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

Sponsor

Technische Universität Dresden (Other)

Overall Status

Recruiting

CT.gov ID

NCT03396718

Collaborator

German Cancer Research Center (Other), National Center for Tumor Diseases (NCT) Dresden (Other), National Center for Tumor Diseases, Heidelberg (Other), Radiation Oncology Working Group of the German Cancer Society (Other)

384

Enrollment

Locations

Arms

123.9

Anticipated Duration (Months)

38.4

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Head-and-neck Squamous Cell Carcinoma	Radiation: De-escalation radio(chemo)therapy - Level 1 Radiation: De-escalation radio(chemo)therapy - Level 2 Radiation: Standard radio(chemotherapy)	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

384 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 4, 2018

Anticipated Primary Completion Date :

Jan 1, 2026

Anticipated Study Completion Date :

Jan 1, 2029

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

rate of locoregional recurrences [24 months after end of treatment]
measured from the last day of treatment

Secondary Outcome Measures

overall survival [60 months and 5 years after end of treatment]
measured from the last day of treatment
acute toxicity [3 months after end of treatment]
The occurrence of acute side effects (up to 90 days after start of treatment) will be recorded and documented based on CTCAE 4.0.
late toxicity [24 months after end of treatment]
The occurrence of late side effects will be recorded and documented based on CTCAE 4.0 after every follow-up visit.
quality of life of cancer patients [24 months after end of treatment]
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.
quality of life - disease specific [24 months after end of treatment]
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.
rate of locoregional recurrences [5 years after end of treatment]
measured from the last day of treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Prof. Anca-Ligia Grosu	Freiburg	Baden-Wuerttemberg	Germany	79106
2	Prof. Daniel Zips	Tübingen	Baden-Wuerttemberg	Germany	72016
3	Prof. Claus Belka	München	Bavaria	Germany	81377
4	Prof. Stephanie Combs	München	Bavaria	Germany	81675
5	Prof. Claus Rödel	Frankfurt am Main	Hesse	Germany
6	Prof. Martin Stuschke	Essen	North Rhine-Westphalia	Germany	45147
7	Prof. Mechthild Krause	Dresden	Saxony	Germany	01307
8	Prof. Volker Budach	Berlin		Germany	10117
9	Prof. Jürgen Debus	Heidelberg		Germany
10	Prof. Heinz Schmidberger	Mainz		Germany

Sponsors and Collaborators

Technische Universität Dresden
German Cancer Research Center
National Center for Tumor Diseases (NCT) Dresden
National Center for Tumor Diseases, Heidelberg
Radiation Oncology Working Group of the German Cancer Society

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)