Invert-Prospective Phase II Randomized Trial of Involved Nodal Versus Elective Neck RadioTherapy

INVERT - Prospective Phase II Randomized Trial of Involved Nodal Versus Elective Neck RadioTherapy

To determine the risk of solitary elective volume recurrence following involved nodal radiotherapy (INRT) versus elective nodal irradiation (ENI)

Study Overview

• Status: Recruiting
• Conditions: Head and Neck Cancer
• Intervention / Treatment: Drug: ENI using IMRT with or without chemotherapy; Radiation: ENI; Radiation: INRT

Detailed Description

Patients are assigned to either elective nodal irradiation (ENI), the current treatment paradigm, or involved nodal radiotherapy (INRT), the experimental treatment. INRT is more specifically targeting potentially cancerous nodes, identified using an AI program developed in-house. The hope is that this more specific targeting will decrease healthy tissue being irradiated, therefore decreasing potential side effects of the radiation treatment.

Patients are blinded during study participation.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sarah Neufeld; Phone Number: 214-645-8525; Email: sarah.hardee@utsouthwestern.edu
• Study Contact Backup: Name: Liliana Robles; Phone Number: 214-645-8525; Email: liliana.robles@utsouthwestern.edu

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • UT Southwestern Medical Center
      • Contact: Sarah Neufeld, MS
      • Principal Investigator: David Sher, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pathologically-proven diagnosis of squamous cell carcinoma of the oropharynx, larynx, or hypopharynx. Squamous cell carcinoma of unknown primary is not allowed.
• Patients must have clinically or radiographically evident measureable disease at the primary site and/or nodal stations. Diagnostic lymph node excision (≤ 2 nodes) is also allowable.
• Patients may undergo a diagnostic or therapeutic transoral resection for a T1-2 tonsil or base of tongue cancer.
• Clinical stage I-IVB (AJCC, 7th edition); stages I-II glottic cancer are excluded
• Age ≥ 18 years.
• ECOG Performance Status 0-2
• All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, 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, 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).
• Neck CT and/or neck MRI, and PET-CT
• Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

• Distant metastasis.
• Inability to undergo either a diagnostic CT with contrast or simulation CT with contrast.
• Inability to undergo PET-CT.
• Stage I and II glottic carcinoma.
• Gross total excision of both the primary and nodal disease.
• Synchronous non-skin cancer primaries outside of the oropharynx, larynx, and hypopharynx except for low- and intermediate-risk prostate cancer and synchronous well-differentiated thyroid cancer; in the latter case, surgery may occur before or after treatment, provided all other eligibility criteria are met.
• Prior invasive malignancy with an expected disease-free interval of less than 3 years.
• Prior systemic chemotherapy for the study cancer; prior chemotherapy for a remote cancer is allowable.
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation fields.
• Subjects may not be receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the chemotherapy agents in this study (if necessary).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
• History of severe immunosuppression, including HIV, and organ or autologous or allogeneic stem cell transplant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Involved and suspicious lymph node delineation and targeting; After the involved and suspicious nodes are contoured, the physician will contour remaining nodes that are present on more than one CT slice and submit them to the AI-Radiomics module for assessment.The nodal gross tumor volume (GTVn, GTVns and GTVnps for involved, suspicious nodes or potentially suspicious) will be contoured on the planning CT, using radiographic and clinical information to define its extent. The total dose for GTVns is 63 Gy in 35 fractions, and the total dose for GTVnps is 56 Gy in 35 fractions. For lymph nodes identified as potentially suspicious by the AI- Radiomics module that are outside of the expected primary draining zone, physicians may not treat the lymph node if the module assesses its estimation uncertainty as greater than 50%.	Drug: ENI using IMRT with or without chemotherapy; This study is a phase II single-blinded randomized trial comparing standard ENI with involved nodal radiotherapy. INRT using intensity modulated radiation therapy (IMRT) with or without chemotherapy (if given, either cisplatin, cetuximab, or carboplatin- paclitaxel); Other Names: cisplatin, cetuximab, or carboplatin- paclitaxel); Radiation: INRT; INRT using intensity modulated radiation therapy (IMRT) with or without chemotherapy (if given, either cisplatin, cetuximab, or carboplatin- paclitaxel)
Active Comparator: Standard radiotherapy with elective neck irradiation (ENI); The elective neck dose is 56 Gy in 35 fractions Lymph nodes measuring 17 mm or greater in any dimension, or showing FDG above adjacent blood pool, may receive 63 Gy in 35 fractions per physician discretion.The elective neck field is determined by the primary site. The Oropharynx: Node-positive side: Levels IB-V and RP nodes Node-negative side: Levels II-IV, RP at discretion of physician For ipsilateral tonsil decision-making, see 4.1.1.6.3 The Larynx: Node-positive side: Levels IB-V Node-negative side: Levels II-IV Subglottic extension: Level VI Hypopharynx: Node-positive side: Levels IB-V and RP nodes Node-negative side: Levels II-V and RP nodes Pyriform sinus involvement: Level VI	Drug: ENI using IMRT with or without chemotherapy; This study is a phase II single-blinded randomized trial comparing standard ENI with involved nodal radiotherapy. INRT using intensity modulated radiation therapy (IMRT) with or without chemotherapy (if given, either cisplatin, cetuximab, or carboplatin- paclitaxel); Other Names: cisplatin, cetuximab, or carboplatin- paclitaxel); Radiation: ENI; ENI using IMRT with or without chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The probability at two years: SEVR in INRT versus ENI patients	The probability at two years will be compared between the arms using a one- sided Fisher's exact test (probability of SEVR between the arms).	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Acute Grade 2+ Dermatitis between ENI vs INRT arms	Comparison of instances of grade 2+ acute dermatitis between patients treated with INRT (involved nodal radiotherapy, study treatment) vs ENI (elective nodal irradiation, standard of care). This will be compared between the arms using a Fisher exact test (2-sided).	Start of RT through 90 days post RT
Incidence of Grade 3+ Dysphagia between ENI vs INRT arms	Comparison of instances of grade 3+ dysphagia between patients treated with INRT (involved nodal radiotherapy, study treatment) vs ENI (elective nodal irradiation, standard of care). This will be compared between the arms using a Fisher exact test (2-sided).	2 years post RT
MDADI Quality of Life composite score	Comparison of MDADI composite scores at 2 years post RT between patients treated with INRT (involved nodal radiotherapy, study treatment) vs ENI (elective nodal irradiation, standard of care). Patients with disease recurrence will be excluded from analysis. At two years, both scores will be compared between the arms using a two-sided T test.	2 years post RT

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: David Sher, MD, University of Texas Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2024
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: June 21, 2024
• First Submitted That Met QC Criteria: June 21, 2024
• First Posted (Actual): June 27, 2024

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Therapeutics; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Platinum Compounds; Cetuximab; Cisplatin; Drug Therapy
• Other Study ID Numbers: STU-2024-0603; 1R01CA251792-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No