Exclusion of Non-involved Uterus From the Target Volume in Locally Advanced Cervical Cancer (EXIT)

Exclusion of Non-involved Uterus Form the Target Volume: an Individualized Treatment for Locally Advanced Cervical Cancer Using Modern Radiotherapy and Imaging Techniques

Both toxicity and local relapse are major concerns in the treatment of locally advanced cervical cancer. The purpose of this study is to ameliorate both by integrating modern imaging (diffusion weighted magnetic resonance imaging; DW-MRI) into the treatment planning of modern radiotherapy. We want to evaluate the safety and effect of excluding the unaffected uterus (as determined on magnetic resonance imaging) from the treatment field. Meanwhile we want to explore the possible use of apparent diffusion coefficient values (DW-MRI) as biomarker of treatment response.

Study Overview

• Status: Completed
• Conditions: Uterine Cervical Neoplasms
• Intervention / Treatment: Other: treatment with EXIT-target volume

Detailed Description

In our previous research we successfully implemented Intensity Modulate Arc Therapy with concurrent administration of cisplatin 40mg/m2 weekly (IMAT-C) in the multimodality treatment of Locally Advanced Cervical Cancer (LACC) . By delivering a higher biological dose to the tumor and lowering the dose to the Organs at Risk (OARs), toxicity significantly dropped and local control improved. However, there remains room for improvement for both toxicity and response to the treatment. Macroscopic tumor rest on hysterectomy reflects the existence of chemoradiation (CRT) resistant foci and correlates with outcome. We hypothesize that both radiotherapy (RT)-related toxicity (a) as well as local response on CRT (b) can be improved by respectively:

1. Reducing the dose on OARs by omitting iconographical non tumor-bearing parts of the uterus from the Clinical Target Volume (CTV).
2. Performing a dose-escalation to those regions within the gross target volume (GTV) pointed out by Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) to be at risk for treatment failure.

To objectivize our hypotheses, we aim at:

1. Demonstrating that omitting iconographical unaffected uterus from the treatment volume leaves no tumor behind in the non-targeted parts of the uterus, leads to lower doses to the OARs and decreases (acute) toxicity.
2. Validating that a high baseline apparent diffusion coefficient (ADC) and an increase in ADC 2 weeks after start of CRT, for the whole tumor as well as for intra-tumoral regions, is prognostic for residual tumor on hysterectomy specimen and to consider the possibility for a further dose-escalation on tumors/intratumoral regions at risk for treatment failure.

Importance to the field: Both toxicity and local relapse are major concerns in the treatment of LACC. Grade ≥ 2 toxicity influences daily life of patients significantly and is present in the majority of patients treated and even with image guided BT local relapse remains the major cause of treatment failure.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • Radiotherapy Department Ghent University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Biopsy proven carcinoma of the uterine cervix
• locally advanced disease (FIGO IB2 or >FIGO IIB or node positive) proven by clinical examination, 18-fluorodeoxyglucose positron emission tomography scan (18FDG PET-CT) and MRI
• no more than 2 distant metastases (other than para-aortic lymph nodes);
• WHO 0-2;
• adequate kidney function for CRT, if inadequate kidney function radiotherapy can be the sole therapeutic regimen;
• not pregnant or breastfeeding
• absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; - willing and able to sign a written informed consent.

Exclusion Criteria:

• Patients unable to undergo MRI for any reason.

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
Other: treatment with EXIT-target volume; The radiotherapeutic treatment plan is based on an EXIT-target volume in which the non-involved uterus is excluded from the target volume. All other delineations are performed conform standard of care.	Other: treatment with EXIT-target volume; exclusion of the unaffected part of the uterus out of the treatment field

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
safety: abscence of tumor in the non-involved and non-high doses irradiated part of the uterus	abscence of tumor in the non-involved (as determined on the pre-treatment MRI) and non-high doses irradiated part of the uterus in the hysterectomy specimen after CRT	within 3 months after last inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
dosimetry	dosimetric comparison of dose on the OARs when comparing study treatment plans compared to treatment of the whole uterus at high doses	within 3 months after last inclusion
number of participants with treatment-related adverse events as assessed by the radiotherapy oncology group toxicity criteria and CTCAEv4.0 for hematology	evaluation of acute toxicity, grade 0 (no toxicity) to grade 5 (treatment related death).	during treatment. 10 days, 1 months and 3 months after ending treatment
number of participants with treatment-related adverse events as assessed by the radiotherapy oncology group toxicity criteria and CTCAEv4.0	evaluation chronic toxicity, grade 0 (no toxicity) to grade 5 (treatment related death).	6, 12, 18 and 24 months after treatment.
local, regional and distant control	defined as absence of disease at the primary tumor bed, the regional lymph nodes and distant sites	1, 3, 6, 12,18 and 24 months after treatment
Correlation of high-Risk regions on IMaging (DW-MRI) with Pathology and regression pattern analysis (CRIMP).	The MRI at fixed time points will be supplemented with diffusion weighing (DW). The ultimate aim is the correlation of tumoral ADC-values of the different DW-MRI with the pathology in order to predict therapy resistance or response to CRT at an early stage or even before start.	Within 6 months after surgery of the last patient

Collaborators and Investigators

• Sponsor: University Hospital, Ghent
• Investigators: Principal Investigator: Katrien Vandecasteele, MD, PhD, University Hospital, Ghent

Publications and helpful links

General Publications

• Vandecasteele K, Tummers P, Van Bockstal M, De Visschere P, Vercauteren T, De Gersem W, Denys H, Naert E, Makar A, De Neve W. EXclusion of non-Involved uterus from the Target Volume (EXIT-trial): an individualized treatment for locally advanced cervical cancer using modern radiotherapy and imaging techniques. BMC Cancer. 2018 Sep 17;18(1):898. doi: 10.1186/s12885-018-4800-0.

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2016
• Primary Completion (Actual): September 22, 2020
• Study Completion (Actual): September 22, 2020

Study Registration Dates

• First Submitted: May 3, 2018
• First Submitted That Met QC Criteria: May 18, 2018
• First Posted (Actual): May 31, 2018

Study Record Updates

• Last Update Posted (Actual): December 19, 2022
• Last Update Submitted That Met QC Criteria: December 16, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: radiotherapy; locally advanced; DW-MRI; target volume
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Uterine Cervical Neoplasms
• Other Study ID Numbers: B670201526181

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: IPD can be shared. Decision is made upon request.

Drug and device information, study documents

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