxicity will be assessed by Symptom scores, QOL and SAE monitoring. The primary end point of the trial is equivalent local regional control and PFS at 3 years. Patients will be followed for 5 years.
Interventions
RADIATIONReduced Dose Radiation
Reduced Dose Radiation (5600 cGy) dose radiotherapy
RADIATIONStandard Dose Radiation
Standard Dose Radiation (7000 cGy) dose radiotherapy
DRUGCarboplatin
Day 1, every 7 days ( + 2 days)
Sponsors
Icahn School of Medicine at Mount Sinai
Biodesign Institute
Arizona State University
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
* Participants must have histologically or cytologically confirmed squamous cell carcinoma of the oropharynx, unknown primary, or nasopharynx that is HPV positive as determined by PCR and p16 positive as determined by IHC. Tissue from the primary site must be available for biomarker studies. PCR and IHC must be performed in the central laboratory (Zhang, MSSM) * Stage 3 or 4 disease without evidence of distant metastases. * At least one clinically evaluable or uni- or bi-dimensionally measurable lesion by RECIST 1.1 criteria. * Age \> 18 years. * No previous surgery, radiation therapy or chemotherapy for SSCHN (other than biopsy or tonsillectomy) is allowed at time of study entry. * ECOG performance status of 0 or 1. * No active alcohol addiction (as assessed by medical caregiver and defined as at least 6 months without activity). * Participants must have adequate bone marrow, hepatic and renal functions as defined in the protocol. * Ability to understand and the willingness to sign a written informed consent document. * Patients with Gilbert's Disease and absent hepatic pathology by history and clinical assessment maybe treated on study with bilirubins \> the ULN for the institution if other liver function studies are within the normal range
Exclusion criteria
* Pregnant or breast feeding women, or women and men of childbearing potential not willing to use adequate contraception while on treatment and for at least 3 months thereafter. * Previous or current malignancies at other sites, with the exception of adequately treated in situ carcinoma of the cervix, basal or squamous cell carcinoma of the skin, thyroid cancer, or other cancer curatively treated by surgery and with no current evidence of disease for at least 5 years. * Symptomatic peripheral neuropathy ≥ grade 2 by NCI Common Terminology Criteria (NCI-CTC) version 4. * Symptomatic altered hearing \> grade 2 by NCI-CTCv4 criteria. * Other serious illnesses or medical conditions including but not limited to: 1. Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry 2. History of significant neurologic or psychiatric disorders including dementia or seizures 3. Active clinically significant uncontrolled infection 4. Active peptic ulcer disease defined as unhealed or clinically active 5. Hypercalcemia 6. Active drug addiction including alcohol, cocaine or intravenous drug use defined as occurring within the 6 months preceding diagnosis 7. Chronic Obstructive Pulmonary Disease, defined as being associated with a hospitalization for pneumonia or respiratory decompensation within 12 months of diagnosis. This does not include obstruction from tumor 8. Autoimmune disease requiring therapy, prior organ transplant, or HIV infection 9. Interstitial lung disease 10. Hepatitis C (test required) * Patients that have experienced an involuntary weight loss of more than 25% of their body weight in the 2 months preceding study entry. * Concurrent treatment with any other anticancer therapy. * Participation in an investigational therapeutic drug trial within 30 days of study entry. * Active smoking within the past 20 years with a cumulative Pack Year history of \> 20 Pack Years or active smoking (Defined as \> 1 cigarette per day) within the last 2 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Progression Free Survival (PFS) | at 3 and 5 years | Progression free survival (PFS) at 5 years in patients with advanced HPV related oropharynx cancer, nasopharynx cancer or unknown primary treated with reduced or standard dose radiation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Local-regional Control | at 3 years | Local-regional control (LRC) at 3 years in patients with advanced HPV related oropharynx cancer or unknown primary treated with reduced or standard dose radiation. |
| Number of Participants With Overall Survival at 5 Years | at 5 years | Overall Survival (OS) 5 years treated with reduced or standard dose CRT. |
| Number of Participants With Acute Toxicity of Chemoradiotherapy (CRT) | at 5 years | Number of participants with acute toxicity treated with reduced or standard dose CRT. |
| Biomarkers Predictive of Failure | at 5 years | To determine biomarkers predictive of failure with either reduced or standard dose radiotherapy. |
| Overall Survival at 15 Years | at 15 years | — |
| Change in MD Anderson Dysphagia Inventory (MDADI) From Baseline | Baseline and 5 years | MDADI is a questionnaire of 20 questions and contains a global subscale, and three other categories of questions (emotional, functional, and physical). The scores are summed and a mean score is calculated. This mean score was multiplied by 20 to obtain a score, with a range of 0 (extremely low functioning) to 100 (high functioning). Thus, a higher MDADI score represented better day-to-day functioning and better QOL. |
| Change in MD Anderson Symptom Inventory Symptom Inventory and Severity (MDASI-HN SI and SS) | Baseline and 5 years | MD Anderson Symptom Inventory Symptom Inventory and Severity (MDASI-HN SI and SS) MDASI Head and Neck is a site-specific MDASI module which includes the core MDASI 13 symptom severity items (SS) and 6 symptom interference items (SI), alongside 9 items relevant to head and neck cancer. The scores are summed and a mean score is calculated on a scale of 0 (low severity or interference) to 10 (high severity or complete interference). In order to calculate the mean score, a majority of the subscale's items must have been completed. A lower or negative score reflects a better quality of life compared to baseline. |
| Change in Xerostomia Questionnaire (XQ) | Baseline and 5 years | XQ is a nine questions survey developed specifically for xerostomia symptoms. The scores are summed and a mean score is calculated on a scale of 0 (low xerostomia interference) to 10 (high xerostomia interference). A lower or negative score reflects a better quality of life compared to baseline. |
| Change in European Organization for Research and Treatment of Cancer Questionnaire for Head and Neck (EORTC HN) | Baseline and 5 years | The EORTC Head and Neck module was specifically designed and validated for head and neck cancer patients. This 35-item questionnaire contains 7 symptom scales (pain, swallowing, senses, speech, social eating, social contact, and sexuality), 6 single-item scales (difficulties of teeth, mouth opening, dry mouth, sticky saliva, coughing, and feeling ill), and 5 items about the additional use of pain medicine, nutritional supplements, and feeding tube and changes in body weight. All items were transformed to scales from 0 to 100, and divided into respective sub-scores of global health (GHS), functional (FS), and symptom scale (SS). Subscales from 0-100. A high score on global health and functional scale represents a better level of functioning, whereas a high score on a symptom scale and head and neck module indicates more severe symptoms. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORKrzysztof Misiukiewicz, M.D.
Icahn School of Medicine at Mount Sinai
Participant flow
Pre-assignment details
23 participants were assessed and started in pre-randomization induction phase. Participants were not randomized until after they completed the pre-randomization phase and TPF induction.
Participants by arm
| Arm | Count |
|---|---|
| Reduced Dose Radiation After TPF induction chemotherapy patients randomized to receive a reduced (5600 cGy) dose radiotherapy with weekly Carboplatin
Reduced Dose Radiation: Reduced Dose Radiation (5600 cGy) dose radiotherapy
Carboplatin: Day 1, every 7 days ( + 2 days) | 12 |
| Standard Dose Radiation After TPF induction chemotherapy patients randomized to receive a standard (7000 cGy) dose radiotherapy with carboplatin
Standard Dose Radiation: Standard Dose Radiation (7000 cGy) dose radiotherapy
Carboplatin: Day 1, every 7 days ( + 2 days) | 8 |
| Total | 20 |
Baseline characteristics
| Characteristic | Standard Dose Radiation | Total | Reduced Dose Radiation |
|---|---|---|---|
| Age, Continuous | 57 years | 56.5 years | 55 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 18 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HPV Status HPV 16 | 6 Participants | 16 Participants | 10 Participants |
| HPV Status Other than HPV 16 | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 4 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 14 Participants | 8 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 8 Participants | 19 Participants | 11 Participants |
| Smoking Status 10-20 pack-years | 3 Participants | 3 Participants | 0 Participants |
| Smoking Status <10 pack-years | 2 Participants | 5 Participants | 3 Participants |
| Smoking Status Never smoker | 3 Participants | 12 Participants | 9 Participants |
| Tumor Site Base of Tongue (BOT) | 5 Participants | 10 Participants | 5 Participants |
| Tumor Site Tonsil | 3 Participants | 10 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 2 / 12 | 1 / 8 |
| other Total, other adverse events | 0 / 0 | 9 / 12 | 8 / 8 |
| serious Total, serious adverse events | 0 / 0 | 2 / 12 | 2 / 8 |
Outcome results
Primary
Number of Participants With Progression Free Survival (PFS)
Progression free survival (PFS) at 5 years in patients with advanced HPV related oropharynx cancer, nasopharynx cancer or unknown primary treated with reduced or standard dose radiation.
Time frame: at 3 and 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Reduced Dose Radiation | Number of Participants With Progression Free Survival (PFS) | at 3 years | 10 Participants |
| Reduced Dose Radiation | Number of Participants With Progression Free Survival (PFS) | at 5 years | 10 Participants |
| Standard Dose Radiation | Number of Participants With Progression Free Survival (PFS) | at 3 years | 7 Participants |
| Standard Dose Radiation | Number of Participants With Progression Free Survival (PFS) | at 5 years | 7 Participants |
Secondary
Biomarkers Predictive of Failure
To determine biomarkers predictive of failure with either reduced or standard dose radiotherapy.
Time frame: at 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reduced Dose Radiation | Biomarkers Predictive of Failure | 0 biomarkers |
| Standard Dose Radiation | Biomarkers Predictive of Failure | 0 biomarkers |
Secondary
Change in European Organization for Research and Treatment of Cancer Questionnaire for Head and Neck (EORTC HN)
The EORTC Head and Neck module was specifically designed and validated for head and neck cancer patients. This 35-item questionnaire contains 7 symptom scales (pain, swallowing, senses, speech, social eating, social contact, and sexuality), 6 single-item scales (difficulties of teeth, mouth opening, dry mouth, sticky saliva, coughing, and feeling ill), and 5 items about the additional use of pain medicine, nutritional supplements, and feeding tube and changes in body weight. All items were transformed to scales from 0 to 100, and divided into respective sub-scores of global health (GHS), functional (FS), and symptom scale (SS). Subscales from 0-100. A high score on global health and functional scale represents a better level of functioning, whereas a high score on a symptom scale and head and neck module indicates more severe symptoms.
Time frame: Baseline and 5 years
Population: Of the 20 participants, 3 had progression of disease, and 2 were excluded due to insufficient survey compliance.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reduced Dose Radiation | Change in European Organization for Research and Treatment of Cancer Questionnaire for Head and Neck (EORTC HN) | EORTC GHS | 5.95 score on a scale | Standard Deviation 27.52 |
| Reduced Dose Radiation | Change in European Organization for Research and Treatment of Cancer Questionnaire for Head and Neck (EORTC HN) | EORTC FS | 5.14 score on a scale | Standard Deviation 30.38 |
| Reduced Dose Radiation | Change in European Organization for Research and Treatment of Cancer Questionnaire for Head and Neck (EORTC HN) | EORTC SS | -3.91 score on a scale | Standard Deviation 22.36 |
| Reduced Dose Radiation | Change in European Organization for Research and Treatment of Cancer Questionnaire for Head and Neck (EORTC HN) | EORTC HN | -2.80 score on a scale | Standard Deviation 20.55 |
| Standard Dose Radiation | Change in European Organization for Research and Treatment of Cancer Questionnaire for Head and Neck (EORTC HN) | EORTC HN | 8.97 score on a scale | Standard Deviation 5.55 |
| Standard Dose Radiation | Change in European Organization for Research and Treatment of Cancer Questionnaire for Head and Neck (EORTC HN) | EORTC GHS | -30.56 score on a scale | Standard Deviation 31.55 |
| Standard Dose Radiation | Change in European Organization for Research and Treatment of Cancer Questionnaire for Head and Neck (EORTC HN) | EORTC SS | 14.97 score on a scale | Standard Deviation 20.67 |
| Standard Dose Radiation | Change in European Organization for Research and Treatment of Cancer Questionnaire for Head and Neck (EORTC HN) | EORTC FS | -6.33 score on a scale | Standard Deviation 19.01 |
Secondary
Change in MD Anderson Dysphagia Inventory (MDADI) From Baseline
MDADI is a questionnaire of 20 questions and contains a global subscale, and three other categories of questions (emotional, functional, and physical). The scores are summed and a mean score is calculated. This mean score was multiplied by 20 to obtain a score, with a range of 0 (extremely low functioning) to 100 (high functioning). Thus, a higher MDADI score represented better day-to-day functioning and better QOL.
Time frame: Baseline and 5 years
Population: Of the 20 participants, 3 had progression of disease, and 2 were excluded due to insufficient survey compliance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reduced Dose Radiation | Change in MD Anderson Dysphagia Inventory (MDADI) From Baseline | -8.12 score on a scale | Standard Deviation 26.21 |
| Standard Dose Radiation | Change in MD Anderson Dysphagia Inventory (MDADI) From Baseline | -8.93 score on a scale | Standard Deviation 18.31 |
Secondary
Change in MD Anderson Symptom Inventory Symptom Inventory and Severity (MDASI-HN SI and SS)
MD Anderson Symptom Inventory Symptom Inventory and Severity (MDASI-HN SI and SS) MDASI Head and Neck is a site-specific MDASI module which includes the core MDASI 13 symptom severity items (SS) and 6 symptom interference items (SI), alongside 9 items relevant to head and neck cancer. The scores are summed and a mean score is calculated on a scale of 0 (low severity or interference) to 10 (high severity or complete interference). In order to calculate the mean score, a majority of the subscale's items must have been completed. A lower or negative score reflects a better quality of life compared to baseline.
Time frame: Baseline and 5 years
Population: Of the 20 participants, 3 had progression of disease, and 2 were excluded due to insufficient survey compliance.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reduced Dose Radiation | Change in MD Anderson Symptom Inventory Symptom Inventory and Severity (MDASI-HN SI and SS) | MDASI-HN SI | 0.64 score on a scale | Standard Deviation 4.4 |
| Reduced Dose Radiation | Change in MD Anderson Symptom Inventory Symptom Inventory and Severity (MDASI-HN SI and SS) | MDASI-HN SS | 0.52 score on a scale | Standard Deviation 2.11 |
| Standard Dose Radiation | Change in MD Anderson Symptom Inventory Symptom Inventory and Severity (MDASI-HN SI and SS) | MDASI-HN SI | 1.56 score on a scale | Standard Deviation 1.92 |
| Standard Dose Radiation | Change in MD Anderson Symptom Inventory Symptom Inventory and Severity (MDASI-HN SI and SS) | MDASI-HN SS | 1.48 score on a scale | Standard Deviation 1.16 |
Secondary
Change in Xerostomia Questionnaire (XQ)
XQ is a nine questions survey developed specifically for xerostomia symptoms. The scores are summed and a mean score is calculated on a scale of 0 (low xerostomia interference) to 10 (high xerostomia interference). A lower or negative score reflects a better quality of life compared to baseline.
Time frame: Baseline and 5 years
Population: Of the 20 participants, 3 had progression of disease, and 2 were excluded due to insufficient survey compliance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reduced Dose Radiation | Change in Xerostomia Questionnaire (XQ) | 2.18 score on a scale | Standard Deviation 4.07 |
| Standard Dose Radiation | Change in Xerostomia Questionnaire (XQ) | 4.38 score on a scale | Standard Deviation 2.39 |
Secondary
Number of Participants With Acute Toxicity of Chemoradiotherapy (CRT)
Number of participants with acute toxicity treated with reduced or standard dose CRT.
Time frame: at 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Reduced Dose Radiation | Number of Participants With Acute Toxicity of Chemoradiotherapy (CRT) | 3 Participants |
| Standard Dose Radiation | Number of Participants With Acute Toxicity of Chemoradiotherapy (CRT) | 1 Participants |
Secondary
Number of Participants With Local-regional Control
Local-regional control (LRC) at 3 years in patients with advanced HPV related oropharynx cancer or unknown primary treated with reduced or standard dose radiation.
Time frame: at 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Reduced Dose Radiation | Number of Participants With Local-regional Control | 10 Participants |
| Standard Dose Radiation | Number of Participants With Local-regional Control | 7 Participants |
Secondary
Number of Participants With Overall Survival at 5 Years
Overall Survival (OS) 5 years treated with reduced or standard dose CRT.
Time frame: at 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Reduced Dose Radiation | Number of Participants With Overall Survival at 5 Years | 10 Participants |
| Standard Dose Radiation | Number of Participants With Overall Survival at 5 Years | 7 Participants |
Secondary
Overall Survival at 15 Years
Time frame: at 15 years