De-escalation of Adjuvant Radio (Chemo) Therapy for HPV-positive Head-neck Squamous Cell Carcinomas (DELPHI)

De-escalation of Adjuvant Radio (Chemo) Therapy for HPV-positive Head and Neck Squamous Cell Carcinomas: A Phase I Study to Reduce Late Toxicity

In patients with squamous cell carcinoma of the oral cavity, the oropharynx and larynx with local advanced tumors (pathologic stage T3 = pT3) and or lymph node involvement (pN+) postoperative radio - or radiochemotherapy is the standard of care. Postoperative radiochemotherapy is indicated in patients with multiple lymph node metastasis, lymph node metastasis with extracapsular spread and / or residual tumor (R1-Status) after resection. Oropharyngeal cancer caused by HPV (human papillomavirus 16 or 18) is a distinct subgroup with a known sensitivity to radiotherapy (RTx) or radiochemotherapy (RCTx). Additionally a superior outcome after R(C)Tx over HPV negative patients was shown for patients treated with primary or adjuvant RCTx. To date it is unknown if the total dose of the radiotherapy can be safely reduced with the aim to decrease the therapy associated late effects.

Patients with a HPV associated carcinoma that take part in the study will be treated with a reduced radiotherapy dose, chemotherapy will be prescribed based on clinical factors (number of affected lymph node, presence of extracapsular spread or residual tumor). Radiation dose will be reduced in two steps.

Study Overview

• Status: Recruiting
• Conditions: Head-and-neck Squamous Cell Carcinoma
• Intervention / Treatment: Radiation: De-escalation radio(chemo)therapy - Level 1; Radiation: De-escalation radio(chemo)therapy - Level 2; Radiation: Standard radio(chemotherapy)

Detailed Description

For all patients taking part in the study the HPV status of the resected tumor will be determined centrally by p16 immunohistochemistry and confirmation will be done by HPV DNA assessment using Polymerase Chain Reaction (PCR)-based array. Patients positive for HPV will be treated with a reduced RT dose to the tumor and to elective neck. HPV negative patients will be treated with standard radio- or radiochemotherapy. Patients deemed at high risk for locoregional recurrences (presence of extracapsular spread, residual tumor or multiple affected nodes) will be treated separately from patients deemed at intermediate risk (T>=3, and / or 1-3 nodes positive). The high risk group will be treated with a higher dose and concurrent chemotherapy. After inclusion of 30 patients per treatment group, follow up for the patients will be awaited for two years and safety of the intervention will be assessed. The second de-escalation level will only be opened for accrual if not more than three locoregional recurrences will occur per treatment group.

• Study Type: Interventional
• Enrollment (Estimated): 304
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mechthild Krause, Prof.; Phone Number: +49 351 458 2238; Email: mechthild.krause@uniklinikum-dresden.de
• Study Contact Backup: Name: Fabian Lohaus, MD; Phone Number: +49 351 458 2238; Email: fabian.lohaus@uniklinikum-dresden.de

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Not yet recruiting
    • Prof. Volker Budach
    • Contact: Volker Budach, Prof.; Phone Number: +49 30 450 527 152
    • Principal Investigator: Volker Budach, Prof.
  • Heidelberg, Germany
    • Recruiting
    • Prof. Jürgen Debus
    • Contact: Jürgen Debus, Prof.
  • Baden-Wuerttemberg
    • Freiburg, Baden-Wuerttemberg, Germany, 79106
      • Recruiting
      • Prof. Anca-Ligia Grosu
      • Contact: Anca-Ligia Grosu, Prof.; Phone Number: +49 761 270 94610; Email: anca.grosu@uniklinik-freiburg.de
      • Principal Investigator: Ana-Ligia Grosu, Prof.
    • Tübingen, Baden-Wuerttemberg, Germany, 72016
      • Recruiting
      • Prof. Daniel Zips
      • Contact: Daniel Zips, Prof.; Phone Number: +49 7071/29-8 21 65; Email: ROInfo@med.uni-tuebingen.de
      • Principal Investigator: Daniel Zips, Prof.
  • Bavaria
    • München, Bavaria, Germany, 81377
      • Recruiting
      • Prof. Claus Belka
      • Contact: Claus Belka, Prof.; Phone Number: +49 89 7095 4520; Email: Claus.Belka@med.uni-muenchen.de
      • Principal Investigator: Claus Belka, Prof.
    • München, Bavaria, Germany, 81675
      • Recruiting
      • Prof. Stephanie Combs
      • Contact: Stephanie Combs, Prof.; Phone Number: +49 89 41 40-45 02; Email: radonk@lrz.tum.de
      • Principal Investigator: Stephanie Combs, Prof.
  • Hesse
    • Frankfurt am Main, Hesse, Germany
      • Recruiting
      • Prof. Claus Rödel
      • Contact: Claus Rödel, Prof.
  • North Rhine-Westphalia
    • Essen, North Rhine-Westphalia, Germany, 45147
      • Recruiting
      • Prof. Martin Stuschke
      • Contact: Martin Stuschke, Prof.; Phone Number: +49 201 / 723-23 20; Email: martin.stuschke@uk-essen.de
      • Principal Investigator: Martin Stuschke, Prof.
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • Recruiting
      • Prof. Mechthild Krause
      • Contact: Mechthild Krause, Prof.; Phone Number: +493514582238; Email: str.studien@uniklinikum-dresden.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Condition after surgical removal of a squamous cell carcinoma of the oropharynx and adequate lymph node dissection
• Indication for adjuvant radiotherapy or radiochemotherapy in the interdisciplinary tumor board
• Good general state (ECOG performance status 0 or 1)
• Adequate compliance to ensure closely follow-up
• Patient's consent and written consent
• Neck dissection of at least the tumor bearing side

Additional Inclusion Criteria Arm intermediate risk (at least one of the criteria must be fulfilled):

• pT3 and R0 and / or
• histologically confirmed involvement of lymph nodes (n = 1-3) and no extracapsular extension of the lymph node metastasis

Additional Inclusion Criteria Arm high risk (at least one of the criteria must be fulfilled):

• residual tumor (R1 status) and / or
• pathologic stage T4 (pT4) status and / or
• more than 3 infected lymph nodes and / or
• extracapsular extension of at least one lymph node metastasis

Exclusion Criteria:

• Patients with a cumulative nicotine abuse > 30 packyears. These patients are not included in the intervention arms, but are always included in the observation arms (regardless of HPV status).
• radiologically presumed or histologically confirmed distant metastasis
• R2 resection or macroscopically visible residual tumor after surgery
• no neck dissection
• interval between last operation and planned irradiation start > 7 weeks
• contraindication against a guideline-appropriate adjuvant radiation or radiochemotherapy according to the clinical risk constellation
• tumor disease in the last five years before the beginning of the study (except basaliomas of the skin, in-situ carcinoma of the cervix uteri or breast, or tumors with similar prognosis which are considered to be very likely to be cured)
• malignant tumor disease in the head and neck region, regardless of interval and prognosis
• Pre-irradiation with risk of dose overlap
• participation in another clinical trial if further experimental therapy is necessary or the treatments/ protocols are mutually exclusive (e.g. altered chemotherapy, additional consolidation chemotherapy). Allowed is the additional participation in observation studies or supportive therapy studies.
• diseases or conditions which do not allow the person concerned to assess the nature and scope and possible consequences of the clinical trial
• pregnant or lactating women
• evidence that the participant is not expected to comply with the study protocol (e.g. lack of cooperation)
• missing written consent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Interventional Arm A - HPV(+); De-escalation Radio(chemo)therapy - Level 1	Radiation: De-escalation radio(chemo)therapy - Level 1; 54/ 59,4 Gy
Experimental: Interventional Arm B - HPV(+); De-escalation Radio(chemo)therapy - Level 2	Radiation: De-escalation radio(chemo)therapy - Level 2; 48,8/ 55 Gy
Active Comparator: Observational Arm A - HPV(-); Standard Radio(chemo)therapy	Radiation: Standard radio(chemotherapy); 60/ 66 Gy
Active Comparator: Observational Arm B - HPV(+); Standard Radio(chemo)therapy	Radiation: Standard radio(chemotherapy); 60/ 66 Gy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rate of locoregional recurrences	measured from the last day of treatment	24 months after end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall survival	measured from the last day of treatment	60 months and 5 years after end of treatment
acute toxicity	The occurrence of acute side effects (up to 90 days after start of treatment) will be recorded and documented based on CTCAE 4.0.	3 months after end of treatment
late toxicity	The occurrence of late side effects will be recorded and documented based on CTCAE 4.0 after every follow-up visit.	24 months after end of treatment
quality of life of cancer patients	The assessment of quality of life (QoL) is carried out using the EORTC quality of life questionnaire (QLQ) C30. Quality of life will be documented immediately before the start of therapy, after completion of postoperative radiotherapy and at every follow-up visit. QOL will be measured as change from baseline over time.	24 months after end of treatment
quality of life - disease specific	The assessment of quality of life (QOL) is carried out using the EORTC quality of life questionnaire (QLQ) disease-specific module for head and neck cancer H&N35. Quality of life will be documented immediately before the start of therapy, after completion of postoperative radiotherapy and at every follow-up visit. QOL will be measured as change from baseline over time.	24 months after end of treatment
rate of locoregional recurrences	measured from the last day of treatment	5 years after end of treatment

Collaborators and Investigators

• Sponsor: Technische Universität Dresden
• Collaborators: German Cancer Research Center; National Center for Tumor Diseases, Heidelberg; Radiation Oncology Working Group of the German Cancer Society; National Center for Tumor Diseases (NCT) Dresden
• Investigators: Study Chair: Mechthild Krause, Prof., University of Technology, University Hospital Carl Gustav Carus, Department of Radiation Therapy and Radiation Oncology, German Consortium for Translational Cancer Research (DKTK)

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2018
• Primary Completion (Estimated): November 30, 2029
• Study Completion (Estimated): November 30, 2032

Study Registration Dates

• First Submitted: October 24, 2017
• First Submitted That Met QC Criteria: January 10, 2018
• First Posted (Actual): January 11, 2018

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: September 8, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: radiotherapy; Oropharyngeal cancer; postoperative; Head and neck cancer; HPV; radiochemotherapy; de-intensification
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck
• Other Study ID Numbers: STR-DELPHI-2016

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