Precision Radiotherapy Using MR-linac for Pancreatic Neuroendocrine Tumours in MEN1 Patients (PRIME)

PRIME Study: Precision Radiotherapy Using MR-linac for Pancreatic Neuroendocrine Tumours in MEN1 Patients

Patients with the Multiple Endocrine Neoplasia type 1 (MEN1) syndrome are genetically predisposed for developping multiple pancreatic neuro-endocrine tumours (pNET). The management of small (pNET) in both MEN1 and sporadic cases, pose a major clinical challenge. At present, pancreatic surgery is the only curative treatment but it is associated with high morbidity. To reduce the morbidity ascosiated with surgery and thereby potentially improve quality of life for MEN1 patients introduction of less invasive techniques for treatment of pNET is important. High-dose-high precision MR-guided radiotherapy (MRgRT) holds promise as a new less invasive treatment option for pNET. The aim of this study is to assess efficiacy and safety of MRgRT for treatment of pNET in MEN1 patients.

Study Overview

• Status: Recruiting
• Conditions: Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumor of Pancreas
• Intervention / Treatment: Radiation: High-dose-high precision MR-guided radiotherapy

Detailed Description

Background Patients with the Multiple Endocrine Neoplasia type 1 (MEN1) syndrome are genetically predisposed for developping multiple pancreatic neuro-endocrine tumours (pNET), with a cumulative pNET incidence of over 80% at an age of 80 years. In MEN1 patients, metastatic pNET is the primary cause of premature death.

The management of small (pNET) in both MEN1 and sporadic cases, pose a major clinical challenge. At present, pancreatic surgery is the only curative treatment. Since surgery is associated with significant short- and long-term morbidity the management of small pNET depends on carefully outweighing the risk of liver metastasis leading to premature death and the morbidity of pancreatic surgery. Guidelines advocate that for tumours smaller than 2 cm an intensive watchful waiting strategy seems to be safe. However, although most pNETs remain indolent for years, many lesions eventually progress and metastasize. To prevent the development of metastases for growing tumours or tumours above 2 cm a surgical resection is advised. Due to the high incidence of pNET in the MEN1 population many MEN1 patients receive surgery for pNET in their lifespan and cope with the morbidity of pancreatic surgery. To reduce the morbidity ascosiated with surgery and thereby potentially improve quality of life for MEN1 patients introduction of less invasive techniques for treatment of pNET is important.

High-dose-high precision MR-guided radiotherapy (MRgRT) holds promise as a new less invasive treatment option for pNET. With MRgRT accurate and precise delivery of high irradiation dose levels to the pNET is possible, while monitoring the tumor with MR imaging. The UMC Utrecht has pioneered the development of this technology, and gained experience with MRgRT treatments for patients with pancreatic adenocarcinoma and other upper abdominal malignancies.

Aim Aim of this project is to assess the safety and efficacy of high-dose-high precision MRgRT for pNET in a cohort of MEN1 patients that will require surgery in the near future.

Methods Efficacy and safety of MRgRT will be explored in a prospective cohort study of MEN1 patients with pNET, the Precision Radiotherapy using MRLInac for Pancreatic Neuroendocrine Tumours in MEN1 patients (PRIME)study. The PRIME study is a single arm interventional cohort study, recruiting 20 MEN1 patients enrolled in the Dutch MEN1 Study Groups (DMSG) longitudinal cohort. Eligible patients are patients with pNET surpassing 2.0 cm, and patients with a growing pNET measuring between 1.0- 2.0 cm. Patients who give informed consent will receive MRgRT with a minimum dose to the tumour bed of 40 Gy in 5 fractions delivered within 2 weeks. The primary outcome will be the change in maximum diameter of pNET at follow-up MRI scan at 12 months after diagnosis. Secondary outcome parameters include incidence of surgical resection following MRgRT, toxicity of radiotherapy, quality of life, endocrine and exocrine pancreatic functioning, metastases free survival, overall survival and tumour characteristics on follow-up MRI.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Joanne M de Laat, MD, PhD; Phone Number: +31302507397; Email: J.M.deLaat-4@umcutrecht.nl
• Study Contact Backup: Name: Gerlof D Valk, MD, PhD; Phone Number: +31302507397; Email: G.D.Valk@umcutrecht.nl

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Recruiting
    • UMC Utrecht
    • Contact: Joanne M de Laat, MD, PhD; Phone Number: +31302507397; Email: J.M.deLaat-4@umcutrecht.nl
    • Contact: Gerlof D Valk, MD, PhD; Phone Number: +31302507397; Email: G.D.Valk@umcutrecht.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

All patients meeting the following criteria will be assessed for in the tumour board:

• lesions measuring between 2cm and 3cm.
• pNET lesions with a size between 1.0 and 2.0 cm and moderate growth of the lesion (2-4 mm/ year) on sequential follow-up scans.
• pNET lesions with a size between 1.0 and 2.0 cm and minimal growth of the lesion (1 mm/ year) reconfirmed on 3 or more sequential follow-up scans.
• Patients with in situ remaining 1.0 - 2.0 cm lesions after previous resection of a larger lesion.

All patients with such lesion and an indication for surgery are considered eligible for participation in the PRIME study.

Exclusion Criteria:

• Suspected malignant pNET as per the tumour board assessment, including the criteria:
• pNET lesions of more than 3 cm in size
• rapid growth of pNET lesions with more than 4mm per year
• Symptomatic pNET because of hormone production, with the exception of gastrinomas which are located in the submucosa of the duodenum
• concurrent treatment with a somatostatin analog
• concurrent treatment with chemotherapy
• peptide receptor radionuclide therapy in the past 12 months
• history of radiotherapy in the upper abdominal region
• MRI contraindications as per usual clinical care, such as claustrophobia and metal or electronic implants not compatible with MRI.
• Pregnancy
• (Other) metastatic disease
• WHO performance score 3-4

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: High-dose-high precision MR-guided radiotherapy; Radiotherapy for pancreatic NET will be delivered in an image-guided, hypofractionated scheme of 5 fractions of 8 Gy, prescribed to 95% of the planning target volume (PTV). Treatment is delivered on alternate days 2 or 3 times a week with a maximum overall treatment time of 14 days on the 1.5T MR-Linac (Elekta Unity MR-Linac). The Gross Tumor Volume (GTV) is defines as the pNET visible on pre-treatment CT and MRI scan. No clinical target volume (CTV) is used. The PTV is made by adding a 3mm margin to the GTV. The treatment plan is a 9-14 field intensity modulated radiotherapy (IMRT) plan with dose prescribed to 95% of the PTV. While respecting the dose constraints to adjacent tissues

Radiation: High-dose-high precision MR-guided radiotherapy; MR-guided radiotherapy as described in the group information

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in tumor size	Change in maximal diameter of pNET measured at follow-up MRI	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumour progression	Number of patients with signs of growth or metastasis at follow-up	12 months
Pancreatic surgery	Number of patients that require surgical treatment following MRgRT	12 months
Toxicity of radiotherapy	Toxicity of radiotherapy graded according to Common Terminology Criteria for Adverse Events v4.0 scale	12 months
Health-related quality of life by SF-36	Short Form Health Survey 36 items	6 months, 12 months
Health-related quality of life by Eq5D	EuroQol 5D instrument	6 months, 12 months
Health-related quality of life by PROMIS-29	PROMIS 29 profile	6 months, 12 months
fasting glucose	fasting glucose in evaluation of endocrine and exocrine pancreatic function	12 months
blood cell count,	blood cell count in evaluation of endocrine and exocrine pancreatic function	12 months
serum iron	serum iron v	12 month in evaluation of endocrine and exocrine pancreatic function
vitamin B12	vitamin B12 in evaluation of endocrine and exocrine pancreatic function	12 months
folate	folate in evaluation of endocrine and exocrine pancreatic function	12 months
faecal fat test	faecal fat test in evaluation of endocrine and exocrine pancreatic function	12 months
faecal trypsin	faecal trypsin in evaluation of endocrine and exocrine pancreatic function	12 months
faecal elastase	faecal elastase in evaluation of endocrine and exocrine pancreatic function	12 months
metastases free survival	Measured at follow-up imaging	12 months
overall survival	survival	12 months

Collaborators and Investigators

• Sponsor: J.M. de Laat
• Collaborators: Radboud University Medical Center; University Medical Center Groningen; Maastricht University Medical Center; Erasmus Medical Center; Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: August 25, 2021
• First Submitted That Met QC Criteria: August 31, 2021
• First Posted (Actual): September 8, 2021

Study Record Updates

• Last Update Posted (Actual): December 1, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Genetic Diseases, Inborn; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplastic Syndromes, Hereditary; Pancreatic Diseases; Neoplasms, Multiple Primary; Pancreatic Neoplasms; Neuroendocrine Tumors; Endocrine Gland Neoplasms; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type 1
• Other Study ID Numbers: NL77809.041.21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be placed in a repository and made available upon reasonable request, as stated in our data management plan.
• IPD Sharing Time Frame: Upon closure of the study database untill a minumum of 15 years
• IPD Sharing Access Criteria: Upon reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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