DELPHI
Overview
- Study title: De-escalation of adjuvant radio(chemo)therapy for HPV-positive head and neck squamous cell carcinoma. A phase I study on the reduction of late toxicity
- Study design: Prospective, multicentre, two-arm, non-randomised treatment study (Phase I study)
- Study participants: Patients with head and neck squamous cell carcinoma (HNSCC) after surgery and before adjuvant radiotherapy.
- Study objective: To test safety and reduced late toxicity by dose reduction of adjuvant radio(chemo)therapy for HPV-positive head and neck squamous cell carcinoma.
- Clinical.trials.gov-Identifier / NCT-ID: NCT03396718
Study status: Currently recruiting
DELPHI (De-escalation of adjuvant radio(chemo)therapy for HPV-positive head and neck squamous cell carcinoma) is a prospective, multicentre, non-randomised phase I study. Adult patients with head and neck squamous cell carcinoma (HNSCC) who have already undergone surgery and have not yet received adjuvant radiotherapy are eligible to participate.
Carcinomas of the head and neck region caused by human papillomavirus (HPV) respond particularly well to radiotherapy or radiochemotherapy. The primary aim of the DELPHI study is to determine whether the dose of adjuvant radiotherapy can be reduced in patients with HPV-positive HNSCC without increasing the risk of recurrences. The study also investigates whether a reduced radiation dose can lessen the late toxicity associated with radiotherapy.
Cancer patients can take part in the DELPHI study via the participating Comprehensive Cancer Centres and hospitals at the NCT/DKTK sites in Heidelberg, Freiburg, Tübingen, Munich (LMU), Munich (TU), Frankfurt, Essen, and Dresden. Further study centres are planned in Berlin, Cologne, Ulm, Augsburg, Regensburg and Würzburg.
DELPHI is a prospective, two-arm, non-randomised phase I study comprising several subgroups within the intervention arm. It enrols adult patients with head and neck squamous cell carcinoma. Eligible patients must have already undergone surgery and must not have received prior radiotherapy.
The HPV status of the tumour is centrally determined in all study participants using p16 immunohistochemistry and HPV DNA analysis via PCR-based array.
- Patients with HPV-positive HNSCC are treated with a reduced radiation dose in the intervention arm.
- In the control arm, patients with HPV-negative HNSCC receive the standard radiation dose (observation arm).
Patients in both study arms receive chemotherapy if clinically indicated, according to current treatment guidelines.
A total of 304 patients may be enrolled in DELPHI, including 152 HPV-positive patients in the intervention arm.
Aims of the DELPHI study:
For patients with locally advanced carcinomas of the head and neck region (pathological stage T3 = pT3) and/or lymph node involvement (pN+), radiotherapy or radiochemotherapy following surgery represents the standard treatment. Carcinomas of the head and neck region caused by the human papilloma virus (most commonly HPV 16) form a subgroup that is particularly sensitive to radiotherapy or radiochemotherapy. It remains unclear whether the total radiation dose can be reduced in these patients without compromising treatment efficacy. Such a reduction would be desirable in order to minimise treatment-related side effects.
The aim of the DELPHI study is therefore to demonstrate,
- that the radiation dose can be reduced in patients with HPV-positive tumours without increasing the incidence of locoregional recurrence.
- and that a reduced radiotherapy dose lowers both acute and late toxicity.
Inclusion criteria
Main inclusion criteria:
- Age ≥18 years
- Prior surgical resection of an oropharyngeal squamous cell carcinoma with adequate lymph node dissection
- Indication for postoperative radiotherapy or radiochemotherapy as determined by an interdisciplinary tumour board
- Good general condition (the patient's performance status is rated 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG))
- Written informed consent obtained from the patient
- Sufficient compliance to allow for reliable follow-up
Additional inclusion criteria for the "intermediate risk" subgroup (IR, at least one criterion must be fulfilled) in the intervention arm:
- pT3 and R0 and/or
- Histologically confirmed lymph node involvement (n=1-3) without extracapsular extension
Additional inclusion criteria for the "high risk" subgroup (HR, at least one criterion must be fulfilled) in the intervention arm:
- Residual tumour present (R1 resection status) and/or
- T4 status and/or
- More than 3 affected lymph nodes and/or
- Extracapsular extension of at least one lymph node metastasis
Exclusion criteria
- Heavy smokers or ex-smokers with a history of more than 30 pack years, e.g., 1 pack per day for 30 years). Note: These patients cannot be included in the intervention arm, but can be included in the control arm.
- Suspected or histologically confirmed distant metastasis (M1)
- Visible residual tumour after surgery (R2)
- Interval of more than 7 weeks between the last surgical procedure and the planned start of radiotherapy
- Prior radiotherapy with potential dose overlap
- Contraindications to radiotherapy or radiochemotherapy in accordance with current clinical guidelines
- History of malignant disease within the five years prior to study entry (except basal cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other malignancies with a comparably favourable prognosis and high likelihood of cure)
- Previous tumour disease in the head and neck area regardless of treatment, time interval and prognosis
- No cervical lymph node dissection performed
- Participation in another clinical trial with experimental tumour therapies. Please note: Participation in observational studies or studies on supportive therapy is permitted)
- Pregnancy or breastfeeding
- Absence of written informed consent
- Medical conditions or mental disorders preventing the patient from understanding the nature, scope, and potential consequences of the clinical trial
- Evidence or strong suspicion that the patient will not be able to comply with the study protocol (e.g., lack of cooperation)
The treating oncologist identifies eligible participants based on the study-specific inclusion and exclusion criteria and registers the patient at the study centre. The patient receives comprehensive information about the study during a consultation with the study physician in the respective study centre. This is followed by the patient's decision regarding participation and the provision of written informed consent, if he chooses to take part. The subsequent course of the study is then as follows:
1. Registration and HPV screening
The HPV-16 status of the tumour is centrally determined in all study participants using p16 immunohistochemistry and HPV DNA analysis with a PCR-based array.
2. Intervention arm A (dose level 1)
Clinical criteria are used to determine the need for additional chemotherapy: patients classified as high risk (HR) receive standard cisplatin-based chemotherapy in addition to radiotherapy (RCT), patients with low/intermediate risk (IR) only receive radiotherapy (RT). Clinical criteria for risk classification include the number of affected lymph nodes, extracapsular growth or residual tumour. An initial cohort of 30 patients in each risk group receives treatment at the first dose level. Radiotherapy is reduced in an initial dose level (59.4 Gy for the HR group; 55 Gy for the IR group).
3. First interim analysis after 24 months
If fewer than two locoregional recurrences are observed among the first 10 patients per risk group in intervention arm A during a follow-up period of 24 months, the study proceeds to a second dose reduction scheme involving additional HPV16-positive HNSCC patients in intervention arm B.
4. Intervention arm B (dose level 2)
Clinical criteria are initially used to decide on additional chemotherapy: patients with high risk (HR) receive standard cisplatin chemotherapy in addition to radiotherapy (RCT), patients with low/intermediate risk (IR) only receive radiotherapy (RT). Clinical criteria for risk classification include the number of affected lymph nodes, extracapsular growth or residual tumour. Thirty people in each risk group then receive appropriate radiotherapy or radiochemotherapy. The radiotherapy is reduced in a second dose level (55 Gy for the HR group; 48.4 Gy for the IR group).
5. Final data analysis after 24 months
Following a 24-month follow-up period for all 30 patients in each risk group, a final data analysis is conducted. Based on the results, the appropriate radiation dose for a subsequent randomised clinical trial will be defined.
6. Control arm A (observation arm A, HPV-negative)
A decision regarding the addition of chemotherapy is initially based on clinical risk factors. Patients classified as high risk (HR) receive chemotherapy in addition to radiotherapy (RCT), while those with low or intermediate risk (IR) receive radiotherapy (RT) alone. Risk classification depends on factors such as the number of affected lymph nodes, presence of extracapsular extension, or residual tumour. Radiotherapy is administered at the standard dose: 66 Gy for the HR group and 60 Gy for the IR group.
7. Control arm B (observation arm B, HPV-positive)
During the initial 24-month follow-up period for the first 10 patients in each risk group, all newly enrolled participants are assigned to the control arm. Specifically, HPV-negative patients continue to be enrolled in control arm A. HPV-16-positive patients are assigned to control arm B, where they receive the same treatment as HPV-negative patients in control arm A — namely, radiotherapy at the standard dose.
Coordinating Principal Investigator
Prof Mechthild Krause
Carl Gustav Carus University Hospital
Clinic and Polyclinic for Radiotherapy and Radiooncology
Fetscherstrasse 74
01307 Dresden
Contact details outpatient clinic Dresden:
Phone: +49 (0)351 458 2238
E-mail: str.studien-at-uniklinikum-dresden.de