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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Oropharyngeal Cancer
• Intervention / Treatment: Procedure: Resection; Radiation: Radiotherapy; Drug: Chemotherapy; Procedure: Salvage neck dissection

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 280
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Berlin Charité
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg Eppendorf
  • Baden- Würtemberg
    • Mannheim, Baden- Würtemberg, Germany, 68167
      • Universitäts- HNO- Klinik Mannhein
  • Baden-Württemberg
    • Karlsruhe, Baden-Württemberg, Germany, 76135
      • St. Vincentius- Kliniken Karlsruhe
    • Ulm, Baden-Württemberg, Germany, 89075
      • Universitatsklinikum Ulm
  • Bayern
    • Dachau, Bayern, Germany, 85221
      • Helios Amper- Klinikum Dachau
  • Brandenburg
    • Neuruppin, Brandenburg, Germany, 16816
      • Ruppiner Klinken GmbH
    • Potsdam, Brandenburg, Germany, 14467
      • Klinikum Ernst von Bergmann gemeinnützige GmbH
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
      • Universitätsklinikum Frankfurt
    • Gießen, Hessen, Germany, 35385
      • Universitätsklinikum Gießen
    • Marburg, Hessen, Germany, 35037
      • Philipps-Universitat Marburg
  • Niedersachsen
    • Stade, Niedersachsen, Germany, 21682
      • Elbekliniken Stade- Buxtehude GmbH, Klinikum Stade und Klinik Dr. Hancken
    • Wolfsburg, Niedersachsen, Germany, 38440
      • Klinikum Wolfsburg
  • Nordrhein-Westfalen
    • Gummersbach, Nordrhein-Westfalen, Germany, 51643
      • Kreiskliniken Gummersbach-Waldbröl GmbH Klinik Oberberg
    • Köln, Nordrhein-Westfalen, Germany, 50937
      • Universitätsklinikum Köln
  • Rheinland-Pfalz
    • Koblenz, Rheinland-Pfalz, Germany, 56073
      • Katholischen Krankenhaus Koblenz
  • Saarland
    • Homburg, Saarland, Germany, 22421
      • Universität des Saarlandes
  • Sachsen
    • Leipzig, Sachsen, Germany, 04103
      • Universitätsklinik Leipzig / Borna Sana Kliniken Leipziger Land
  • Schleswig- Holstein
    • Lübeck, Schleswig- Holstein, Germany, 23538
      • Universitätsklinikum Schleswig-Holstein Campus Lübeck
  • Thüringen
    • Jena, Thüringen, Germany, 07757
      • Universitätsklinikum Jena

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Resection/adjuvant radio(-chemo)therapy; 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; 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.; Other Names: Transoral Surgery; Radiation: Radiotherapy; 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; Drug: Chemotherapy; 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.
Active Comparator: Adjuvant radio(-chemo)therapy/salvage neck dissection; 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; 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; Drug: Chemotherapy; 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.; Procedure: Salvage neck dissection; +/- Salvage neck dissection 12±2 weeks after treatment

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tertiary objectives include comparisons of treatment effects between HPV- Status	Subgroup analysis of HPV-positive and HPV-negative oropharynx carcinoma	Up to 36 month

Collaborators and Investigators

• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Collaborators: Charite University, Berlin, Germany; University Hospital Ulm; University Medical Center Gießen and Marburg GmbH
• Investigators: Principal Investigator: Chia-Jung Busch, PD Dr., Universitätsklinikum Hamburg-Eppendorf

Publications and helpful links

General Publications

• Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010 Jul 1;363(1):24-35. doi: 10.1056/NEJMoa0912217. Epub 2010 Jun 7.
• Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008 Feb 1;26(4):612-9. doi: 10.1200/JCO.2007.14.1713.
• Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Brandsma J, Sasaki C, Joe J, Camp RL, Rimm DL, Psyrri A. Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis. J Clin Oncol. 2006 Feb 10;24(5):736-47. doi: 10.1200/JCO.2004.00.3335. Epub 2006 Jan 9.
• Mehanna H, Beech T, Nicholson T, El-Hariry I, McConkey C, Paleri V, Roberts S. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer--systematic review and meta-analysis of trends by time and region. Head Neck. 2013 May;35(5):747-55. doi: 10.1002/hed.22015. Epub 2012 Jan 20.
• Licitra L, Zigon G, Gatta G, Sanchez MJ, Berrino F; EUROCARE Working Group. Human papillomavirus in HNSCC: a European epidemiologic perspective. Hematol Oncol Clin North Am. 2008 Dec;22(6):1143-53, vii-viii. doi: 10.1016/j.hoc.2008.10.002.
• Pfister DG, Spencer S, Brizel DM, Burtness B, Busse PM, Caudell JJ, Cmelak AJ, Colevas AD, Dunphy F, Eisele DW, Gilbert J, Gillison ML, Haddad RI, Haughey BH, Hicks WL Jr, Hitchcock YJ, Jimeno A, Kies MS, Lydiatt WM, Maghami E, Martins R, McCaffrey T, Mell LK, Mittal BB, Pinto HA, Ridge JA, Rodriguez CP, Samant S, Schuller DE, Shah JP, Weber RS, Wolf GT, Worden F, Yom SS, McMillian NR, Hughes M; National Comprehensive Cancer Network. Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2014 Oct;12(10):1454-87. doi: 10.6004/jnccn.2014.0142.
• Gregoire V, Lefebvre JL, Licitra L, Felip E; EHNS-ESMO-ESTRO Guidelines Working Group. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May;21 Suppl 5:v184-6. doi: 10.1093/annonc/mdq185. No abstract available.
• Wegscheider K, Drabik A, Bleich C, Schulz H. [Benefit assessment in health services research and epidemiology]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2015 Mar;58(3):298-307. doi: 10.1007/s00103-014-2106-1. German.
• Lorincz BB, Mockelmann N, Busch CJ, Knecht R. Functional outcomes, feasibility, and safety of resection of transoral robotic surgery: single-institution series of 35 consecutive cases of transoral robotic surgery for oropharyngeal squamous cell carcinoma. Head Neck. 2015 Nov;37(11):1618-24. doi: 10.1002/hed.23809. Epub 2014 Aug 28.
• Boscolo-Rizzo P, Gava A, Baggio V, Marchiori C, Stellin M, Fuson R, Lamon S, Da Mosto MC. Matched survival analysis in patients with locoregionally advanced resectable oropharyngeal carcinoma: platinum-based induction and concurrent chemoradiotherapy versus primary surgical resection. Int J Radiat Oncol Biol Phys. 2011 May 1;80(1):154-60. doi: 10.1016/j.ijrobp.2010.01.032. Epub 2010 Sep 23.
• Hicks WL Jr, Kuriakose MA, Loree TR, Orner JB, Schwartz G, Mullins A, Donaldson C, Winston JM, Bakamjian VY. Surgery versus radiation therapy as single-modality treatment of tonsillar fossa carcinoma: the Roswell Park Cancer Institute experience (1971-1991). Laryngoscope. 1998 Jul;108(7):1014-9. doi: 10.1097/00005537-199807000-00012.
• O'Hara J, MacKenzie K. Surgical versus non-surgical management of early stage oropharyngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2011 Mar;268(3):437-42. doi: 10.1007/s00405-010-1362-4. Epub 2010 Aug 27.
• Bussmann L, Laban S, Wittekindt C, Stromberger C, Tribius S, Mockelmann N, Bottcher A, Betz CS, Klussmann JP, Budach V, Muenscher A, Busch CJ. Comparative effectiveness trial of transoral head and neck surgery followed by adjuvant radio(chemo)therapy versus primary radiochemotherapy for oropharyngeal cancer (TopROC). BMC Cancer. 2020 Jul 29;20(1):701. doi: 10.1186/s12885-020-07127-2.

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2018
• Primary Completion (Anticipated): May 5, 2024
• Study Completion (Anticipated): May 5, 2024

Study Registration Dates

• First Submitted: March 2, 2018
• First Submitted That Met QC Criteria: September 28, 2018
• First Posted (Actual): October 1, 2018

Study Record Updates

• Last Update Posted (Actual): May 17, 2023
• Last Update Submitted That Met QC Criteria: May 15, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: locally advanced; transorally resectable
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Oropharyngeal Neoplasms
• Other Study ID Numbers: TopROC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No