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Squamous Cell Carcinoma of Head and Neck

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Patients with clinical T1N0 stage are offered accelerated radiotherapy to 66 Gy/33fractions with concurrent nimorazole.

Patients with clinical T2N0 stage are offered either accelerated radiotherapy to 66 Gy/33fractions with the option of weekly cisplatin to fit patients or hyper-fractionated accelerated radiotherapy to 76 Gy/56fractions both with concurrent nimorazole.

Patients with clinical T1-T2, N1 stage are offered accelerated radiotherapy to 66 Gy/33 fractions and nimorazole with the addition of concurrent weekly cisplatin 40 mg/sqm to fit patients.

Accelerated or hyper-fractionated radiotherapy

Intensity-Modulated Radiation Therapy (IMRT)

Concurrent weekly cisplatin 40 mg/sqm to fit patients

Nimorazole.

Robotic-assisted resection of the primary oropharyngeal tumour and ipsilateral selected neck dissection of lymph node levels II-IV. Patients with a primary base of tongue cancer or with significant involvement of tongue base or the soft palate defined as above 1 cm, will be offered a bilateral neck dissection of levels II-IV.

Transoral Robotic Surgery (TORS) with neck dissection

Hani Ibrahim Channir, MD, PhD

Thomas Kjærgaard, MD, PhD

Pernille Lassen, MD, PhD

Niclas Rubek, MD

Jeppe Friborg, MD, PhD

Christian Godballe, MD, PhD

Jørgen Johansen, MD

Christian von Buchwald, MD, DMSc.

Oropharyngeal squamous cell carcinoma (OPSCC) is now the most frequently diagnosed head and neck cancer in Denmark which is mainly due to the increase of Human Papillomavirus (HPV). Patients with HPV-positive OPSCC have a significantly higher survival rate compared to HPV-negative OPSCC. The traditional primary treatment modality in Denmark is Intensity Modulated Radiation Therapy (IMRT), and in advanced stages in combination with chemotherapy. Since 2009, Transoral Robotic Surgery (TORS) has enabled surgeons to perform minimally invasive surgery as an alternative to standard radiotherapy treatment which is considered the primary treatment for OPSCC in many countries. There is a lack of randomised trials comparing long-term functional outcomes after TORS or IMRT. Current data are mostly derived from retrospective studies with selection bias. However, several small retrospective studies have shown promising results when comparing the two treatment modalities in favour of TORS with regards to treatment related swallowing function and quality of life (QoL) without compromising survival outcomes.

This study aims to evaluate the early and long-term functional outcomes following two treatment arms 1) TORS combined with neck dissection and 2) IMRT±concurrent chemotherapy with a special focus on swallowing-related QoL.

The current study is performed as a nationwide randomized phase III study that aims to investigate the long-term functional outcomes after primary TORS and neck dissection vs. IMRT±concurrent chemotherapy for early-stage oropharyngeal squamous cell carcinoma.

The study is a registered Danish Head and Neck Cancer Group (DAHANCA) 34 protocol.

The investigators hypothesise that primary TORS±adjuvant therapy will significantly improve the QoL at 12 months follow-up compared to IMRT±concurrent chemotherapy.

Primary endpoint: QoL measured by a composite MD Anderson Dysphagia Inventory (MDADI) score evaluated at 12 months follow-up after treatment (10-point difference)

Study design:

Patients who meet the inclusion criteria will be recruited from three Danish head and neck cancer centers: Copenhagen University Hospital Rigshospitalet, Aarhus University Hospital and Odense University Hospital.

Prior to treatment, all patients will be reviewed and examined at a multidisciplinary team conference.

Included patients will be randomized in 2:1 ratio:

Arm 1 (experimental), n=92 patients: TORS+neck dissection. Arm 2 (control), n=46 patients: IMRT±concurrent chemotherapy

DAHANCA Secretariat is responsible for the randomization key to either experimental or control arm. The investigators will stratify for p16, sex, tumour location and clinical tumor- and nodal-stage (T- and N-stage) classification at time of inclusion to avoid an uneven distribution in the experimental arm compared to the control arm.

Specifics for the experimental arm:

Patients with clinically positive neck (cN+) will be offered a staging neck within 8 days prior to the planned TORS. Based on final pathology of the neck specimen, patients will either be referred for definitive IMRT± concurrent chemotherapy (extracapsular extension (ECE), or more than two lymph node metastases) or they will undergo TORS (no extracapsular exension and maximally two lymph node metastases).

For patients with clinically no evidence of lymph node metastasis (cN0), neck dissection can be performed either before (within 8 days) or concurrently (same day procedure) with TORS.

Indications for adjuvant radiotherapy:

Nodal site:

* More than two lymph node metastases
* Two lymph node metastases and both above 1 cm in diameter.
* Any pathological positive lymph nodes (pN+) with extracapsular extension (ECE)
* A neck dissection nodal yield of less than 10 lymph nodes per side (after total embedding of the remaining fat tissue)

Tumour site:

* Involved or close resection margins of \< 2 mm if free margins was not obtained after supplementary resections per-operatively or after re-resection in a secondary procedure.
* In case of stage migration to tumour stages T3 or T4, in an otherwise radical operation (R0), adjuvant therapy will be offered based on a postoperative consultation between the patient, the surgeon and an oncologist.

Indications for adjuvant chemotherapy:

• Insufficient resection margin (\<2mm) or ECE

Specifics for the control arm:

Radiotherapy Quality Assurance Reviews are aimed to be performed before the third treatment fraction by a team from another head-neck oncology center consisting of one physicist and one oncologist. The patient specific review will address the following points according to the DAHANCA guideline: Clinical Target Volume (CTV) and Organs-at-Risk (OAR) delineation, target dose coverage, OAR dose sparing and treatment length.

Funding: The study protocol was initiated by the Department of Otorhinolaryngology, Head \& Neck surgery at Copenhagen University Hospital Rigshospitalet. Funding grants have been received by the Danish Health Authority ("Midler til eksperimentel kræftkirurgi"), by the Copenhagen University Hospital Rigshospitalet ("Rammebevilling") and Odense University Hospital ("Forskningspulje mellem OUH og RH").

Data management and ethical considerations: Data is stored and handled in accordance with the Danish Data Agency regulations, The General Data Protection Regulation (GDPR) 2016/679 in European Union (EU) law on data protection and privacy for all individual citizens of the EU and the European Economic Area (EEA), and in compliance with the national data agreement between the study locations in compliance with the Danish Data Protection Agency approval (ID: RH-2017-362).

During the trial, the Good Clinical Practice (GCP) unit in Aarhus will monitor the study trial according to the given protocol and the current legislation. The monitoring period will consist of the first 12 months of inclusion until the primary endpoint.

This study has been approved by the Regional Committee on Health Research Ethics (ID: H-17031827)

Quality of Life After Primary TORS vs IMRT for Patients With Early-stage Oropharyngeal Squamous Cell Carcinoma

Quality of Life After Primary Transoral Robotic Surgery vs Intensity-modulated Radiotherapy for Patients With Early-stage Oropharyngeal Squamous Cell Carcinoma: A Randomized National Trial

Difference in swallowing related quality of life measured by a composite MD Anderson Dysphagia Inventory (MDADI) score. The MDADI is a 20-item self-administered questionnaire that quantifies swallowing-related quality of life. Each item is scored on a 5 point Likert scale (strongly disagree, disagree, no opinion, agree, strongly agree). The composite MDADI score summarizes overall performance on remaining 19-items of the MDADI, as a weighted average of the physical, emotional, and functional subscale questions. Summary and subscale MDADI scores are normalized to range from 20 (extremely low functioning) to 100 (high functioning).

Tube dependency defined as number of days/weeks/months with tube inserted

Fiberendoscopic Evaluation of Swallowing (FEES) is rated by following scales: a 8-point Penetration-Aspiration Scale (PAS) where a score of 1 reflects no entry of material into the airway, scores of 2-5 reflect penetration of material past the laryngeal additus into the supraglottic space and traveling as far as the true vocal folds, while scores of 6-8 reflect tracheal aspiration of material below the true vocal folds; Yale Pharyngeal Residue Severity Rating Scale: image-based assessment of post-swallow pharyngeal residue severity as observed during swallowing. Five-point ordinal rating scale based on residue location (vallecula and pyriform sinus) and amount (none, trace, mild, moderate, and severe); the summary DIGEST grading: grade 1= mild, grade 2= moderate, grade 3= severe, and grade 4= life threatening pharyngeal dysphagia.

Modified Barium Swallowing (MBS) is a fluoroscopic procedure designed to determine whether food or liquid is aspirated. Following scales are used to assess MBS: a 8-point Penetration-Aspiration Scale (PAS): a score of 1 reflects no entry of material into the airway, scores of 2-5 reflect penetration of material past the laryngeal additus into the supraglottic space and traveling as far as the true vocal folds, while scores of 6-8 reflect tracheal aspiration of material below the true vocal folds; the summary DIGEST grading: grade 1= mild, grade 2= moderate, grade 3= severe, and grade 4= life threatening pharyngeal dysphagia.

Measured by The European Organization for Research and Treatment of Cancer Quality of Life Questionnaires EORTC-QLQ-H\&N35. The head and neck-specific module EORTC QLQ-H\&N35 contains 35 items, which can be condensed into 7 multi-item and 11 single-item scales. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.

Measured by The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ-C30. The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.

Daily (experimental arm) or weekly (control arm) self-reported visual analogue scale (VAS) score from 0-10 points in which a higher score indicates greater pain intensity. Measured until no treatment-related pain is recorded by the patient and with no need of treatment-related pain medication

Defined as the time (number of days) before returning to work or failure to do so after treatment.

Monitoring of events of bleeding, lymphedema or impaired nerve function after staging neck dissection

Evaluation of nerve function at risk during surgery (spinal accessory, hypoglossal, marginal mandibular branch of the facial nerve, lingual and vagal nerve) will be assessed by a clinical examination based on the innervation and function of each nerve during follow-up after surgery. Nerve function is determined as dichotomous variable: functioning/not-functioning.

Using The Radiation Therapy Oncology Group/The European Organization for Research and Treatment of Cancer (RTOG/EORTC) Late Radiation Morbidity Score. Uses a grading system from 0-5 for different tissue organs: 0 - no symptoms, 5 - death directly related to radiation effects

Time from randomization to death from any cause.

Time from randomization to sign of cancer is found.

Time from randomization to death from the disease (oropharyngeal cancer).

Time from randomization to distant recurrence

Time from randomization to recurrence in same T-site or N-site as initial cancer localization

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Quality of Life After Primary TORS vs IMRT for Patients With Early-stage Oropharyngeal Squamous Cell Carcinoma	NCT04124198	Oropharynx Canc... Oropharynx Squa... Carcinoma, Squa... Carcinoma Oropharyngeal N... Neoplasms, Squa... Neoplasms, Glan... Neoplasms by Hi... Pharyngeal Neop... Otorhinolaryngo... Head and Neck N... Neoplasms by Si... Otorhinolaryngo... Pharyngeal Dise... Papillomavirus ... Virus Diseases DNA Virus Infec... Tumor Virus Inf... Quality of Life	Intensity-Modul... Cisplatin Nimorazole. Transoral Robot...	18 Years -	Rigshospitalet, Denmark
Quality of Life After Primary TORS vs IMRT for Patients With Early-stage Oropharyngeal Squamous Cell Carcinoma	NCT04124198	Oropharynx Canc... Oropharynx Squa... Carcinoma, Squa... Carcinoma Oropharyngeal N... Neoplasms, Squa... Neoplasms, Glan... Neoplasms by Hi... Pharyngeal Neop... Otorhinolaryngo... Head and Neck N... Neoplasms by Si... Otorhinolaryngo... Pharyngeal Dise... Papillomavirus ... Virus Diseases DNA Virus Infec... Tumor Virus Inf... Quality of Life	Intensity-Modul... Cisplatin Nimorazole. Transoral Robot...	18 Years -	Rigshospitalet, Denmark

Spots Global Cancer Trial Database for pharyngeal neoplasms malignant and unspecified