Clinical trial NCT04124198: Quality of Life After Primary TORS vs IMRT for Patients With Early-stage Oropharyngeal Squamous Cell Carcinoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Oropharynx Cancer
Oropharynx Squamous Cell Carcinoma
Carcinoma, Squamous Cell
Carcinoma
Oropharyngeal Neoplasms
Neoplasms, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Pharyngeal Neoplasms Malignant and Unspecified
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Otorhinolaryngologic Diseases
Pharyngeal Diseases
Papillomavirus Infections
Virus Diseases
DNA Virus Infections
Tumor Virus Infections
Quality of Life
Keywords: Oropharyngeal squamous cell carcinoma T1-T2, N0-1
Transoral robotic surgery
Intensity Modulated Radiation Therapy
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Naestved Hospital
name: Herlev Hospital
name: Aarhus University Hospital
name: Odense University Hospital
First posted: 2019-10-11
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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)

Eligibility criteria: Inclusion Criteria:

1. 18 years or older
2. Able to provide informed consent
3. The Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status 0-2
4. Histologically confirmed oropharyngeal squamous cell carcinoma (exclusively palatine tonsils and base of tongue tumours) with known p16 status
5. Clinical tumour stage cT1-2 according to The Union for International Cancer Control (UICC), tumor (T), nodes (N), and metastases (M), (TNM) classification, 8th edition.
6. Clinical nodal stage cN0-1 according to UICC, TNM classification, 8th edition, however in p16 positive patients with unilateral metastasis, only a nodal metastasis up to a maximum of 4 cm in greatest diameter according to pre-operative imaging will be included.
7. Diagnostic imaging including computed tomography/magnetic resonance imaging (CT/MRI) performed within 14 days at time of randomization.
8. A tumour that is considered resectable according to MRI, clinical examination and/or ultrasound

Exclusion Criteria:

1. Serious medical comorbidities or ECOG/WHO performance status \>2. Other contraindications to radiotherapy, chemotherapy or surgery
2. Inability to attend full course of radiotherapy or follow-up visits in the outpatient clinic
3. Distant metastasis
4. Clinically and radiologic signs of nodal extracapsular extension
5. Previous radiotherapy of the head and neck
6. Previous head and neck cancer
7. Significant trismus (maximum inter-incisal opening ≤ 35mm) \[46\]
8. Unable or unwilling to complete quality of life questionnaires
9. Posterior pharyngeal wall involvement
10. Pregnancy

Primary outcomes:
measure: Swallowing related quality of life by MDADI
timeFrame: evaluated at baseline, 3 and 12 months after treatment
Secondary outcomes:
measure: Nasogastric or percutaneus tube dependency
timeFrame: evaluated at baseline, 3 and 12 months after treatment
measure: Swallowing function by fiberendoscopic evaluation
timeFrame: evaluated at baseline, 3 and 12 months after treatment
measure: Swallowing function by modified barium swallowing
timeFrame: evaluated at baseline, 3 and 12 months after treatment
measure: Patient reported quality of life by EORTC-QLQ-H&N35
timeFrame: evaluated at baseline, 3 and 12 months after treatment
measure: Patient reported quality of life by EORTC QLQ-C30
timeFrame: evaluated at baseline, 3 and 12 months after treatment
measure: Treatment-related pain
timeFrame: evaluated at baseline up to 12 months after treatment
measure: Weight
timeFrame: evaluated at baseline, 3 and 12 months after treatment
measure: Patients returning to work after treatment
timeFrame: evaluated at baseline, 3 and 12 months after treatment
measure: Morbidity after staging neck after staging neck dissection
timeFrame: evaluated from time of neck dissection up to 14 days after treatment
measure: Nerve function
timeFrame: evaluated at baseline and up to 12 months after treatment
measure: Late toxicity
timeFrame: evaluated at 3, 6, 12, 24, 36, 48 and 60 months after treatment
measure: Overall survival
timeFrame: evaluated from time of randomization up to 5 years
measure: Disease-free survival
timeFrame: evaluated from time of randomization up to 5 years
measure: Disease-specific survival
timeFrame: evaluated from time of randomization up to 5 years
measure: Distant recurrence
timeFrame: evaluated from time of randomization up to 5 years
measure: Loco-regional recurrence
timeFrame: evaluated from time of randomization up to 5 years
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital Rigshospitalet
city: Odense
country: Denmark
facility: Odense University Hospital
Study officials:
affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Copenhagen University Hospital Rigshospitalet
name: Christian von Buchwald, MD, DMSc.
role: STUDY_CHAIR
affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Copenhagen University Hospital Rigshospitalet
name: Niclas Rubek, MD
role: PRINCIPAL_INVESTIGATOR
References: