Background
Methods/design
Study design
Primary endpoint
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OS
- ◦ Defined as time from randomization to death from any cause
Secondary endpoints
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2-year PFS (comparison with historical controls)
- ◦ Time from randomization to disease progression at any site or death PFS events are defined as death from any cause, or first recurrence of tumor at any site (including local, regional, or distant). Second primary tumors (e.g. head and neck cancer at a different site, such as laryngeal cancer) will not be included as PFS events.
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2-year OS and PFS comparisons between Arm 1 and Arm 2
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Swallowing-related QOL at 1-year post-treatment
- ◦ Assessed using the MDADI
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QOL at other time points
- ◦ Assessed using the MDADI, the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Cancer Patients general (QLQ-C30) and head & neck (H&N35) scales, the Voice Handicap Index (VHI-10), the Neck Dissection Impairment Index (NDII), the Patient Neurotoxicity Questionnaire (PNQ), and the EuroQOL 5-Dimension 5-Level (EQ-5D-5 L).
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Toxicity
- ◦ Assessed by the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4
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Other functional measurements, including, measured by:
- ◦ Feeding tube rate at 1-year
- ◦ Common Toxicity Criteria for Adverse Events (CTC-AE) Dysphagia scores
Inclusion criteria
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Minimum age 18
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Willing to provide informed consent
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Eastern Cooperative Oncology Group (ECOG) performance status 0–2
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Histologically confirmed squamous cell carcinoma
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HPV+ tumor, as determined by: positive p16 status, real-time polymerase chain reaction (PCR) or in-situ hybridization. Central confirmation is not required.
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Primary tumor site in the oropharynx (includes tonsil, base of tongue, soft palate, walls of oropharynx)
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Eligible for curative intent treatment, with likely negative resection margins at surgery. For patients where adequate transoral access is in question, they will first have an examination under anesthesia ensure adequate exposure can be obtained prior to randomization.
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Smokers and non-smokers are included. Patients will be stratified by < 10 versus ≥10 pack-year smoking history. Pack-years are calculated by multiplying the number of years smoked by the number of packs of cigarettes smoked per day. One pack is considered to contain 20 cigarettes.
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Tumor stage (AJCC 8th edition): T1 or T2
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Nodal stage (AJCC 8th edition): N0, N1 or N2
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For patients who may require chemotherapy (i.e. patients with multiple lymph nodes positive or a single node more than 3 cm in size, in any plane; see section 6): complete blood count/differential obtained within 4 weeks prior to randomization, with adequate bone marrow function, hepatic, and renal function, defined as: Absolute neutrophil count > 1.5 × 109/L; Hemoglobin > 80 g/L; platelets > 100 × 109/L; Bilirubin < 35 μmol/L; AST, ALT < 3 x the upper limit of normal; serum creatinine < 130 μmol/L or creatinine clearance ≥50 mL/min
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Head and neck multidisciplinary clinic (radiation oncologist and surgeon) and multidisciplinary tumor board presentation prior to randomization.
Exclusion criteria
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Unambiguous clinical or radiological evidence of ENE on pre-treatment imaging. This includes the presence of matted nodes, defined as 3 or more nodes that are abutting with loss of intervening fat planes.
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Serious medical comorbidities or other contraindications to RT, surgery or chemotherapy
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Inability to attend full course of RT or follow-up visits
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History of previous head and neck RT or previous head and neck cancer within 5 years
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Metastatic disease present
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Prior invasive malignant disease within 5 years, with the exception of non-melanoma skin cancer
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Lactating or pregnant women
Pre-treatment evaluation
- History and physical examination (including laryngopharyngoscopy) by a radiation oncologist and head and neck surgeon within 8 weeks prior to randomization
- For patients where adequate transoral access is in question, they will have an examination under anesthesia to ensure adequate exposure can be obtained prior to randomization
- Staging imaging within 12 weeks prior to randomization: Contrast-enhanced CT of the neck and chest or MRI of the neck with CT of the chest or whole body PET/CT
- Documentation of smoking history
- Histological confirmation of squamous cell carcinoma
- p16+ or HPV+ tumor status, as defined above
- Dental evaluation within 6 weeks prior to randomization
- Audiogram before initiation of treatment, with baseline CTCAE grade assessment
- Assessment of all baseline symptoms, including assessment of dysphagia, using CTC-AE version 4 within 2 weeks prior to randomization. Baseline dysphagia CTC-AE will be scored in all patients.
- Completion of QOL scoring within 2 weeks of randomization
- CBC/differential, hepatic (AST, ALT, total bilirubin) and renal function testing (BUN and creatinine, or creatinine clearance) within 4 weeks prior to randomization, if chemotherapy would be required
- Pregnancy test for women of child-bearing age, within 2 weeks prior to randomization
- Blood sample for whole genome sequencing analysis prior to initiation of treatment
- Informed consents must be obtained prior to any study specific activities
Interventions
Primary radiotherapy (Arm 1)
Radiation Alone: Accelerated radiation | Concurrent chemotherapy: Weekly cisplatin 40 mg/m2 for 6 cycles | |
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Nodal status | Node negative (N0) OR Single node less than 3 cm in maximal diameter | Multiple lymph nodes OR Single lymph node more than 3 cm in maximal diameter |
Fractionation | Radiation over 5 weeks, with 6 fractions a week 6th weekly fraction given on a weekday with a minimum 6 h intrafraction interval, or on a Saturday | Daily radiation, Monday-Friday over 6 weeks |
Special conditions | In patients > 70 years of age, standard fractionation (daily, Monday-Friday over 6 weeks) can be used at the discretion of the radiation oncologist | In patients who are deemed unfit for weekly cisplatin, the dose and/or schedule can be modified, or cetuximab or weekly carboplatin AUC 1.5 can be used, at the discretion of the medical oncologist. |
- 60 Gy in 30 fractions: Gross Tumor and Involved Nodes
- 54 Gy in 30 fractions: High risk subclinical areas.
- 48 Gy in 30 fractions: Low-risk nodal areas
Radiotherapy Volume | Definition |
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GTV_P | Gross tumour volume |
GTV_N | Gross nodes: – > 1.5 cm long axis – > 1 cm short axis – Necrotic – PET positive |
CTV60 | Combination of GTV_P and GTV_N with a 5 mm expansion, excluding natural boundaries of spread |
CTV54 | – A 1 cm expansion on the GTV_P – Any nodal level that contains a positive node. – Any node < 1 cm in short axis the radiation oncologist deems suspicious for harbouring disease. This node plus an additional 5 mm margin will be included in the CTV54. – The first echelon draining nodal levels. This is nearly always level 2, but should include the lateral retropharyngeal nodes (RP) for soft palate and posterior pharyngeal wall extension. |
CTV48 | – Patients that are node negative: ◦ Ipsilateral: II-IV. RP only if extension to posterior pharyngeal wall or soft palate ◦ Contralaterala: II-IV, RP only if extension to posterior pharyngeal wall or soft palate – All patients with N1 (ipsilateral) nodal disease: ◦ Ipsilateral: Ib, II-V, RP ◦ Contralaterala: II-IV, RP only if extension to posterior pharyngeal wall or soft palate – All patients with N2 disease: ◦ Ipsilateral and contralateral: Ib, II-V, RP |
Primary TOS (Arm 2)
- ENE
- Positive margins or close resection margins (< 3 mm)
- More than 1 lymph node positive, or any lymph node > 3 cm in size on pathology
- LVI
- pT3–4 disease
- 60 Gy in 30 fractions: Area of positive margins or ENE
- 54 Gy in 30 fractions: Operative bed, including primary tumor location and all dissected nodal levels
- 48 Gy in 30 fractions: Undissected areas considered to be at low-risk of harbouring microscopic disease.
- 50 Gy in 25 fractions: Operative bed, including primary tumor location and all dissected nodal levels
- 45 Gy in 25 fractions: Undissected areas considered to be at low-risk of harbouring microscopic disease.
Radiotherapy Volume | Definition | |
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With ENE or positive margins (30 fractions over 6 weeks) | Without ENE or positive margins (25 fractions over 5 weeks) | |
CTV60 | Areas of positive margins and/or ENE | |
CTV54 | CTV50 | Entire tumor bed and any dissected neck nodal levels |
CTV48 | CTV45 | Undissected nodal areas that must be treated based on pathological results. Treatment volumes must include nodal levels adjacent to areas containing involved nodes (eg. if there is a level II node positive, levels Ib and V must be included) – All patients with N1 (ipsilateral) nodal disease: ◦Ipsilateral: Ib, II-V, RP ◦Contralaterala: II-IV, RP only if extension to posterior pharyngeal wall or soft palate – All patients with N2 disease: ◦Ipsilateral and contralateral: Ib, II-V, RP |
Unilateral vs. Bilateral radiation
- tonsil primary
- < 1 cm extension into the tongue base or palate
- no posterior pharyngeal wall extension
- no ENE
- N0, or only a single ipsilateral lymph node positive
- tonsil primary
- < 1 cm extension into the tongue base or palate
- no posterior pharyngeal wall extension
- no ENE
- more than one ipsilateral lymph node positive, but are all less than 6 cm, and are all in level II.
Radiotherapy technique, immobilization, localization and planning
Quality assurance
Radiotherapy quality assurance
- Discussion of each radiotherapy plan at head and neck quality assurance (QA) rounds prior to, or within the first week of treatment
- Physics staff will confirm all dose delivery for IMRT plans (including arc-based treatments) before treatment.
- Cone-beam CT and/or orthogonal x-rays will be used daily to verify treatment positioning, as per institutional standard practice.
- Prior to enrolling patients, each centre will be given a sample CT dataset for contouring, planning and physics QA. Enrollment can begin once the plan and QA have been approved at the London Regional Cancer Program (LRCP).
Surgery quality assurance
- absent (node without metastasis or nodal metastasis with smooth/rounded leading edge confined to thickened capsule/pseudocapsule)
- minimal (tumor extends ≤1 mm beyond the lymph node capsule)
- present - extensive (tumor extends > 1 mm beyond the lymph node capsule (includes soft tissue metastasis))
Subject discontinuation / withdrawal
Follow-up evaluation
Disease progression and new primary
Measurement of outcomes
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Survival outcomes:
- ◦ OS: time from randomization until death from any cause
- ◦ PFS: time from randomization to either progression or death, whichever occurs first.
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QOL outcomes (measured at baseline and at 6-month intervals except PNQ):
- ◦ MDADI
- ◦ EORTC QLQ-C30 and H&N35 scales
- ◦ NDII
- ◦ VHI-10
- ◦ PNQ will be completed at 1 year post-treatment.
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Economic assessment:
- ◦ EQ-5D-5 L: administered at baseline and 6 month intervals. Quality adjusted life years (QALYs) will be assessed as the area under the preference-weighted survival curve. Overall costs of each treatment strategy will be abstracted from the available literature. The incremental cost effectiveness ratios (ICERs) between treatment arms will be compared through the standard method of ratio between differences in costs and QALYs. Point estimates for these differences can be derived from multivariable generalized estimating equations (GEE) or general linear model (GLM) analyses.
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Toxicity outcomes:
- ◦ CTC-AE toxicities will be recorded during treatment and at every follow-up visit.