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

Abstract

Background: Definitive chemoradiotherapy is standard of care in locally advanced cervical cancer (LACC). Both toxicity and local relapse remain major concerns in this treatment. We hypothesize that a magnetic resonance imaging (MRI) based redefining of the radiotherapeutic target volume will lead to a reduction of acute and late toxicity. In our center, chemoradiotherapy followed by hysterectomy was implemented successfully in the past. This enables us to assess the safety of reducing the target volume but also to explore the biological effects of chemoradiation on the resected hysterectomy specimen.

Methods: The EXIT-trial is a phase II, single arm study aimed at LACC patients. This study evaluates whether a MRI-based exclusion of the non-tumor-bearing parts of the uterus out of the target volume results in absence of tumor in the non-high doses irradiated part of the uterus in the hysterectomy specimen. Secondary endpoints include a dosimetric comparison of dose on normal tissue when comparing study treatment plans compared to treatment of the whole uterus at high doses; acute and chronic toxicity, overall survival, local relapse- and progression-free survival. In the translational part of the study, we will evaluate the hypothesis that the baseline apparent diffusion coefficient (ADC) values of diffusion weighted MRI and its evolution 2 weeks after start of CRT, for the whole tumor as well as for intra-tumoral regions, is prognostic for residual tumor on the hysterectomy specimen.

Discussion: Although MRI is already used to guide target delineation in brachytherapy, the EXIT-trial is the first to use this information to guide target delineation in external beam radiotherapy. Early therapy resistance prediction using DW-MRI opens a window for early treatment adaptation or further dose-escalation on tumors/intratumoral regions at risk for treatment failure.

Trial registration: Belgian Registration: B670201526181 (prospectively registered, 26/11/2015); ClinicalTrials.gov Identifier: NCT03542942 (retrospectively registered, 17/5/2018).

Keywords: Apparent diffusion coefficient; Diffusion weighted MRI; Locally advanced cervical cancer; Target volume; Uterus.

Fig. 1

Workflow per patient and situation of the different time-points for each study. DW-MRI: diffusion-weighted MRI; PTV_EXIT: planning target volume as defined within the EXIT-trial; MRI HRT: Magnetic resonance imaging of the HRT specimen; FDG-PET: 18-fluorodeoxyglucose PET scan; PTV: planning target volume; MRI: magnetic resonance imaging. C: weekly chemotherapy; RT: radiotherapy; D98: dose received in 98% of the volume. *: Imaging which requires extra effort of the patient; **: only if node-positive at diagnosis

Fig. 2

delineation of treatment volumes following state-of-the-art (a en b) en EXIT-trial (a en c). a delineation of elective lymph node areas are state-of-the-art and identical in standard treatment & the EXIT_trial. Clinical target volume (CTV) of the lymph nodes (lnn) = CTV_Lnn (yellow) = elective lnn areas (common, external and internal lnn, obturator and presacral region; inclusion of para-aortic lnn if any pelvic lnn are affected). Planning target volume (PTV) of the lnn (PTV_Lnn; blue) is created using an isotropic margin of 5 mm around the CTV_Lnn. b GTV of the primary tumor (GTV_prim = red): primary tumor delineated using T2 weighted MRI images (state of the art). CTV of the primary tumor (CTV_prim = blue): includes GTV_prim, whole uterus, non-affected parts of the cervix and parametria, upper vaginal 1/3 to ½ (minimal vaginal margin of 2 cm to the GTV_prim). PTV of the primary tumor (PTV_prim = purple): margin around the CTV_prim of 10 mm antero-posterior (AP); 5 mm left-right (LR) and 5 mm supero-inferior (SI)

Fig. 3

3D-mold. Example of a 3D-mold model created in Blender. The uterus, mold and knobs are depicted respectively in white, blue and green. The mold supports the uterus specimen, while the tissue is fixated to the knobs during sugery

Fig. 4

Dose Volume Histograms with and without the entire uterus included in the planning target volume. Dose Volume Histograms (DVHs) of 2 patients treated with a partial (yellow) or entire uterus (red) included in the planning target volume (PTV). a and c red contour = entire uterus included in the PTV; yellow contour = only the parts of the uterus closer than two cm of the gross tumor volume (GTV = red flooded contour) are included in the PTV. c and d DVHs of patient a and c respectively; the red DVHs correspond with the red contour (whole uterus); the yellow DVHs correspond with the yellow contour (selected parts of the uterus included in the CTV). The tail towards 62Gy in the DVH of the PTV corresponds with the SIB given to the GTV. In the first patient (a) the uterus lies in anteflexed position causing high doses to the bladder when irradiated entirely. A small reduction of PTV by reducing the amount of uterus included in the PTV causes a huge reduction in dose delivered to the bladder (b). A reduction of the PTV in case of a normal positioned uterus causes mainly a reduction in the irradiated volume of small bowel (d). Due to the large amounts of small bowel delineated, the reduction in terms of percentage seems small. However, in this case the amount of small bowel receiving 45Gy is reduced with 8%, which corresponds with 59 cc