PROTECT: On-line Adaptive Proton Therapy for Cervical Cancer

Official title

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

Overview

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.

Interventions

• 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.
• 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.
• 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.

Primary outcome measures

• Dmean to the pelvic bones [Time frame: During treatment]
• Mean V15Gy to the bowel [Time frame: During treatment]

Secondary outcome measures (12)

• Key dosimetric parameters of the bladder [Time frame: During treatment]
• Key dosimetric parameters of the rectum [Time frame: During treatment]
• Key dosimetric parameters of the sigmoid [Time frame: During treatment]
• Key dosimetric parameters of the bowel [Time frame: During treatment]
• Key dosimetric parameters of the body [Time frame: During treatment]
• Key dosimetric parameters of the pelvic bones [Time frame: During treatment]
• Key dosimetric parameter of the kidneys [Time frame: During treatment]
• Key dosimetric parameters of the spinal cord [Time frame: During treatment]
• Other dosimetric parameters of critical organs [Time frame: During treatment]
• Overall survival [Time frame: At Month 12 after end of treatment]
• Complete response [Time frame: At Month 3 after end of treatment]
• Pelvic recurrence-free survival [Time frame: At Month 12 after end of treatment]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Netherlands · 2 centers

• Leiden University Medical Center — Leiden
• Erasmus Medical Center — Rotterdam

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 PMID 34680328

Identifiers

NCT: NCT05406856 · NL77911.058.21

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗