Image Assisted Optimization of Proton Radiation Therapy in Chordomas and Chondrosarcomas (CHIPT)

Defining Optimal Imaging Strategies for Diagnosis, Treatment, and Treatment Evaluation of Chordomas and Chondrosarcomas of the Axial Skeleton

Rationale: Chordomas and chondrosarcomas located in the axial skeleton are malignant neoplasms of bone. These tumors share the same clinical challenges, as the effect of the disease is more a function of their local aggressiveness than their tendency to metastasize (20% metastasize). The local aggressive behavior can cause debilitating morbidity and mortality by destruction of nearby located critical neurovascular structures. Imaging has, in addition to histopathology, a role in diagnosis and in guiding (neo)adjuvant and definitive treatment. Despite the low sensitivity to radiotherapy, proton radiotherapy has been successfully used as an adjunct to resection or as definitive treatment for aggressive chordomas and chondrosarcomas, making it a standard indication for proton therapy in the Netherlands.

Chordomas and chondrosarcomas consist, especially after previous therapy, of non-viable and viable tumor components. Identification of these viable components by functional imaging is important to determine the effect of previous therapy, as change in total tumor volume occurs more than 200 days after change of functional imaging parameters.

Objective: The main objective of this study is to determine if functional MRI parameters change within 6 months, and earlier than volumetric changes after start of proton beam therapy. This would allow timely differentiation between affected and unaffected (viable) tumor components, which can be used for therapy adjustment.

Secondary objectives: Determine which set of parameters (PET-CT and secondary MRI) can predict clinical outcome (tumor specific mortality, development of metastases, morbidity secondary to tumor activity and morbidity secondary to treatment); determine what type of imaging can accurately identify viable tumor nodules relative to critical anatomical structures; improving understanding of relevance of changing imaging parameters by correlating these with resected tumor.

Study design: Prospective cohort study Study population: LUMC patients diagnosed with primary or recurrent chordoma or chondrosarcoma in the axial skeleton. A number of 20 new patients per year is expected.

Main study parameters: Volumetric and functional MR imaging parameters including permeability parameters.

Secondary parameters are generated by PET-CT (SUV, MTV and TLG), MR (perfusion, permeability and diffusion), therapy (proton beam dose mapping, surgery) and clinical outcome. End points are disease specific survival, progression free survival (including development of metastases), side effects of treatment, and functional outcome (see CRF). In patients who are treated with surgical resection following neo-adjuvant therapy, the surgical specimen will be correlated with imaging findings.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Treatment and clinical management will not be affected in this study, thus the additional burden, risks, and benefits associated with participation in this study are minimal.

Two extra MRI and one PET-CT examination will be planned during proton therapy.

Study Overview

• Status: Recruiting
• Conditions: Magnetic Resonance Imaging; Chondrosarcoma; Chordoma; Proton Therapy; Bone Neoplasm of Vertebral Column; PET-CT

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Stijn Krol, dr. PhD; Phone Number: +31624539398; Email: A.D.G.Krol@lumc.nl
• Study Contact Backup: Name: Vesna Miladinovic; Phone Number: +31682225869; Email: v.miladinovic@lumc.nl

Study Locations

• Netherlands
  • South Holland
    • Delft, South Holland, Netherlands, 2629 JH
      • Recruiting
      • HollandPTC
      • Contact: Stijn Krol, MD PhD; Phone Number: +31624539398; Email: A.D.G.Krol@lumc.nl
      • Contact: Charlotte van der Vos, PhD; Phone Number: +31885011186; Email: c.vander.vos@hollandptc.nl
      • Principal Investigator: Stijn Krol, MD PhD
    • Leiden, South Holland, Netherlands, 2333 ZA
      • Recruiting
      • LUMC
      • Contact: Vesna Miladinovic; Phone Number: +31682225869; Email: v.miladinovic@lumc.nl
      • Contact: Stijn Krol, MD PhD; Phone Number: +31624539398; Email: A.D.G.Krol@lumc.nl
      • Principal Investigator: Hans Bloem, prof. MD PhD
      • Sub-Investigator: Stijn Krol, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients referred to HollandPTC, or LUMC, or the Netherlands Committee of Bone tumors, histologically diagnosed with primary or recurrent chordoma or chondrosarcoma in the axial skeleton (clivus, spine and sacrum), and accepted for standard proton beam therapy.

Description

Inclusion Criteria:

• Histologically diagnosed with primary or recurrent chordoma or chondrosarcoma in the axial skeleton (clivus, spine and sacrum)
• Accepted for standard proton beam therapy

Exclusion Criteria:

• Diagnosis other than chordoma or chondrosarcoma is made.
• Patient refuses (parts) of the standard treatment protocol.
• Patient refuses MRI due to claustrophobia.
• Patient not suitable for MRI due to the presence of MRI incompatible implants.
• Incapacitated patients.
• Patient doesn't allow coded data to be used for analysis.
• Patient is under 50 years of age.
• Lesion size less than 1cm.
• Patients with WHO 3 and higher.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vp(max), Vp(min)	MRI permeability parameter - tumor plasma volume	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rel Enhancement (%)	MRI perfusion parameter showing the signal enhancement of a pixel of certain dynamic relative to that same pixel in the reference dynamic. The reference dynamic is normally the first, pre-contrast dynamic.	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
Max Enhancement (%)	MRI perfusion parameter showing difference between peak intensity S1 and S0.	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
Max Rel Enhancement (%)	MRI perfusion parameter showing maximum of all relative enhancements over all dynamics	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
Time of arrival T0 (s)	MRI perfusion parameter showing time at which the signal intensity increases for at least 20% compared to the baseline (referred to as initial signal intensity S0). The baseline is the average of the signal intensities of all timepoints before the contrast uptake starts.	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
Time To Peak (s)	MRI perfusion parameter showing time till contrast agent bolus reaches peak intensity	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
Wash In Rate (sˉ¹)	MRI perfusion parameter showing maximum slope between T0 and time of peak intensity T1	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
Wash Out Rate (sˉ¹)	MRI perfusion parameter showing maximum slope between time of peak intensity T1 and the end of the measurement	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
Brevity of Enhancement (s)	MRI perfusion parameter showing time between point of maximum wash in rate and maximum wash out rate.	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
Ktrans	MRI permeability parameter - transfer constant between blood plasma and Extravascular Extracellular Space (EES), also called vascular permeability	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
kep	MRI permeability parameter showing rate between EES and blood plasma (also called Tracer Efflux Rate)	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
Ve	MRI permeability parameter showing Extravascular Volume fraction (Leakage space); defined as Ktrans / kep	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
Area under the curve (AUC)	MRI permeability and perfusion parameter showing area Under the Curve of all time curves	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
mean ADC, Min ADC, Max ADC	MRI diffusion parameters	At inclusion, 4 and 8 weeks, 5,11,17 and 23 months after the start date of proton therapy treatment
SUV	Standard uptake value extracted from PET-CT imaging	At inclusion and and 11 months following the start date fo proton therapy
MTV	Metabolic tumor volume extracted from PET-CT imaging	At inclusion and and 11 months following the start date fo proton therapy
TLG	Total lesion glycolysis extracted from PET-CT imaging	At inclusion and and 11 months following the start date fo proton therapy

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: HollandPTC; Varian Medical Systems
• Investigators: Principal Investigator: Stijn Krol, MD PhD, LUMC/HollandPTC; Principal Investigator: Hans Bloem, prof. MD PhD, LUMC

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2021
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: March 29, 2021
• First Submitted That Met QC Criteria: April 1, 2021
• First Posted (Actual): April 6, 2021

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: MRI; Chordoma; PET-CT; Chondrosarcoma; Proton therapy
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Musculoskeletal Diseases; Neoplasms, Germ Cell and Embryonal; Bone Diseases; Neoplasms, Connective Tissue; Sarcoma; Bone Neoplasms; Chordoma; Chondrosarcoma
• Other Study ID Numbers: 41335

Drug and device information, study documents

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