PIRATES: Image-guided Hyper-fractioned Dose-escalation With Proton Therapy for Head and Neck Cancer (PIRATES)

Proton Image-guided Radiation Assignment for Therapeutic Escalation Via Selection of Locally Advanced Head and Neck Cancer Patients

In this study the safety & feasibility of image-guided mid-treatment hyper-fractioned dose-escalation with proton therapy will be assessed for the treatment of locally advanced HPV-negative squamous cell oropharyngeal cancer

Study Overview

• Status: Recruiting
• Conditions: Head and Neck Cancer; Oropharyngeal Cancer
• Intervention / Treatment: Radiation: Image guided hybrid hyper-fractioned dose escalation with proton therapy

Detailed Description

For this study, the investigators propose a novel design to safely achieve tumor radiation dose escalation with proton therapy plus standard-of-care concomitant chemotherapy. Through mid-treatment image guidance, the tumor boost dose is determined; subsequently, only that GTV boost will receive a total dose of 80 Gy through hybrid hyperfractionation. This refers to twice-daily radiation in the last 15 fraction days. The combination of boost dose hyperfractionation and proton therapy is anticipated to prevent critical normal tissue damage within both the high- and intermediate-dose regions. This novel treatment approach aims to minimize critical toxicities while improving locoregional control for head and neck cancer patients who are at a higher risk of disease relapse.

• Study Type: Interventional
• Enrollment (Estimated): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands
    • Recruiting
    • UMC Groningen
    • Contact: L.V. van Dijk, dr.; Phone Number: 031655257381; Email: l.v.van.dijk@umcg.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

• Biopsy proven diagnosis of squamous cell carcinoma originating in the oropharynx.
• Routine staging procedures, including CT of the head and neck region and chest, head and neck FDG-PET/CT and MRI (treatment planning allowed), and endoscopic evaluation when indicated.
• Negative for p16

• Locally advanced disease, specifically meeting all following criteria:

  • Stage III-IV
  • T-stage 2-4
  • All N-stages (N0-3)
  • M0
• Eligible for primary concurrent chemoradiation using conventionally fractionated radiotherapy 70 Gy combined with weekly cisplatin
• Eastern Cooperative Oncology Group (ECOG) performance score ≥2
• Age ≥18 years
• Written informed consent

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study; patients that:

• underwent definitive resection of their primary tumor or nodal disease, except for incisional or excisional biopsies.

received radiation therapy in the head and neck area in the past

• have no detectable tumor anymore at both the primary site and lymph nodes at week 4 in treatment, because there will not be a volume to boost.
• are unable or unwilling to give written, informed consent
• have contra-indications for chemotherapy. This is at the discretion of the treating medical oncologist.
• are unable to tolerate intravenous contrast for both CT and MRI, having an estimated GFR < 60 ml/min/1.73 m2 or any contraindications to gadolinium-based contrast agents.
• have any evidence of iron overload on pre-imaging laboratory studies.
• have other serious illnesses or medical conditions present at entry in the study, including (but not limited to): immunodeficiency virus (HIV) infection or other conditions of persistent immunodeficiency, neurologic or psychiatric disorders, active disseminated intravascular coagulation, unstable cardiac disease despite treatment or uncontrolled diabetes mellitus.
• Women who are pregnant or breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Image guided hybrid hyper-fractioned dose escalation with proton therapy

Radiation: Image guided hybrid hyper-fractioned dose escalation with proton therapy; Radiation: Image-guided hybrid hyper-fractioned dose escalation with proton therapy The investigational radiation regime will be administered in a two-part schedule: The first 4 weeks (i.e. first 20 fractions) of the radiation treatment of the pathological tumor will be according to the conventional clinical standard with proton therapy: 20x 2 Gy to the CTV70 and 20 x 1.55 Gy to the CTV54.; In week 4 (~ fraction 16) GTV80 will be determined on conventional weekly CT and additional MR imaging (conventional clinical protocol). Only this adapted tumor volume, the so-called GTV80, will receive the dose escalation (i.e., 80.5 Gy).; In the last 3 weeks (last 15 fractions) patients will be radiated twice per day (i.e. hyperfractionation). The GTV80, CTV70 and CTV54 will receive 1.55 Gy in the morning, and the GTV80 and CTV70 will receive additional dose in the afternoon.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and feasibility	The number of dose limiting toxicity (DLT) events, defined as grade ≥4 mucositis, grade ≥4 ulceration, grade ≥4 dermatitis, grade ≥4 aspiration, grade ≥4 osteonecrosis and grade ≥3 myelopathy	Within 6 months after radiotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor response rate	Preliminary tumor response rates measured on the standard follow-up MRI scan	All SFP time points (baseline, weekly during RT, 6 weeks, 6, 12, 18, 24 months after treatment
Disease-free, overall survival and time-weighted locoregional control	Preliminary disease-free, overall survival and time-weighted locoregional control analyses	All SFP time points (baseline, weekly during RT, 6 weeks, 6, 12, 18, 24 months after treatment
Completing radiotherapy regimen	Completion of treatment with a maximum of 2 fraction interruption	End of radiotherapy
Completing chemotherapy regimen	Percentage of patients completing the complete chemotherapy regimen	End of chemotherapy
Toxicity after chemoradiation	Rates of grade ≥3 mucositis, dermatitis, aspiration, dysphagia, hearing impaired, xerostomia, weight loss, trismus, hoarseness, oropharyngeal pain (according to CTCAEv5).	At 6 months after chemoradiation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other physician rated toxicities	All other physician rated toxicities (CTCAEv5), including all grades	All SFP time points (baseline, weekly during RT, 6 weeks, 6, 12, 18, 24 months after treatment
Patient-rated symptoms	Patient-rated symptoms (EORTC QLQ-H&N35)	All SFP time points (baseline, weekly during RT, 6 weeks, 6, 12, 18, 24 months after treatment
Quality of life	Quality of life (EORTC QLQ-C30)	All SFP time points (baseline, weekly during RT, 6 weeks, 6, 12, 18, 24 months after treatment
WHO performance	WHO performance	All SFP time points (baseline, weekly during RT, 6 weeks, 6, 12, 18, 24 months after treatment

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: May 31, 2024
• First Submitted That Met QC Criteria: May 31, 2024
• First Posted (Actual): June 6, 2024

Study Record Updates

• Last Update Posted (Actual): April 3, 2025
• Last Update Submitted That Met QC Criteria: March 31, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Dose-escalation; Adaptive radiotherapy; Proton therapy; Hyperfractionation; Image guidance therapy
• Additional Relevant MeSH Terms: Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Head and Neck Neoplasms; Oropharyngeal Neoplasms
• Other Study ID Numbers: 18646

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
• product manufactured in and exported from the U.S.: No