Individualized Radiation Dose Prescription in HNSCC Based on F-MISO-PET Hypoxia-Imaging (INDIRA-MISO)

Individualized Radiation Dose Prescription in HNSCC Based on F-MISO-PET Hypoxia-Imaging: Multi-center, Randomized Phase-II-trial

The trial evaluates the value of radiation dose escalation based on Hypoxia detection by 18F_misonidazole Positron Emission Tomography (18F-MISO-PET) for primary radiochemotherapy of head and neck squamous cell carcinoma. Patients negative for human papillomavirus (HPV) and with hypoxic tumours after 2 weeks of radiochemotherapy are randomized to completion of standard radiochemotherapy or radiochemotherapy with escalated radiation dose. An additional interventional arm includes a carbon ion boost. HPV positive tumours can be included in a control arm. Primary endpoint is local tumour control 2 years after radiochemotherapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Head and Neck Squamous Cell Carcinoma
• Intervention / Treatment: Radiation: standard radiochemotherapy; Radiation: dose-escalated radiochemotherapy; Radiation: dose-escalated radiochemotherapy with carbon ion boost

Detailed Description

Previous preclinical data and a prospective validated patient cohort have shown that patients with head and neck squamous cell carcinoma, whose tumours are hypoxic after 2 weeks of primary radiochmeotherapy, have a significantly lower chance of locoregional tumour control. The multi-center trial evaluates the value of radiation dose escalation based on hypoxia detection by 18F_misonidazole Positron Emission Tomography (18F-MISO-PET) for primary radiochemotherapy of head and neck squamous cell carcinoma. Patients negative for human papillomavirus (HPV) and with hypoxic tumours after 2 weeks of radiochemotherapy are randomized to completion of standard radiochemotherapy (70 Gy) or radiochemotherapy with escalated radiation dose (77 Gy). An additional interventional arm includes a carbon ion boost to 77 Gy. HPV positive tumours can be included in a control arm. Primary endpoint is local tumour control 2 years after radiochemotherapy. Secondary endpoints include acute and late toxicity (CTCAE 5.0), regional tumor control, overall survival, disease free survival, distant metastases, kinetics analysis of dynamic FMISO-PET scans, Quality of life (QoL). The hypothesis is that local tumour control 2 years after radiochemotherapy is higher in the dose escalated compared to the control arm.

• Study Type: Interventional
• Enrollment (Estimated): 276
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mechthild Krause, Prof. Dr.; Phone Number: +49 351 458 2238; Email: mechthild.krause@uniklinikum-dresden.de
• Study Contact Backup: Name: Esther Troost, Prof.Dr.Dr.; Phone Number: +49 351 458 7433; Email: esther.troost@uniklinikum-dresden.de

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Charite University Hospital
    • Contact: Volker Budach, Prof.
  • München, Germany, 81377
    • Ludwig-Maximilian-Universität, Klinikum Großhadern
    • Contact: Claus Belka, Prof.
  • Baden-Wuerttemberg
    • Freiburg, Baden-Wuerttemberg, Germany, 79106
      • Medical Faculty, Albert-Ludwigs-Universität Freiburg, Department of Radiation Oncology
      • Contact: Grosu Anca, Prof. Dr.
    • Heidelberg, Baden-Wuerttemberg, Germany, 69120
      • Department of Radiation Oncology Heidelberg University Medical School
      • Contact: Jürgen Debus, Prof. Dr.
      • Principal Investigator: Jürgen Debus
    • Mannheim, Baden-Wuerttemberg, Germany, 68167
      • Universitätsmedizin Mannheim, Klinik für Strahlentherapie und Radioonkologie
      • Contact: Frank Giordano, Prof.
  • Bavaria
    • Würzburg, Bavaria, Germany, 97080
      • Uniklinikum Wuerzburg
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • Mechthild Krause
      • Contact: Mechthild Krause, Prof. Dr.; Phone Number: +493512238; Email: str.studien@uniklinikum-dresden.de
    • Leipzig, Saxony, Germany, 04103
      • Universitatsklinikum Leipzig
      • Contact: Nils Nicolay, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age: older than 18 years
• WHO (ECOG) performance status 0-2
• Histological proven HNSCC
• HPV negative tumors or HPV positive tumors
• Stage III, IVA or IVB HNSCC according to UICC and AJCC guidelines
• Tumor classified as irresectable or patient inoperable or patient refused surgery
• Tumor extension and localization suitable for radiochemotherapy with curative intent
• Simultaneous standard chemotherapy with cisplatin applicable (no contra-indications)
• Dental examination and -treatment before start of therapy
• For women with childbearing potential and men in reproductive ages adequate contraception.
• Ability of subject to understand character and individual consequences of the clinical trial
• Written informed consent (must be available before enrolment in the trial)

Exclusion Criteria:

• Refusal of the patients to take part in the trial
• Presence of distant metastases (UICC stage IVC)
• Previous radiotherapy in the head and neck region
• Second malignancy that is likely to require treatment during the trial intervention or follow-up period or that, in the opinion of the physician, has a considerable risk of recurrence or metastases within the follow-up period
• Serious disease or medical condition with life expectancy of less than one year
• Participation in competing interventional trial on cancer treatment
• Patients who are not suitable for radiochemotherapy
• Pregnant or lactating women
• Patients not able to understand the character and individual consequences of the trial
• Nasopharyngeal Carcinomas

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

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: standard radiochemotherapy, hypoxic; HPV (-), hypoxic in 18F-MISO PET after 2 weeks of radiochemotherapy, randomized to standard radiation dose, 70 Gy standard radiochemotherapy	Radiation: standard radiochemotherapy; Patients will receive simultaneous radiochemotherapy, however the simultaneous chemotherapy is standard and not part of the evaluation in this trial. Present standard chemotherapy is cisplatinum 40 mg/m²/week (chemotherapy over the whole course of radiotherapy). Radiotherapy is applied to doses of 54 Gy(RBE)/ 1.8 Gy(RBE) per fraction to the adjuvant region and 70 Gy(RBE)/ 2 Gy(RBE) per fraction to the tumor and involved lymphonodes. Radiotherapy is always applied with 5 fractions per week.
Experimental: dose-escalated radiochemotherapy, hypoxic; HPV (-), hypoxic in 18F-MISO PET after 2 weeks of radiochemotherapy, randomized to escalated radiation dose, 77 Gy radiochemotherapy	Radiation: dose-escalated radiochemotherapy; Patients will receive simultaneous radiochemotherapy, however the simultaneous chemotherapy is standard and not part of the evaluation in this trial. Present standard chemotherapy is cisplatinum 40 mg/m²/week (chemotherapy over the whole course of radiotherapy). Radiotherapy is applied to doses of 54 Gy(RBE)/ 1.8 Gy(RBE) per fraction to the adjuvant region, 70 Gy(RBE)/ 2 Gy(RBE) per fraction to the tumor and involved lymphonodes and, if "hypoxic" and randomized to the intervention arm, 77 Gy(RBE)/ 2.2 Gy(RBE) per fraction to the primary tumor and lymphonode metastases > 2 cm. Radiotherapy is always applied with 5 fractions per week.
Experimental: escalated radiochemoth., carbon boost, hypoxic; HPV (-), hypoxic in 18F-MISO PET after 2 weeks of radiochemotherapy, non-randomised arm (only possible in the trial center Heidelberg), 77 Gy radiochemotherapy (boost with carbon)	Radiation: dose-escalated radiochemotherapy with carbon ion boost; Patients will receive simultaneous radiochemotherapy, however the simultaneous chemotherapy is standard and not part of the evaluation in this trial. Radiotherapy is applied to doses of 54 Gy(RBE)/ 1.8 Gy(RBE) per fraction to the adjuvant region, 70 Gy(RBE)/ 2 Gy(RBE) per fraction to the tumor and involved lymphonodes and, if "hypoxic" and treated in the study site Heidelberg, 77 Gy(RBE)/ 2.2 Gy(RBE) per fraction to the primary tumor and lymphonode metastases > 2 cm using a carbon ion boost. Radiotherapy is always applied with 5 fractions per week.
Other: standard radiochemotherapy, oxic; HPV (-), oxic in 18F-MISO PET after 2 weeks of radiochemotherapy, 70 Gy standard radiochemotherapy	Radiation: standard radiochemotherapy; Patients will receive simultaneous radiochemotherapy, however the simultaneous chemotherapy is standard and not part of the evaluation in this trial. Present standard chemotherapy is cisplatinum 40 mg/m²/week (chemotherapy over the whole course of radiotherapy). Radiotherapy is applied to doses of 54 Gy(RBE)/ 1.8 Gy(RBE) per fraction to the adjuvant region and 70 Gy(RBE)/ 2 Gy(RBE) per fraction to the tumor and involved lymphonodes. Radiotherapy is always applied with 5 fractions per week.
Other: standard radiochemotherapy (70 Gy); HPV (+), HPV positive patients will get the same imaging and clinical examinations as HPV negative patients. This measure is necessary to further elucidate the prognostic role of hypoxia and HPV status and their correlation, the information will be important for consecutive clinical trials. 70 Gy standard radiochemotherapy.	Radiation: standard radiochemotherapy; Patients will receive simultaneous radiochemotherapy, however the simultaneous chemotherapy is standard and not part of the evaluation in this trial. Present standard chemotherapy is cisplatinum 40 mg/m²/week (chemotherapy over the whole course of radiotherapy). Radiotherapy is applied to doses of 54 Gy(RBE)/ 1.8 Gy(RBE) per fraction to the adjuvant region and 70 Gy(RBE)/ 2 Gy(RBE) per fraction to the tumor and involved lymphonodes. Radiotherapy is always applied with 5 fractions per week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
local tumour control	Local tumour control (MRI, CT, PET or clinical evaluation) in the randomized dose-escalated arm compared to the randomized non dose escalated arm (arms 1 and 2).	Local tumor control 2 years after end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
late toxicity	late toxicity based on CTCAE 5.0	30 days to 2 years after radiochemotherapy
survival	Overall survival	2 years after radiochemotherapy
quality of life EORTC QLQ-C30/HN-35	EORTC-QLQ (C30 and HN-35) Sheets (General for tumour diseases and specific for head and neck cancer)	regularly up to 2 years after radiochemotherapy
acute toxicity	acute toxicity based on CTCAE 5.0	during treatment and up to 30 days after radiochemotherapy

Collaborators and Investigators

• Sponsor: Technische Universität 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 (Estimated): July 1, 2024
• Primary Completion (Estimated): September 30, 2025
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: February 26, 2019
• First Submitted That Met QC Criteria: March 5, 2019
• First Posted (Actual): March 6, 2019

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: Head and neck cancer; HPV; radiochemotherapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Signs and Symptoms, Respiratory; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Hypoxia
• Other Study ID Numbers: STR-INDIRA-MISO-2014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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