Comparing Sentinel Lymph Node (SLN) Biopsy With Standard Neck Dissection for Patients With Early-Stage Oral Cavity Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II/III trial studies how well sentinel lymph node biopsy works and compares sentinel lymph node biopsy surgery to standard neck dissection as part of the treatment for early-stage oral cavity cancer. Sentinel lymph node biopsy surgery is a procedure that removes a smaller number of lymph nodes from your neck because it uses an imaging agent to see which lymph nodes are most likely to have cancer. Standard neck dissection, such as elective neck dissection, removes many of the lymph nodes in your neck. Using sentinel lymph node biopsy surgery may work better in treating patients with early-stage oral cavity cancer compared to standard elective neck dissection.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine if patient-reported neck and shoulder function and related quality of life (QOL) at 6 months after surgery using the Neck Dissection Impairment Index (NDII) is superior with sentinel lymph node (SLN) biopsy compared to elective neck dissection (END) for treatment of early-stage oral cavity squamous cell carcinoma (OCSCC) (cT1-2N0). (Phase II) II. To determine if disease-free survival (DFS) is non-inferior with SLN biopsy compared to END for treatment of early-stage OCSCC (cT1-2N0). (Phase III) III. To determine if patient-reported neck and shoulder function and related QOL at 6 months after surgery using NDII is superior with SLN biopsy compared to END for treatment of early-stage OCSCC (cT1-2N0). (Phase III) SECONDARY OBJECTIVES: I. To compare patterns of failure (local-regional relapse and distant metastasis) between surgical arms. II. To measure and compare overall survival (OS) between surgical arms. III. To measure and compare the toxicity of the two surgical arms. IV. To measure longitudinal patient-reported neck and shoulder function and related QOL between surgical arms, using the following instruments: IVa. Neck Dissection Impairment Index (NDII). IVb. Abbreviated Disabilities of the Arm, Shoulder and Hand (QuickDASH). IVc. Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N). V. To assess the length of hospitalization, post-operative drain placement, and operative morbidity between arms. VI. To estimate the negative predictive rate of fludeoxyglucose F-18 (FDG)-positron emission tomography/computed tomography (PET/CT) for N0 neck in patients with T1 and T1-2 oral cavity squamous cell cancer (OCSCC) patients in the END arm. VII. To assess nodal metastases rates between arms. VIII. To assess the pathologic false omission rate (FOR) in the SLN biopsy arm. IX. To determine if patient-reported neck and shoulder function and related QOL at 6 months after surgery using the NDII is superior with the SLN biopsy compared to the END in low-risk patients. EXPLORATORY OBJECTIVES: I. To compare changes in patient-reported outcomes (European Quality of Life Five Dimension Five Level Scale Questionnaire [EQ-5D-5L]) between surgical arms. II. To collect biospecimens for future translational science studies. III. To assess the DFS between arms in low-risk patients. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive an imaging agent via injection and undergo planar imaging and single photo emission computed tomography/computed tomography (SPECT/CT) over 1-2 hours. Patients then undergo SLN biopsy. GROUP II: Patients undergo standard END. After completion of study treatment, patients are followed up 3 weeks after surgery, every 3 months for year 1, every 4 months for year 2, every 6 months for year 3, then yearly thereafter.

Official Title
-----------------
Randomized Phase II/III Trial of Sentinel Lymph Node Biopsy Versus Elective Neck Dissection for Early-Stage Oral Cavity Cancer

Conditions
-----------------
Buccal Mucosa Squamous Cell Carcinoma, Floor of Mouth Squamous Cell Carcinoma, Gingival Squamous Cell Carcinoma, Hard Palate Squamous Cell Carcinoma, Lip Squamous Cell Carcinoma, Lower Alveolar Ridge Squamous Cell Carcinoma, Oral Cavity Squamous Cell Carcinoma, Retromolar Trigone Squamous Cell Carcinoma, Stage I Lip and Oral Cavity Cancer AJCC v8, Stage II Lip and Oral Cavity Cancer AJCC v8, Tongue Squamous Cell Carcinoma, Upper Alveolar Ridge Squamous Cell Carcinoma

Intervention / Treatment
-----------------
* Procedure: Computed Tomography (CT)
* Drug: Imaging Agent
* Procedure: Neck Dissection
* Procedure: Planar Imaging
* Procedure: Sentinel Lymph Node Biopsy
* Procedure: Single Photon Emission Computed Tomography


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: PRIOR TO STEP 1 REGISTRATION INCLUSION: Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma of the oral cavity, including the oral (mobile) tongue, floor of mouth (FOM), mucosal lip, buccal mucosa, lower alveolar ridge, upper alveolar ridge, retromolar gingiva (retromolar trigone; RMT), or hard palate prior to registration Appropriate stage for study entry (T1-2N0M0; American Joint Committee on Cancer [AJCC] 8th edition [ed.]) based on the following diagnostic workup: History/physical examination within 42 days prior to registration Imaging of head and neck within 42 days prior to registration PET/CT scan or contrast neck CT scan, or gadolinium-enhanced neck magnetic resonance imaging (MRI) or lateral and central neck ultrasound; diagnostic quality CT is preferred and highly recommended for the PET/CT when possible. Imaging of chest within 42 days prior to registration; chest x-ray, CT chest scan (with or without contrast) or PET/CT (with or without contrast) Surgical assessment within 42 days prior to registration. Patient must be a candidate for surgical intervention with sentinel lymph node (SLN) biopsy and potential completion neck dissection (CND) or elective neck dissection (END) Surgical resection of the primary tumor will occur through a transoral approach with anticipation of resection free margins Zubrod performance status 0-2 within 42 days prior to registration For women of child-bearing potential, negative serum or urine pregnancy test within 42 days prior to registration The patient or a legally authorized representative must provide study-specific informed consent prior to study entry Only patients who are able to read and understand English are eligible to participate as the mandatory patient reported NDII tool is only available in this language PRIOR TO STEP 2 RANDOMIZATION: FDG PET/CT required prior to step 2. Note: FDG PET/CT done prior to step 1 can be submitted for central review. PET/CT node negative patients, determined by central read, will proceed to randomization. PET/CT node positive patients will go off study, but will be entered in a registry and data will be collected to record the pathological outcome of neck nodes for diagnostic imaging assessment and future clinical trial development NOTE: All FDG PET/CT scans must be performed on an American College of Radiology (ACR) accredited scanner (or similar accrediting organization) The patient must complete NDII prior to step 2 registration Exclusion Criteria: PRIOR TO STEP 1 REGISTRATION EXCLUSION: Definitive clinical or radiologic evidence of regional (cervical) and/or distant metastatic disease Prior non-head and neck invasive malignancy (except non-melanomatous skin cancer, including effectively treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or cervix) unless disease free for ≥ 2 years Diagnosis of head and neck squamous cell carcinoma (SCC) in the oropharynx, nasopharynx, hypopharynx, and larynx Unable or unwilling to complete NDII (baseline only) Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields Patient with severe, active co-morbidity that would preclude an elective or completion neck dissection Pregnancy and breast-feeding mothers Incomplete resection of oral cavity lesion with a positive margin; however, an excisional biopsy is permitted Prior surgery involving the lateral neck, including neck dissection or gross injury to the neck that would preclude surgical dissection for this trial. Prior thyroid and central neck surgery is permissible; biopsy is permitted. Note: Borderline suspicious nodes that are ≥ 1 cm with radiographic finding suggestive of NOT malignant should be biopsied using ultrasound-guided (U/S-guided) fine-needle aspiration (FNA) biopsy Underlying or documented history of hematologic malignancy (e.g., chronic lymphocytic leukemia [CLL]) or other active disease capable of causing lymphadenopathy (sarcoidosis or untreated mycobacterial infection) Actively receiving systemic cytotoxic chemotherapy, immunosuppressive, anti-monocyte or immunomodulatory therapy Currently participating in another investigational therapeutic trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sentinel Lymph Node (SLN) Biopsy<br>Patients receive an imaging agent via injection and undergo planar imaging and SPECT/CT over 1-2 hours. Patients then undergo SLN biopsy. | Procedure: Computed Tomography (CT)<br>* Undergo SPECT/CT scan<br>* Other names: tomography;Drug: Imaging Agent<br>* Receive imaging agent via injection<br>* Other names: Image Enhancement Agent;Procedure: Planar Imaging<br>* Undergo planar imaging<br>Procedure: Sentinel Lymph Node Biopsy<br>* Undergo SLN biopsy<br>* Other names: SNB;Procedure: Single Photon Emission Computed Tomography<br>* Undergo SPECT/CT scan<br>* Other names: Tomography, Emission-Computed, Single-Photon;|
| Active Comparator: Elective Neck Dissection (END)<br>Patients undergo standard END. | Procedure: Computed Tomography (CT)<br>* Undergo SPECT/CT scan<br>* Other names: tomography;Procedure: Neck Dissection<br>* Undergo standard elective neck dissection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-reported neck and shoulder function (Phase II/III) | Will be evaluated and compared using the Neck Dissection Impairment Index (NDII), a 10-item tool between the two treatment arms. It is assumed that a 7.5-point (change from Baseline to 6 months) between arm difference is clinically meaningful. The hypothesis of no between-arm difference in 6-month NDII scores will be tested using the ANCOVA model at one-sided significance level of 0.10. Point estimates and 95% confidence intervals (CIs) for the mean NDII scores at 6 months for each treatment arm and for the between-arm difference at 6-months based on the proposed model will be provided. | From Baseline (Before surgery) to 6 months post-surgery | 
| Disease-Free Survival | An event for disease-free survival is local recurrence, regional recurrence, distant metastasis, or death due to any cause. Disease-free survival time is randomization date to the date of event or last known follow-up (censoring). Rates will be estimated using the Kaplan-Meier method and between-arm differences compared using the log-rank test. | From randomization to local/regional recurrence, distant metastasis, or death due to any cause, whichever comes first, assessed up to 11 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | An event for overall survival is death due to any cause. Overall survival time is randomization date to date of event or last known follow-up (censoring). Rates will be estimated using the Kaplan-Meier method and between-arm differences compared using the log-rank test. | From randomization to death due to any cause, assessed up to 11 years | 
| Loco-regional Failure | An event for local-regional failure is local or regional recurrence. Local-regional failure time is randomization date to date of event, precluding event, or last known follow-up (censoring). Rates will be estimated using the cumulative incidence method and between arm differences compared using cause-specific log-rank test. | From the time of randomization to the date of failure, date of precluding event, or last known follow-up date, assessed up to 11 years | 
| Distant metastasis | An event is the occurrence of distant metastasis. Distant metastasis time is randomization to date of event, precluding event, or last known follow-up (censoring). Rates will be estimated using the cumulative incidence method and between-arm differences compared using cause-specific log-rank test. | From the time of randomization to the date of distant metastasis, date of precluding event, or last known follow-up date, assessed up to 11 years | 
| Patient-reported shoulder-related QOL, function impairment and disability | Patient reported using Abbreviated Disabilities of the Arm, Shoulder, and Hand (QuickDASH) with scores of 0-100. A higher score indicates greater disability. | Baseline, 3 weeks, 3, 6, 12 months post-surgery. Analysis occurs at the same time as the primary endpoint. | 
| General quality of life | Will be measured using the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) to measure Functional Assessment of Cancer Therapy-Head and Neck-Trial Outcome Index (FACT-TOI) scores on a scale from 0-96. A higher score indicates better quality of life. | Baseline, 3 weeks, 3, 6, 12 months post-surgery. Analysis occurs at the same time as the primary endpoint. | 
| Nodal metastasis detection rate | Defined as the proportion of patients with pathologic positive nodes using the pathology results. | During surgery. Analysis occurs at the same time as the primary endpoint. | 
| Pathologic false omission rate | Measured within the sentinel lymph node biopsy (SLN) arm only. Defined as the proportion of patients with false negative results among negative SLN patients. | During surgery. Analysis occurs at the same time as the primary endpoint. | 
| Post-surgery patient-reported outcome | Measured by NDII in low-risk oral cavity squamous cell carcinoma patients using ANCOVA comparison model. | At 6 months post-surgery. Analysis occurs at the same time as the primary endpoint. |