PROTECT: On-line Adaptive Proton Therapy for Cervical Cancer (PROTECT)

PROTECT: On-line Adaptive Proton Therapy for Cervical Cancer to Reduce the Impact on Morbidity and the Immune System

This prospective, multicenter, nonrandomized phase-II-trial investigates in clinical practice the differences between intensity modulated proton therapy (IMPT) and standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) in the effects on dose-volume parameters and treatment-related morbidity for women with locally advanced cervical cancer undergoing chemoradiation.

Study Overview

• Status: Recruiting
• Conditions: Uterine Cervical Neoplasms; Locally Advanced Cervical Carcinoma
• Intervention / Treatment: Radiation: External beam radiation therapy: IMRT/VMAT; Drug: Cisplatin; Radiation: Brachytherapy; Radiation: External beam radiation therapy: IMPT

Detailed Description

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a highly effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient's quality of life (QoL) and may affect ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anouk Corbeau, MSc; Phone Number: +31 71 529 7893; Email: a.corbeau@lumc.nl
• Study Contact Backup: Name: Stephanie M. de Boer, MD, PhD; Phone Number: +31 71 529 9380; Email: s.m.de_boer.onco@lumc.nl

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Recruiting
    • Leiden University Medical Center
    • Contact: Anouk Corbeau, MSc; Phone Number: +31 71 529 7893; Email: a.corbeau@lumc.nl
    • Contact: Stephanie M. de Boer, MD, PhD; Phone Number: +31 71 529 9380; Email: s.m.de_boer.onco@lumc.nl
    • Principal Investigator: Stephanie M. de Boer, MD, PhD
    • Sub-Investigator: Anouk Corbeau, MSc
  • Rotterdam, Netherlands, 3015 GD
    • Not yet recruiting
    • Erasmus Medical Center
    • Contact: Remi A. Nout, professor; Phone Number: +31 10 704 1366; Email: r.nout@erasmusmc.nl
    • Contact: Jan Willem M. Mens, MD; Phone Number: +31 10 703 0751; Email: j.w.m.mens@erasmusmc.nl
    • Principal Investigator: Remi A. Nout, professor

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically confirmed diagnosis of cervical cancer (squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma, HPV positive or negative) with an indication for curative treatment with primary chemoradiation with concurrent cisplatin followed by 3D image-guided adaptive brachytherapy.
• Indication to include the common iliac region (minimum 5, maximum 8) or the common iliac and para-aortic regions (minimum 7, maximum 10) into the elective clinical target volume of the external beam radiotherapy.
• No distant metastasis beyond the para-aortic lymph node chain as determined by diagnostic imaging (CT or PET-CT scan)
• Age ≥ 18 years
• WHO 0-1

• Adequate systemic organ function:

  • Creatinine clearance (> 50 cc/min)
  • Adequate bone marrow function : white blood cells (WBCs) ≥3.0 x 109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l
• Patients must be accessible for treatment and follow-up
• Written informed consent according to the local Ethics Committee requirements

Exclusion Criteria:

• Small cell cancer, melanoma and other rare histological types of the cervix.

• History of another primary malignancy that could conceivably be active evaluated by the study physician. Examples of exception include, but are not limited to:

  • Malignancy treated with curative intent and with no known active disease ≥5 years.
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
• Other severe diseases such as recent myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias
• Previous pelvic or abdominal radiotherapy
• History of active primary immunodeficiency
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn's disease])
• The use of immunosuppressive drugs at baseline
• Contraindications for weekly Cisplatin (or Carboplatin)
• Contraindications for the use of MRI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: IMRT/VMAT group; This group receives standard of care curative treatment with primary external beam radiation therapy (IMRT/VMAT), combined with chemotherapy, followed by 3D image (MRI)-guided adaptive brachytherapy.	Radiation: External beam radiation therapy: IMRT/VMAT; EBRT is given to a total dose of 45 Gy in 25 daily fractions of 1.8 Gy in 5 weeks. Involved nodes are boosted using a simultaneous integrated boost (SIB) to reach a total EBRT plus brachytherapy dose of 60 Gy EQD2 to provide high nodal control.; Other Names: Intensity Modulated Radiation Therapy; Volumetric Modulated Arc Therapy; Drug: Cisplatin; The standard chemotherapy regimen is weekly cisplatin (40 mg/m2) for 5 weeks.; Radiation: Brachytherapy; Brachytherapy is performed using a high-dose rate (HDR) after loading system to deliver a boost to any residual tumor and the cervix. Brachytherapy dose is (21-) 28 Gy in fractions of 7 Gy specified at 100% isodose around the high-risk CTV, according to the EMBRACE-II prescription protocol. The aim is to reach an equivalent dose in 2 Gy fractions including EBRT (EQD2_D90) of the high-risk CTV between 90-95 Gy, using MRI-guided adaptive brachytherapy.
Experimental: IMPT group; This group receives curative treatment with primary external beam radiation therapy (IMPT), combined with chemotherapy, followed by 3D image (MRI)-guided adaptive brachytherapy.	Drug: Cisplatin; The standard chemotherapy regimen is weekly cisplatin (40 mg/m2) for 5 weeks.; Radiation: Brachytherapy; Brachytherapy is performed using a high-dose rate (HDR) after loading system to deliver a boost to any residual tumor and the cervix. Brachytherapy dose is (21-) 28 Gy in fractions of 7 Gy specified at 100% isodose around the high-risk CTV, according to the EMBRACE-II prescription protocol. The aim is to reach an equivalent dose in 2 Gy fractions including EBRT (EQD2_D90) of the high-risk CTV between 90-95 Gy, using MRI-guided adaptive brachytherapy.; Radiation: External beam radiation therapy: IMPT; EBRT is given to a total dose of 45 Gy in 25 daily fractions of 1.8 Gy in 5 weeks. Involved nodes are boosted using a simultaneous integrated boost (SIB) to reach a total EBRT plus brachytherapy dose of 60 Gy EQD2 to provide high nodal control.; Other Names: Intensity Modulated Proton Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dmean to the pelvic bones	Mean dose to the pelvic bones (Gy).	During treatment
Mean V15Gy to the bowel	Mean volume of the bowel (cc) receiving 15Gy.	During treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Key dosimetric parameters of the bladder	Mean volume of the bladder (%) receiving greater than or equal to 15, 30, and 40Gy.	During treatment
Key dosimetric parameters of the rectum	Mean volume of the rectum (%) receiving greater than or equal to 15, 30, and 40Gy.	During treatment
Key dosimetric parameters of the sigmoid	Mean volume of the sigmoid (%) receiving greater than or equal to 15, 30, and 40Gy.	During treatment
Key dosimetric parameters of the bowel	Mean volume of the bowel (cc) receiving greater than or equal to 30 and 40Gy.	During treatment
Key dosimetric parameters of the body	Mean dose to the body (Gy) and mean volume of the body (cm3) receiving greater than or equal to 10 Gy.	During treatment
Key dosimetric parameters of the pelvic bones	Mean volume of the pelvic bones (% or cc) receiving greater than or equal to 10, 20, and 40Gy.	During treatment
Key dosimetric parameter of the kidneys	Mean dose to the kidneys (Gy).	During treatment
Key dosimetric parameters of the spinal cord	Mean volume of the spinal cord (%) receiving greater than or equal to 15 and 30Gy.	During treatment
Other dosimetric parameters of critical organs	Mean volume of an organ at risk (% or cc) receiving greater than or equal to xGy.	During treatment
Overall survival	The percentage (%) of included patients who are alive after start of treatment	At Month 12 after end of treatment
Complete response	Absence of disease in the cervix, uterus, upper vagina, and parametria.	At Month 3 after end of treatment
Pelvic recurrence-free survival	The time from start of treatment to the first occurrence of pelvic recurrence.	At Month 12 after end of treatment
Distant recurrence-free survival	The time from start of treatment to the first occurrence of distant recurrence.	At Month 12 after end of treatment
Health-related Quality of Life	For the evaluation of patient reported symptoms and QoL, the European Organization for Research and Treatment of Cancer (EORTC)-core (C-30) questionnaire, the CX24 module for cervical cancer, and six additional questions from EN24 module will be used.	At baseline, week 4 of EBRT, end of treatment, and at Month 3, Month 6, Month 9, and Month 12 after end of treatment
Safety and tolerability (toxicity)	Toxicity will be graded according to the NCI-CTCAE version 5.0.	At baseline, week 4 of EBRT, end of treatment, and at Month 3, Month 6, Month 9, and Month 12 after end of treatment
The effect on the local immune system (analyzed with the Nanostring PanCancer IO 360 panel)	Tumor biopsies will be collected for evaluation of the impact of treatment on the local immune response.	At baseline and at the first brachytherapy session
The effect on the systemic immune system	Blood samples will be collected for immune-monitoring. Full blood count, peripheral blood mononuclear cells, leukocyte differentiation, APC quality, T cell reactivity, and immune composition changes will be measured.	At baseline, week 4 of treatment, and at Month 1, Month 2, Month 3, and Month 12 after end of treatment
The effect on bone marrow fat fraction	Patients will have an MR scan with Dixon technique for evaluation of bone marrow fat fraction in the vertebral column and femoral necks.	At baseline, for brachytherapy purposes, and at Month 3 and Month 12 after end of treatment.

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Erasmus Medical Center; HollandPTC
• Investigators: Principal Investigator: Stephanie M. de Boer, MD, PhD, Leiden University Medical Center

Publications and helpful links

General Publications

• Corbeau A, Nout RA, Mens JWM, Horeweg N, Godart J, Kerkhof EM, Kuipers SC, van Poelgeest MIE, Kroep JR, Boere IA, van Doorn HC, Hoogeman MS, van der Heide UA, Putter H, Welters MJP, van der Burg SH, Creutzberg CL, de Boer SM. PROTECT: Prospective Phase-II-Trial Evaluating Adaptive Proton Therapy for Cervical Cancer to Reduce the Impact on Morbidity and the Immune System. Cancers (Basel). 2021 Oct 15;13(20):5179. doi: 10.3390/cancers13205179.

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2022
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: May 11, 2022
• First Submitted That Met QC Criteria: June 1, 2022
• First Posted (Actual): June 7, 2022

Study Record Updates

• Last Update Posted (Actual): October 11, 2023
• Last Update Submitted That Met QC Criteria: October 10, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Proton therapy; Non-randomized phase-II trial; Primary chemoradiotherapy; Organ sparing therapy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Uterine Cervical Neoplasms; Antineoplastic Agents; Cisplatin
• Other Study ID Numbers: NL77911.058.21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After completion of the trial and publication of the final results, data will be available upon request with a scientific proposal. Approval by the trial management group is necessary.
• IPD Sharing Time Frame: After final publication
• IPD Sharing Access Criteria: Approval by the trial management group is necessary
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; 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