Comparative Effectiveness Trial of Transoral Head and Neck Surgery Followed by Adjuvant Radio(Chemo)Therapy Versus Primary Radiochemotherapy for Oropharyngeal Cancer

Study Overview
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Brief Summary
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Comparative Effectiveness Trial of Transoral Head and Neck Surgery followed by adjuvant Radio(chemo)therapy versus primary Radiochemotherapy for Oropharyngeal Cancer

Detailed Description
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This trial investigates the effectiveness of transoral head and neck surgery (TOS) for locally advanced, but transorally resectable oropharyngeal cancer followed by risk-adapted adjuvant therapy versus primary radiochemotherapy (definitive chemoradiotherapy, CRTX). Both treatments are internationally accepted standards. The choice of the treatment strategy depends on the preference of the responsible attending physician and on the country of residence. Internationally, mostly definitive chemoradiotherapy is regarded as the standard of care for oropharyngeal cancer. In Germany, however, transoral surgical resection is also well established and commonly practiced. The key question therefore is whether one of the two therapies is more effective than the other in clinical daily routine under the given conditions of our health care system and with a realistic, non-ideal patient cohort. For this reason, a comparative effectiveness research (CER) concept will be applied in this setting. The aim of this trial is primarily to show a superiority of the surgical approach in terms of local and locoregional control and secondarily to compare functional outcome and quality of life.

Official Title
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Comparative Effectiveness Trial of Transoral Head and Neck Surgery Followed by Adjuvant Radio(Chemo)Therapy Versus Primary Radiochemotherapy for Oropharyngeal Cancer

Conditions
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Oropharyngeal Cancer

Intervention / Treatment
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* Procedure: Resection
* Radiation: Radiotherapy
* Drug: Chemotherapy
* Procedure: Salvage neck dissection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven SCC of the oropharynx; T1, N2a-c, M0; T2, N1-2c, M0; T3, N0-2c, M0, with only amendable to transoral resection) Primary tumor must be resectable through transoral approach p16 immunohistochemitry by local pathology or FFPE tissue must be available for central HPV diagnostic Written and signed informed consent Briefing through surgeon and radiation oncologist ECOG PS ≥2, Karnofsky PS ≥ 60 % Age ≥ 18 Curative treatment intent Adequate bone marrow function: leucocytes > 3.0 x 109/L, neutrophils > 1.5 x 109/L, platelets > 80 x 109/L, hemoglobin > 9.5 g/dL Adequate liver function: Bilirubin < 2.0 g/dL, SGOT, SGPT, < 3 x ULN If of childbearing potential, willingness to use effective contraceptive method for the study duration and 2 months post-dosing. dental examination and appropriate dental therapy if needed prior to Confidential TopROC 2017_03_24 Version 1.0 Seite 15 von 124 beginning of radiotherapy Nutritional evaluation prior to initiation of therapy and optional prophylactic gastrostomy (PEG) tube placement Exclusion Criteria: Prior invasive malignancy except controlled skin cancer or carcinoma in situ of cervix Unknown primary (CUP), nasopharynx, hypopharynx, laryngeal or salivary gland cancer Metastatic disease Serious co-morbidity, e.g. high-grade carotid artery stenosis, congestive heart failure NYHA grade 3 and 4, liver cirrhosis CHILD C Hemoglobin level <9.5g/dl within 4 weeks before randomization Pregnancy or lactation Women of child-bearing potential with unclear contraception Previous treatment with chemotherapy, radiotherapy, EGFR-targeting agents or surgery exceeding biopsy in head and neck Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study screening Social situations that limit compliance with study requirements or patients with an unstable condition (e.g., psychiatric disorder, a recent history of drug or alcohol abuse, interfering with study compliance, within 6 months prior to screening) or otherwise thought to be unreliable or incapable of complying with the requirements of the protocol Patients institutionalized by official means or court order Deficient

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, two-arm, open label, multicenter, randomized, controlled comparative effectiveness study. The trial is based on an event-driven design: the final analysis will be performed when all events have been observed or the study was terminated at one of the interim analyses.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Resection/adjuvant radio(-chemo)therapy<br>Transoral surgical resection within 4 weeks after randomization Neck dissection can be performed during resection of the primary tumor or within 4 weeks after randomization 6-7 weeks standard risk-adapted adjuvant radio(-chemo)therapy 56-66 Gy (chemotherapy according to arm B if necessary), start within 6 weeks post-surgery | Procedure: Resection<br>* Definitive surgery should generally be performed within 2 weeks, but not more than 4 weeks after randomization. The appropriately indicated neck dissection(s) may be performed either prior to, during the same session, or within 2 weeks after the resection of the primary tumor, but not later than 4 weeks following randomization. The primary tumor is to be resected with clear margins (R0) and en bloc in all cases. Frozen section assessment must be routinely and readily available.<br>* Other names: Transoral Surgery;Radiation: Radiotherapy<br>* 6-7 weeks standard risk-adapted adjuvant radiotherapy 56-66 Gy, start within 6 weeks post-surgery Arm B: 6-7 weeks standard radiotherapy (IMRT-technique), start within 4 weeks after randomization, 70-72 Gy, SIB possible<br>Drug: Chemotherapy<br>* The investigational medicinal product (IMP) are the chemotherapeutical drugs Cisplatin, Mitomycin C and 5-FU. According to local routine, chemotherapy protocols as listed in study protocol should be used.<br>|
| Active Comparator: Adjuvant radio(-chemo)therapy/salvage neck dissection<br>6-7 weeks standard radiotherapy (IMRT-technique), start within 4 weeks after randomization 70-72 Gy, SIB possible Cisplatin 100 mg/m2 on days 1, 22, 43 or Cisplatin once weekly (30-40 mg/m2) on days 1, 8, 15, 22, 29, 36 or Mitomycin C 10 mg/m2 d1, 29 and 5-FU 600 mg/m2/day iv on days 1-5 or Cisplatin 20 mg/m² + 5-FU 600 mg/m²/day iv d 1-5 and 29-33 +/- Salvage neck dissection 12±2 weeks after treatment | Radiation: Radiotherapy<br>* 6-7 weeks standard risk-adapted adjuvant radiotherapy 56-66 Gy, start within 6 weeks post-surgery Arm B: 6-7 weeks standard radiotherapy (IMRT-technique), start within 4 weeks after randomization, 70-72 Gy, SIB possible<br>Drug: Chemotherapy<br>* The investigational medicinal product (IMP) are the chemotherapeutical drugs Cisplatin, Mitomycin C and 5-FU. According to local routine, chemotherapy protocols as listed in study protocol should be used.<br>Procedure: Salvage neck dissection<br>* +/- Salvage neck dissection 12±2 weeks after treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to local or locoregional failure or death from any cause | The primary objective of this study is to evaluate the effectiveness of primary surgical versus non-surgical treatment of patients with locally advanced, but transorally resectable oropharyngeal cancer in terms of time to local or locoregional failure or death from any cause (LRF). | Defined as time from randomization up to 36 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival (OS) in both study arms, follow-up visits until the end of study | Until 3 years after randomization | 
| Disease-free survival | Disease-free survival (DFS) in both study arms. CT- Scans will be performed at month 3, month 6, 18, 30 and in case of suspicion of recurrence | Until 3 years after randomization | 
| Effectiveness in terms of toxicity | Effectiveness in terms of toxicity in both study arms. Monitoring of AE's/SAE's from randomization to 28 days after the last administration of IMP and/or 5 months after randomization in this trial | Until 3 years after randomization | 
| Effectiveness in terms of morbidity | Effectiveness in terms of morbidity (including swallowing function by MDADI Score) by late morbidity documentation in both study arms. | Until 3 years after randomization | 
| Quality of life evaluated by patient | Quality of life Questionnaires using QLQ H&N-43 in both study arms | Until 3 years after randomization | 
| Quality of life evaluated by patient | CareQuality of life Questionnaires using EORTC QLQ-C30 both study arms | Until 3 years after randomization | 
| Cost-utility | Cost-utility in both study armsusing Questionnaire Health Care Utilization and Productivity loss. | Until 3 years after randomization | 
| Cost-effectiveness | Cost-effectiveness in both study arms using Questionnaire Health Utilization and Productivity loss. | Until 3 years after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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locally advanced, transorally resectable