Human Papillomavirus-Related Carcinoma, Oropharyngeal Cancer
Conditions
Keywords
Radiation Dose Hypofractionation
Brief summary
This is a single arm Phase I study of de-intensified hypofractionated radiation therapy for favorable human papilloma virus-associated oropharynx cancer. It will evaluate the tolerability of a de-intensified hypofractionated radiation therapy regimen completed in 3 weeks (with equivalent biologically effective dose to 60 Gy in 30 fractions) with concurrent weekly cisplatin.
Detailed description
Standard of care radiation therapy (RT) for head and neck squamous cell carcinoma (HNSCC) involves conventional fractionation delivered over a course of 7 weeks. Although hypofractionated RT (HFRT) delivering higher dose of RT each day over a shorter overall treatment time has been studied and adopted as standard of care in many disease sites including breast and prostate cancers, data on HFRT in HNSCC is limited. There is a strong radiobiological rationale for HFRT for HNSCC to decrease the overall treatment time and thus the effects of accelerated repopulation in this disease entity. In addition, if similar outcomes can be achieved with a reduced number of fractions, cost effectiveness of care can be improved while minimizing the disruption to the patient's personal and professional lives. A substantial decrease in treatment time may improve compliance and financial toxicity associated with the patient's oncologic treatment. The global COVID-19 pandemic is highlighting the health risk to society at large of having no viable alternative to a 7 week daily RT course for HNSCC, especially in the setting of compromised immune systems associated with concurrent chemotherapy frequently used in this patient population. Thus, the study of HFRT for HNSCC is both timely and potentially paradigm changing for practices across the United States. The incidence of human papilloma virus (HPV)-associated oropharynx cancer is increasing in the United States, now accounting for 70-80% of all oropharynx cancers. It has a favorable prognosis vs. non-HPV-associated cancers and studies are ongoing to determine the best strategy to de-intensified therapy while maintaining good oncologic outcomes. The purpose of this single-arm Phase I study is to assess the tolerability and signal for efficacy of de-intensified HFRT for favorable HPV-associated oropharynx cancer. De-intensification will be achieved in two ways. First, the equivalent biologically effective dose (BED) of HFRT used on trial will be 60 Gy of conventionally fractionationated RT (vs. the current standard of care of 70 Gy). Second, the elective nodal volume irradiated will be limited to involved nodal levels and one immediately adjacent level (vs. the current standard of care of entire bilateral neck nodal regions). Patients will complete RT in 15 fractions (3 weeks) with concurrent weekly cisplatin on dose level 0. If a 3-week regimen is not well-tolerated, a 20 fraction regimen will be used on dose level -1.
Interventions
Hypofractionated intensity modulated radiotherapy with concurrent chemotherapy (weekly cisplatin)
Sponsors
Gateway for Cancer Research
University of Texas Southwestern Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Rolling 6 dose finding cohort followed by dose expansion cohort
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Pathologically-proven diagnosis of T1-3 (up to 6 cm), N0-2 (AJCC 8th edition) p16 positive squamous cell carcinoma of the oropharynx (except T1-2N0 as noted in the
Exclusion criteria
) 2. ≤10 pack-year smoking history and not actively smoking 3. Age ≥18 years 4. ECOG performance status 0-2 or Karnofsky Performance Status 50-100 5. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 6. Negative serum or urine pregnancy test within 2 weeks before registration for women of childbearing potential. 7. Ability to understand and the willingness to sign a written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximally Tolerated Dose/Fractionation of Hypofractionated Radiation Therapy | 3 months | The number of participants experiencing dose-limiting toxicities (DLTs) will be used to determine the maximally tolerated dose (MTD) or optimal fractionation of hypofractionated radiation therapy. Level 0: 46.5 Gy in 15 fractions Level -1: 52 Gy in 20 fractions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinician-reported Late Toxicities | 3-12 months | As measured by CTCAE v5.0 |
| Percentage of Participants With Locoregional Control | 12 months | Locoregional control defined as freedom from locoregional recurrence. Locoregional recurrence defined as biopsy-proven viable cancer originating from the primary tumor site (i.e. oropharynx) or a lymph node basin above the clavicles. |
| Percentage of Participants With Progression Free Survival | 1-12 months | Progression-free survival defined as time from start of treatment to time of progression or death. |
| Percentage of Participants With Overall Survival | 24 months | Overall survival defined as time from start of treatment o time of death. |
| Clinician-reported Acute Toxicities | 0-3 months | Toxicities as measured by CTCAE v5.0 |
| Head and Neck Patient-reported Quality of Life | 1-12 months | Change from baseline in head and neck patient-reported outcomes quality of life, as measured by the University of Washington Quality of Life questionnaire (UW-QOL), assessed at specified time points (baseline,1, 3, 6, and 12 months) during and after treatment. Higher scores on UW-QOL subscales indicate better quality of life, 0 being worst and 100 being the best outcome. A paired t test was used to compare questionnaire results over time with P \< .05 considered statistically significant. UW-QOL was divided into 2 subscales of physical and social-emotional function with change of 0.5 x standard deviation (SD) and 0.8 x SD considered moderate and large effect, respectively. Scale title: Patient-reported quality of life at baseline and after treatment (0-100) Physical UW-QOL minimum: 45.83 Physical UW-QOL maximum: 100 Social-Emotional UW-QOL minimum: 17.5 Social-Emotional UW-QOL maximum: 100 |
| General Patient-reported Quality of Life | 1-12 months | EuroQol-5 dimensions (EQ-5D-5L): 1-5, higher scores mean worse quality of life. Index score: 0-1, higher scores mean better quality of life. Visual Analog scale: 0-100, higher scores mean better quality of life. |
| Feeding Tube Dependence | 1-12 months | Dependence on tube feeds defined as any participant with daily use of ≥2 nutritional supplements per day via the feeding tube at the time of evaluation. |
| Swallowing-related Patient-reported Quality of Life | 1-12 months | Change from baseline in swallowing-related quality of life, as measured by the MD Anderson Dysphagia Inventory (MDADI) total score, assessed at specified time points (baseline,1, 3, 6, and 12 months) during and after treatment. Higher scores indicate better function, 0-100. Analyses were descriptive, and a paired t test was used to compare questionnaire results over time with P \< .05 considered statistically significant. MDADI composite score difference of 10 was deemed clinically meaningful. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Phase: Hypofractionated Radiotherapy With Cisplatin 46.5 Gy in 15 fractions, 5 fractions/week, with (weekly cisplatin 40 mg/m2) | 6 |
| Dose Expansion Phase: Hypofractionated Radiotherapy With Cisplatin 46.5 Gy in 15 fractions, 5 fractions/week, with (weekly cisplatin 40 mg/m2) | 18 |
| Total | 24 |
Baseline characteristics
| Characteristic | Dose Escalation Phase: Hypofractionated Radiotherapy With Cisplatin | Dose Expansion Phase: Hypofractionated Radiotherapy With Cisplatin | Total |
|---|---|---|---|
| Age, Customized Age (median range) | 59.6 years | 58.9 years | 59.5 years |
| Race/Ethnicity, Customized Race/ethnicity African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/ethnicity Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/ethnicity Hispanic | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race/ethnicity Other/unknown | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Race/ethnicity White | 4 Participants | 14 Participants | 18 Participants |
| Region of Enrollment United States | 6 Participants | 18 Participants | 24 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 18 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 24 |
| other Total, other adverse events | 24 / 24 |
| serious Total, serious adverse events | 6 / 24 |
Outcome results
Primary
Maximally Tolerated Dose/Fractionation of Hypofractionated Radiation Therapy
The number of participants experiencing dose-limiting toxicities (DLTs) will be used to determine the maximally tolerated dose (MTD) or optimal fractionation of hypofractionated radiation therapy. Level 0: 46.5 Gy in 15 fractions Level -1: 52 Gy in 20 fractions
Time frame: 3 months
Population: Patients were enrolled using a rolling 6 design at dose level 0 (46.5 Gy in 15 fractions). Enrollment was paused to assess dose-limiting toxicity (DLT; grade 4 toxicity or persistent grade 3 mucositis ≤ 3 months post-treatment). Dose level 0 was evaluated for DLT occurrence. Following this, an expansion cohort was opened, bringing total enrollment to 24 participants. No participants were enrolled at dose level -1 (52 Gy in 20 fractions).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hypofractionated radiotherapy with concurrent chemotherapy | Maximally Tolerated Dose/Fractionation of Hypofractionated Radiation Therapy | 0 Participants |
Comparison: Estimation Parameter: Maximally Tolerated Dose/Fractionation Description: The maximally tolerated dose (MTD)/fractionation of hypofractionated radiation therapy was determined based on the incidence of dose-limiting toxicities (DLTs) observed during the dose-escalation phase.~Estimate: 46.5 Gy × 15 fractions
Secondary
Clinician-reported Acute Toxicities
Toxicities as measured by CTCAE v5.0
Time frame: 0-3 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Oral mucositis (grade 3) | 5 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Oral mucositis (grade 2) | 15 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Odynophagia/sore throat (grade 2) | 18 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Weight loss/anorexia (grade 2) | 13 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Dysphagia ( grade 2) | 11 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Dysgeusia (grade 2) | 9 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Xerostomia (grade 2) | 7 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Nausea/vomiting (grade 2) | 2 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Odynophagia/sore throat (grade 3) | 1 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Weight loss/anorexia (grade 3) | 2 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Dysphagia (grade 3) | 2 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Acute Toxicities | Nausea/vomiting (grade 3) | 1 Participants |
Secondary
Clinician-reported Late Toxicities
As measured by CTCAE v5.0
Time frame: 3-12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Late Toxicities | Dysphagia (grade 2) | 1 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Late Toxicities | Weight loss/anorexia (grade 2) | 1 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Late Toxicities | Xerostomia (grade 2) | 1 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Late Toxicities | Grade 3 AE | 0 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Late Toxicities | Grade 4 AE | 0 Participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Clinician-reported Late Toxicities | Grade 5 AE | 0 Participants |
Secondary
Feeding Tube Dependence
Dependence on tube feeds defined as any participant with daily use of ≥2 nutritional supplements per day via the feeding tube at the time of evaluation.
Time frame: 1-12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hypofractionated radiotherapy with concurrent chemotherapy | Feeding Tube Dependence | Acute follow up period | 2 participants |
| Hypofractionated radiotherapy with concurrent chemotherapy | Feeding Tube Dependence | Late follow up period | 1 participants |
Secondary
General Patient-reported Quality of Life
EuroQol-5 dimensions (EQ-5D-5L): 1-5, higher scores mean worse quality of life. Index score: 0-1, higher scores mean better quality of life. Visual Analog scale: 0-100, higher scores mean better quality of life.
Time frame: 1-12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hypofractionated radiotherapy with concurrent chemotherapy | General Patient-reported Quality of Life | Index score Enrollment | 0.916 score on a scale | Standard Deviation 0.163 |
| Hypofractionated radiotherapy with concurrent chemotherapy | General Patient-reported Quality of Life | Index score 1 mo | 0.879 score on a scale | Standard Deviation 0.107 |
| Hypofractionated radiotherapy with concurrent chemotherapy | General Patient-reported Quality of Life | Index score 3 mo | 0.909 score on a scale | Standard Deviation 0.12 |
| Hypofractionated radiotherapy with concurrent chemotherapy | General Patient-reported Quality of Life | Index score 6 mo | 0.915 score on a scale | Standard Deviation 0.166 |
| Hypofractionated radiotherapy with concurrent chemotherapy | General Patient-reported Quality of Life | Index score 12 mo | 0.933 score on a scale | Standard Deviation 0.103 |
| Hypofractionated radiotherapy with concurrent chemotherapy | General Patient-reported Quality of Life | Visual Analog Scale Enrollment | 86.8 score on a scale | Standard Deviation 12.4 |
| Hypofractionated radiotherapy with concurrent chemotherapy | General Patient-reported Quality of Life | Visual Analog Scale 1 mo | 79.1 score on a scale | Standard Deviation 11.5 |
| Hypofractionated radiotherapy with concurrent chemotherapy | General Patient-reported Quality of Life | Visual Analog Scale 3 mo | 81.9 score on a scale | Standard Deviation 12 |
| Hypofractionated radiotherapy with concurrent chemotherapy | General Patient-reported Quality of Life | Visual Analog Scale 6 mo | 86.1 score on a scale | Standard Deviation 9.8 |
| Hypofractionated radiotherapy with concurrent chemotherapy | General Patient-reported Quality of Life | Visual Analog Scale 12 mo | 88.9 score on a scale | Standard Deviation 8 |
Secondary
Head and Neck Patient-reported Quality of Life
Change from baseline in head and neck patient-reported outcomes quality of life, as measured by the University of Washington Quality of Life questionnaire (UW-QOL), assessed at specified time points (baseline,1, 3, 6, and 12 months) during and after treatment. Higher scores on UW-QOL subscales indicate better quality of life, 0 being worst and 100 being the best outcome. A paired t test was used to compare questionnaire results over time with P \< .05 considered statistically significant. UW-QOL was divided into 2 subscales of physical and social-emotional function with change of 0.5 x standard deviation (SD) and 0.8 x SD considered moderate and large effect, respectively. Scale title: Patient-reported quality of life at baseline and after treatment (0-100) Physical UW-QOL minimum: 45.83 Physical UW-QOL maximum: 100 Social-Emotional UW-QOL minimum: 17.5 Social-Emotional UW-QOL maximum: 100
Time frame: 1-12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hypofractionated radiotherapy with concurrent chemotherapy | Head and Neck Patient-reported Quality of Life | Physical Baseline | 93.4 score on a scale | Standard Deviation 9.9 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Head and Neck Patient-reported Quality of Life | Physical 1 mo | 74.9 score on a scale | Standard Deviation 11.4 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Head and Neck Patient-reported Quality of Life | Physical 3 mo | 80.3 score on a scale | Standard Deviation 11.3 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Head and Neck Patient-reported Quality of Life | Physical 6 mo | 84.8 score on a scale | Standard Deviation 11.7 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Head and Neck Patient-reported Quality of Life | Physical 12 mo | 85.3 score on a scale | Standard Deviation 11.7 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Head and Neck Patient-reported Quality of Life | Social-Emotional Baseline | 89.4 score on a scale | Standard Deviation 16.5 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Head and Neck Patient-reported Quality of Life | Social-Emotional 1 mo | 79.9 score on a scale | Standard Deviation 10.3 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Head and Neck Patient-reported Quality of Life | Social-Emotional 3 mo | 87.6 score on a scale | Standard Deviation 10 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Head and Neck Patient-reported Quality of Life | Social-Emotional 6 mo | 90.0 score on a scale | Standard Deviation 13.8 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Head and Neck Patient-reported Quality of Life | Social-Emotional 12 mo | 92.1 score on a scale | Standard Deviation 10.4 |
Secondary
Percentage of Participants With Locoregional Control
Locoregional control defined as freedom from locoregional recurrence. Locoregional recurrence defined as biopsy-proven viable cancer originating from the primary tumor site (i.e. oropharynx) or a lymph node basin above the clavicles.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hypofractionated radiotherapy with concurrent chemotherapy | Percentage of Participants With Locoregional Control | 86.2 percentage of participants |
Secondary
Percentage of Participants With Overall Survival
Overall survival defined as time from start of treatment o time of death.
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hypofractionated radiotherapy with concurrent chemotherapy | Percentage of Participants With Overall Survival | 95.8 percentage of participants |
Secondary
Percentage of Participants With Progression Free Survival
Progression-free survival defined as time from start of treatment to time of progression or death.
Time frame: 1-12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hypofractionated radiotherapy with concurrent chemotherapy | Percentage of Participants With Progression Free Survival | 82 percentage of participants |
Secondary
Swallowing-related Patient-reported Quality of Life
Change from baseline in swallowing-related quality of life, as measured by the MD Anderson Dysphagia Inventory (MDADI) total score, assessed at specified time points (baseline,1, 3, 6, and 12 months) during and after treatment. Higher scores indicate better function, 0-100. Analyses were descriptive, and a paired t test was used to compare questionnaire results over time with P \< .05 considered statistically significant. MDADI composite score difference of 10 was deemed clinically meaningful.
Time frame: 1-12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hypofractionated radiotherapy with concurrent chemotherapy | Swallowing-related Patient-reported Quality of Life | Baseline | 86.5 score on a scale | Standard Deviation 13.7 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Swallowing-related Patient-reported Quality of Life | 1 mo | 77.9 score on a scale | Standard Deviation 11.6 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Swallowing-related Patient-reported Quality of Life | 3 mo | 85.5 score on a scale | Standard Deviation 11.3 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Swallowing-related Patient-reported Quality of Life | 6 mo | 87.8 score on a scale | Standard Deviation 12.3 |
| Hypofractionated radiotherapy with concurrent chemotherapy | Swallowing-related Patient-reported Quality of Life | 12 mo | 89.4 score on a scale | Standard Deviation 9.4 |