Summary

This phase III trial compares the effect of lymphatic mapping to standard therapy in guiding radiotherapy to the neck in patients with oropharyngeal cancer. Lymphatic mapping uses dyes and radioactive substances to identify lymph nodes that contain tumor cells. Lymphatic mapping may help determine which side or sides of the neck to treat with radiotherapy.

Objectives

PRIMARY OBJECTIVE:
I. To determine if a lymphatic mapping-guided approach (experimental arm) for management of the contralateral neck has a non-inferior disease-free survival (DFS) compared to bilateral neck radiation therapy (RT) (control arm) in patients with lateralized oropharyngeal squamous cell carcinoma (OPC) not involving or crossing the midline and without clinical contralateral nodal disease.

SECONDARY OBJECTIVES:
I. Swallowing-related quality of life (M.D. Anderson Dysphagia Inventory [MDADI]) and Xerostomia-related quality of life (Xerostomia Questionnaire [(XQ]).
II. Isolated contralateral neck failure (iCNF), overall survival (OS), loco-regional failure (LRF), distant metastases (DM).
III. Radiation therapy (RT)-related toxicities.
IV. Patient reported toxicities (Patient Reported Outcomes – Common Terminology Criteria, PRO CTCAE).
V. Gastrostomy tube usage.
VI. To perform economic analyses (Canadian CCTG Sites Only: resource utilization, lost productivity, financial toxicity (Financial Index of Toxicity [FIT]) cost-utility analysis using health utilization costs and health utilities EuroQOL (EQ-5D).

EXPLORATORY OBJECTIVES
I. Swallowing function using videofluoroscopic swallow studies (sub-study).
II. Head and Neck Cancer Specific QOL (University of Washington Quality of Life Questionnaire [UW-QOL]).
III. Patters of lymphatic drainage using lymphatic mapping/single photon emission computed tomography-computed tomography (SPECT-CT) imaging.
IV. Predicting contralateral lymphatic drainage on SPECT-CT with pre-treatment imaging (computed tomography/magnetic resonance imaging [CT/MRI]) radiomic features.
V. To correlate baseline tumor somatic mutations with risk of recurrence after treatment.
VI. To correlate circulating cell free tumor deoxyribonucleic acid (DNA) (cfDNA) levels with clinical recurrence after treatment.

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM A: Patients receive technetium Tc-99m sulfur colloid via injection and then undergo SPECT/CT. Patients may undergo radiotherapy if mapping shows draining to contralateral lymph nodes. Patients may also receive standard of care chemotherapy.

ARM B: Patients receive usual radiotherapy. Patients may receive usual standard of care chemotherapy.

After completion of study treatment, patients are followed up at 1 month after treatment, every 3 months for 2 years, and then every 6 months thereafter.

Eligibility

1. Patients with pathologically proven diagnosis of lateralized OPC (tonsil, tongue base, soft palate, or pharyngeal wall) not involving or crossing midline. Pathologic confirmation may be from either nodal or primary tumour. Nodal biopsies may include either fine needle aspiration biopsy (configured as a cell block), core biopsy, and or excisional biopsy of involved lymph nodes as long as sufficient tissue is available for p16 immunohistochemistry. If a biopsy is obtained from nodal disease, a clinically apparent and unequivocal primary tumour as well as subsite either on imaging and/or clinical examination must be present.
2. The assessment for determination of lateralization is based on a consensus evaluation between a surgeon and radiation oncologist and must include evaluation of both axial imaging (CT scan of the head and neck with contrast and/or magnetic resonance imaging (MRI) scan of the head and neck) and clinical examination including fiberoptic endoscopy.
3. Human papillomavirus (HPV) positive or negative (by p16 immunohistochemistry). Tumours will be classified as p16 at local sites based on greater than 70% strong diffuse nuclear or nuclear and cytoplasmic staining.
4. Clinical stage T1-3 M0 (Union for International Cancer Control [UICC]/American Joint Committee on Cancer [AJCC] TNM 8th Edition). Nodal disease may include no nodes or single or multiple ipsilateral lymph nodes (largest should be less than 6 cm in maximum diameter). For HPV positive patients, this includes N0-N1 (UICC or AJCC 8th edition). For HPV negative patients, this includes N0-N2b (UICC or AJCC 8th edition). Patients with radiologic extranodal extension without clinical signs of extranodal extension will be eligible for participation, however, those with any form of clinical evidence of extranodal extension will be excluded. Clinical extranodal extension includes any of the following features during clinical examination: skin invasion, deep nodal fixation, and/or clinical signs of cranial nerve or brachial plexus invasion. * Staging will be determined based on clinical examination, axial imaging, and positron emission tomography (PET-CT) imaging.
5. Patients with contralateral/bilateral lymph nodes are not eligible. CT or MRI scan findings suggestive of involved contralateral nodes include lymph nodes with central necrosis, lymph nodes nodal level 2, > 0.8 cm in the retropharyngeal region, and > 1cm in all other nodal levels with a rounded configuration, or a cluster of 3 or more borderline size nodes, or radiographic features of extranodal extension (i.e. loss of plane between the lymph node and surrounding fat).
6. PET-CT scan findings of involved contralateral lymph nodes will be based on visual assessment by local radiologists as per the primary analysis in the ECOG ACRIN 6685 Trial [Lowe 2019]. The concordance using visual assessment is 77% between radiologists and provides a negative predictive value of 87%.
7. PET-CT criteria for nodal positivity or negativity (for image acquisition detail): * Positive Node: Visual analysis: fluorodeoxyglucose (FDG) uptake in the contralateral neck node is greater than blood pool in the adjacent internal jugular vein. * Negative Node: Visual analysis: FDG uptake in the contralateral neck lymph node is equal or less than the blood pool uptake in the adjacent internal jugular vein.
8. The following radiological investigations must be done within 8 weeks of registration: * CT or MRI of the neck (with head imaging as indicated). * PET-CT scan ** Institutions with access to perform PET-CT scan for pre-treatment workup for OCP: PET-CT scan to be done within 8 weeks of registration. Institutions with no access to perform PET-CT scan for pre-treatment workup for OPC: After patient consent and registration, the cost of the PET-CT scan for these cases will be covered. Once the PET-CT scan result is received, if the scan shows no contralateral neck gross diseases as per criterion 4.1.3, and all other eligibility criteria are met, the patient may be randomized. If PET-CT scan shows contralateral neck nodal disease, the patient is not eligible and cannot proceed to randomization. No further data will be collected. * Chest CT scan
9. Planned definitive RT or chemoradiotherapy (CRT) with bilateral neck RT (patients planned for unilateral neck RT are excluded). Based on clinical and radiologic evaluation and in keeping with local institutional standards, the treating radiation oncologist must declare upfront, that in the absence of the present clinical trial, the patient would be treated with bilateral neck RT.
10. Intent to deliver concurrent chemotherapy or not must be known at the time of randomization. As this is a pragmatic trial, even patients who are not candidates for systemic therapy will be eligible for participation.
11. Must be >= 18 years of age.
12. Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
13. Patient is willing to complete the quality of life and/or health utility questionnaires (for Canadian CCTG patients only), if sufficiently fluent in available language(s). The MDADI, UW-QOL, PRO CTCAE, and EQ-5D will be available in validated French and Spanish translations; the XQ will be provided in English. Patients with sufficient verbal ability in English may complete the XQ verbally (clinical research associate [CRA] to read items verbatim). Non-English speaking patients will complete only instruments available in their language(s). Inability (lack of comprehension or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible. The baseline assessment must be completed within required timelines, prior to randomization. After the first consecutive 330 patients who complete BOTH the MDADI and XQ, no further enrolled patients will be required to complete quality of life questionnaires as this is the required sample size for quality of life endpoints.). All English speaking Canadian patients will be required to complete the Financial Index of Toxicity (FIT) Questionnaire and Lost Productivity Questionnaire and all English and French speaking Canadian patients will be required to complete the EQ-5D.
14. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to registration in the trial to document their willingness to participate. * A similar process must be followed for sites outside of Canada as per their respective cooperative group’s procedures.
15. Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
16. The treatment team must be able to commence definitive RT within 28 days (+ 14 days) of randomization. In the experimental arm, this involves arranging lymphatic mapping/SPECT-CT and radiation planning based on SPECT-CT results within the 42 days window.
17. Treating surgeon must confirm that the patient is a candidate to undergo injection procedure for lymphatic mapping either in the nuclear medicine, ambulatory clinic, or operating room setting.
18. Women/men of childbearing potential must have agreed to use a highly effective contraceptive method. A woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. * Women of childbearing potential will have a pregnancy test to determine eligibility as part of the pre-study evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of human chorionic gonadotropin (hCG), as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy.
19. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
20. For patients participating in Swallowing Impairment Sub-study: signed Swallowing Impairment sub-study portion of the optional consent for patients already enrolled in the primary study at participating centres.

Treatment Sites in Georgia