De-intensification of Radiation and Chemotherapy for Low-Risk HPV-related Oropharyngeal SCC: Follow-up Study

De-intensification of Radiation and Chemotherapy for Low-Risk HPV-related Oropharyngeal Squamous Cell Carcinoma

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02281955

Enrollment

115

Registered

2014-11-04

Start date

2014-08-31

Completion date

2024-11-24

Last updated

2025-01-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Carcinoma, Squamous Cell, Head and Neck Neoplasms, Oropharyngeal Neoplasms

Keywords

Human Papillomavirus, Oropharynx, Oropharyngeal Squamous Cell Carcinoma, Squamous Cell Carcinoma, Radiation Therapy, Chemotherapy, p16

Brief summary

The purpose of this research study is to learn about the effectiveness of using lower-intensity radiation and chemotherapy to treat human papillomavirus (HPV) associated low-risk oropharyngeal and/or unknown primary squamous cell carcinomas of the head and neck. The cure rate for this type of cancer is estimated to be high, \> 90%. The standard treatment for this cancer is 7 weeks of radiation with 3 high doses of cisplatin. Sometimes surgery is performed afterwards. This standard regimen causes a lot of side effects and long term complications. This study is evaluating whether a lower dose of radiation and chemotherapy may provide a similar cure rate as the longer, more intensive standard regimen. Patients in this study will receive 1 less week of radiation and a lower weekly dose of chemotherapy.

Detailed description

The proposed study is a follow-up study to NCT01530997. In NCT01530997, patients with HPV positive and/or p16 positive low-risk oropharyngeal squamous cell carcinoma (OPSCC) received de-intensified chemoradiotherapy (CRT) followed by a limited surgical evaluation. The primary endpoint of NCT01530997 was the rate of pathological complete response (pCR) after CRT. Power computations were performed for N=40 and were based on the null hypothesis (H0) that the pCR for de-intensified chemoradiotherapy is at least 87%, the historical rate. The type 1 error for this calculation was 14.2%. 43 patients enrolled and 38 were evaluable for the primary endpoint. The observed pCR rate was 89% (34/38). Since the observed pCR rate was excellent in NCT01530997 and was in concordance with the expected rate, in the proposed study we will not mandate a post-CRT surgical evaluation. Instead a PET/CT 10 to 16 weeks post-CRT will be used to determine whether a surgical evaluation is needed.

Interventions

RADIATIONIntensity Modulated Radiotherapy (IMRT)

All patients will receive Intensity Modulated Radiotherapy Treatments (IMRT). Dose painting IMRT will be used and all doses will be specified to the planning target volume (PTV). The high risk planning target volume (PTV-HR) and standard risk planning target volume (PTV-SR) will be treated to the following respective total doses: 60 Gy and 54 Gy. The dose per fraction to the PTV-HR and PTV-SR will be 2 Gy per day and 1.8 Gy per day respectively. The PTV-HR will include the gross tumor and the PTV-SR will include areas at risk for harboring subclinical microscopic disease.

DRUGCisplatin (or alternative)

Cisplatin is the preferred mandated first choice chemotherapy, however alternative weekly regimens are permissible. Justification for not using cisplatin must be documented. Chemotherapy will be given intravenously weekly during IMRT. 6 total doses will be given. It is preferred that the doses be administered on days 1, 8, 15, 22, 29, and 36; however, this is not mandatory. Chemotherapy will not be given to patients with T0-2 N0-1 disease, ≤ 10 pack years smoking history.

PROCEDUREAssessment for surgical evaluation

Decisions for surgical evaluation will be based on the results of the PET/CT 10 to 16 weeks after CRT and clinical exam (including fiberoptic laryngoscopy) at that time. Other optional imaging studies may be performed. Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of the surgeon, with the goal being to remove any suspected residual tumor with a negative resection margin while maintaining organ preservation. This may include biopsies and/or oncological resections of the primary tumor and lymph node metastases. Patients with a negative PET/CT scan will be observed.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. ≥ 18 years of age (no upper age limit) 2. T0-3, N0 to N2c, M0 squamous cell carcinoma of the oropharynx 3. Biopsy proven squamous cell carcinoma that is HPV and/or p16 positive 4. ≤ 10 pack-years smoking history or ≤ 30 pack-years smoking history WITH ≥ 5 years abstinence from smoking 5. Radiologic confirmation of the absence of hematogenous metastasis within 12 weeks prior to treatment 6. ECOG Performance Status 0-1 7. CBC/differential obtained within 8 weeks prior to treatment, with adequate bone marrow function defined as follows: Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 8.0 g/dl. 8. Adequate renal and hepatic function within 4 weeks prior to registration, defined as follows: Serum creatinine \< 2.0 mg/dl; Total bilirubin \< 2 x the institutional ULN; AST or ALT \< 3 x the institutional ULN. 9. Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential 10. Women of childbearing potential and male participants who are sexually active must practice adequate contraception during treatment and for 6 weeks following treatment. 11. Patients must be deemed able to comply with the treatment plan and follow-up schedule. 12. Patients must provide study specific informed consent prior to study entry

Exclusion criteria

1. Prior history of radiation therapy to the head and neck 2. Prior history of head and neck cancer. 3. Unresectable disease (e.g. immobile node on physical exam, nodal disease that radiographically involves the carotid arteries, nerves) 4. Currently taking Disease Modifying Rheumatoid Drugs (DMRDs) 5. 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 at the time of registration; Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects (Note, however, coagulation parameters are not required for entry into this protocol); Pre-existing ≥ grade 2 neuropathy; Prior organ transplant; Systemic lupus; Psoriatic arthritis. 6. Known HIV positive.

Design outcomes

Primary

Measure	Time frame	Description
2 Year Progression Free Survival After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC)	Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks)	Progression Free Survival (PFS) was defined as the time from the beginning of treatment to cancer progression or death. The outcome measure will be reported as the proportion of patients with PFS at 2 years post-treatment.

Secondary

Measure	Time frame	Description
2 Year Local Control (LC) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC)	Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks).	The outcome measure will be reported as the proportion of patients with LC at 2 years post-treatment.
2 Year Regional Control (RC) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC)	Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks).	The outcome measure will be reported as the proportion of patients with RC at 2 years post-treatment.
2 Year Local-regional Control (LRC) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC)	Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks).	The outcome measure will be reported as the proportion of patients with LRC at 2 years post-treatment.
2 Year Distant Metastasis Free Survival (DMFS) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC)	Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks).	The outcome measure will be reported as the proportion of patients with DMFS at 2 years post-treatment.
2 Year Overall Survival (OS) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC)	Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks).	The outcome measure will be reported as the proportion of patients who are still alive (overall survival) at 2 years post-treatment.

Countries

United States

Participant flow

Recruitment details

Enrolling institutions included University of North Carolina Hospitals (Chapel Hill, NC), University of Florida Hospitals (Gainesville, FL), Rex Hospital (Raleigh, NC), High Point Regional Health (High Point, NC), and Pardee Memorial Hospital (Hendersonville, NC).

Pre-assignment details

115 patients were accrued. One patient voluntarily withdrew prior to treatment. One patient died during treatment secondary to neutropenic sepsis.

Participants by arm

Arm	Count
De-escalated Radiation and Chemotherapy All patients were treated with Intensity Modulated Radiotherapy (IMRT). The total dose to the high-risk regions was 60 Gy at 2 Gy per fraction, 30 fractions, 5 days a week, for 6 weeks. Fifty-four gray was delivered to anatomic regions at risk of subclinical disease as indicated. Unilateral radiotherapy was permitted in patients with well-lateralized tonsil primaries. Cisplatin 30 mg/m2 once per week was the mandated first-choice chemotherapy; however, alternative regimens once per week were permissible. Chemotherapy was given intravenously once per week, preferably on Mondays. Six weekly doses were given concurrently with radiation. Dose modifications were allowed as needed per the treating medical oncologist's discretion. If a patient could not tolerate cisplatin for more than 1 week, he or she was switched to an alternative regimen. Chemotherapy was not given to patients with T0-2 N0-1 disease (AJCC 7th edition).	114
Total	114

Arm

Count

De-escalated Radiation and Chemotherapy

All patients were treated with Intensity Modulated Radiotherapy (IMRT). The total dose to the high-risk regions was 60 Gy at 2 Gy per fraction, 30 fractions, 5 days a week, for 6 weeks. Fifty-four gray was delivered to anatomic regions at risk of subclinical disease as indicated. Unilateral radiotherapy was permitted in patients with well-lateralized tonsil primaries. Cisplatin 30 mg/m2 once per week was the mandated first-choice chemotherapy; however, alternative regimens once per week were permissible. Chemotherapy was given intravenously once per week, preferably on Mondays. Six weekly doses were given concurrently with radiation. Dose modifications were allowed as needed per the treating medical oncologist's discretion. If a patient could not tolerate cisplatin for more than 1 week, he or she was switched to an alternative regimen. Chemotherapy was not given to patients with T0-2 N0-1 disease (AJCC 7th edition).

114

Total

114

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Death	1

Baseline characteristics

Characteristic	De-escalated Radiation and Chemotherapy
Age, Continuous	62 years
HPV/p16 Status HPV-/p16+	12 Participants
HPV/p16 Status HPV+/p16+	46 Participants
HPV/p16 Status HPV unknown/p16+	56 Participants
Marital Status Married	90 Participants
Marital Status Unknown	1 Participants
Marital Status Unmarried	23 Participants
N Stage (AJCC 7th edition) N0	18 Participants
N Stage (AJCC 7th edition) N1	16 Participants
N Stage (AJCC 7th edition) N2a	5 Participants
N Stage (AJCC 7th edition) N2b	57 Participants
N Stage (AJCC 7th edition) N2c	18 Participants
N Stage (AJCC 8th edition) N0	18 Participants
N Stage (AJCC 8th edition) N1	78 Participants
N Stage (AJCC 8th edition) N2	18 Participants
Primary Tumor Location Base of tongue	57 Participants
Primary Tumor Location Tonsil	52 Participants
Primary Tumor Location Unknown primary	5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	7 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants
Race (NIH/OMB) White	104 Participants
Region of Enrollment United States	114 participants
Sex: Female, Male Female	18 Participants
Sex: Female, Male Male	96 Participants
Tobacco Use <= 10 pack-years	38 Participants
Tobacco Use > 10 pack-years	22 Participants
Tobacco Use Never smoked	54 Participants
T Stage T0	5 Participants
T Stage T1	35 Participants
T Stage T2	61 Participants
T Stage T3	13 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	5 / 114
other Total, other adverse events	59 / 114
serious Total, serious adverse events	0 / 114

Outcome results

Primary

2 Year Progression Free Survival After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC)

Progression Free Survival (PFS) was defined as the time from the beginning of treatment to cancer progression or death. The outcome measure will be reported as the proportion of patients with PFS at 2 years post-treatment.

Time frame: Two years after completion of CRT on last enrolled patient (Note: CRT duration is 6 weeks)

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
De-escalated Radiation and Chemotherapy	2 Year Progression Free Survival After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC)	99 Participants

Secondary

2 Year Distant Metastasis Free Survival (DMFS) Rate After De-intensified Chemoradiotherapy (CRT) in Human Papilloma Virus (HPV)-Positive and/or p16 Positive Low-risk Oropharyngeal Squamous Cell Carcinoma (OPSCC)

The outcome measure will be reported as the proportion of patients with DMFS at 2 years post-treatment.