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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Radiation: dose-escalated radiochemotherapy
* Radiation: dose-escalated radiochemotherapy with carbon ion boost
* Radiation: standard radiochemotherapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: standard radiochemotherapy, hypoxic<br>HPV (-), hypoxic in 18F-MISO PET after 2 weeks of radiochemotherapy, randomized to standard radiation dose, 70 Gy standard radiochemotherapy | Radiation: standard radiochemotherapy<br>* 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.<br>|
| Experimental: dose-escalated radiochemotherapy, hypoxic<br>HPV (-), hypoxic in 18F-MISO PET after 2 weeks of radiochemotherapy, randomized to escalated radiation dose, 77 Gy radiochemotherapy | Radiation: dose-escalated radiochemotherapy<br>* 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.<br>|
| Experimental: escalated radiochemoth., carbon boost, hypoxic<br>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<br>* 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.<br>|
| Other: standard radiochemotherapy, oxic<br>HPV (-), oxic in 18F-MISO PET after 2 weeks of radiochemotherapy, 70 Gy standard radiochemotherapy | Radiation: standard radiochemotherapy<br>* 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.<br>|
| Other: standard radiochemotherapy (70 Gy)<br>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<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV, Head and neck cancer, radiochemotherapy