PROTECT: On-line Adaptive Proton Therapy for Cervical Cancer

Not Applicable

Recruiting

• Conditions: Locally Advanced Cervical Carcinoma; Uterine Cervical Neoplasms
• Interventions: Drug: Cisplatin; Radiation: Brachytherapy

• Registration Number: NCT05406856
• Lead Sponsor: Leiden University Medical Center

Brief Summary

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.

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 Timeline

• Study Start: 2022-05-02
• Study First Submitted: 2022-05-11
• Study First Submitted QC: 2022-06-01
• Study First Posted: 2022-06-07
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-10
• Last Update Posted: 2023-10-11
• Primary Completion: 2025-07-01
• Study Completion: 2026-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 30

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
IMRT/VMAT group	Brachytherapy	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.
IMPT group	Brachytherapy	This group receives curative treatment with primary external beam radiation therapy (IMPT), combined with chemotherapy, followed by 3D image (MRI)-guided adaptive brachytherapy.
IMRT/VMAT group	Cisplatin	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.
IMPT group	Cisplatin	This group receives curative treatment with primary external beam radiation therapy (IMPT), combined with chemotherapy, followed by 3D image (MRI)-guided adaptive brachytherapy.

Primary Outcome Measures

Name	Time	Method
Dmean to the pelvic bones	During treatment	Mean dose to the pelvic bones (Gy).
Mean V15Gy to the bowel	During treatment	Mean volume of the bowel (cc) receiving 15Gy.

Secondary Outcome Measures

Name	Time	Method
Distant recurrence-free survival	At Month 12 after end of treatment	The time from start of treatment to the first occurrence of distant recurrence.
Health-related Quality of Life	At baseline, week 4 of EBRT, end of treatment, and at Month 3, Month 6, Month 9, and Month 12 after end of treatment	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.
Safety and tolerability (toxicity)	At baseline, week 4 of EBRT, end of treatment, and at Month 3, Month 6, Month 9, and Month 12 after end of treatment	Toxicity will be graded according to the NCI-CTCAE version 5.0.
The effect on the local immune system (analyzed with the Nanostring PanCancer IO 360 panel)	At baseline and at the first brachytherapy session	Tumor biopsies will be collected for evaluation of the impact of treatment on the local immune response.
The effect on the systemic immune system	At baseline, week 4 of treatment, and at Month 1, Month 2, Month 3, and Month 12 after end of treatment	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.
The effect on bone marrow fat fraction	At baseline, for brachytherapy purposes, and at Month 3 and Month 12 after end of treatment.	Patients will have an MR scan with Dixon technique for evaluation of bone marrow fat fraction in the vertebral column and femoral necks.
Key dosimetric parameters of the bladder	During treatment	Mean volume of the bladder (%) receiving greater than or equal to 15, 30, and 40Gy.
Key dosimetric parameters of the rectum	During treatment	Mean volume of the rectum (%) receiving greater than or equal to 15, 30, and 40Gy.
Key dosimetric parameters of the sigmoid	During treatment	Mean volume of the sigmoid (%) receiving greater than or equal to 15, 30, and 40Gy.
Key dosimetric parameters of the bowel	During treatment	Mean volume of the bowel (cc) receiving greater than or equal to 30 and 40Gy.
Key dosimetric parameters of the body	During treatment	Mean dose to the body (Gy) and mean volume of the body (cm3) receiving greater than or equal to 10 Gy.
Key dosimetric parameters of the pelvic bones	During treatment	Mean volume of the pelvic bones (% or cc) receiving greater than or equal to 10, 20, and 40Gy.
Key dosimetric parameter of the kidneys	During treatment	Mean dose to the kidneys (Gy).
Key dosimetric parameters of the spinal cord	During treatment	Mean volume of the spinal cord (%) receiving greater than or equal to 15 and 30Gy.
Other dosimetric parameters of critical organs	During treatment	Mean volume of an organ at risk (% or cc) receiving greater than or equal to xGy.
Overall survival	At Month 12 after end of treatment	The percentage (%) of included patients who are alive after start of treatment
Pelvic recurrence-free survival	At Month 12 after end of treatment	The time from start of treatment to the first occurrence of pelvic recurrence.
Complete response	At Month 3 after end of treatment	Absence of disease in the cervix, uterus, upper vagina, and parametria.

Trial Locations

Locations (2)

Leiden University Medical Center; 🇳🇱 Leiden, Netherlands

Erasmus Medical Center; 🇳🇱 Rotterdam, Netherlands