ViablE Residual Disease at Intracavitary brachytherapy after Chem-radio Therapy I Carcinoma Cervix:Detection, Characterization and prognostic Significance(VERDICT) Amplification determination of diagnostic accuracy and prognostic utility HINA

Title

ViablE Residual Disease at Intracavitary Brachytherapy after Chemo-radioTherapy in Carcinoma Cervix: Detection and characterization using far infrared imaging (VERDICT)

|Background & Rationale

Concurrent chemoradiation followed by brachytherapy is the current standard of care in carcinoma cervix but distant metastases are the most common site of failure. Characterization of residual viable disease at cervix at the time of brachytherapy may help personalize adjuvant therapy. Detection of the viable residual disease using MRI is inaccurate. Using a far-infrared imaging device with clinical examination may improve accuracy.

|Aim

To develop and test a far-infrared subsurface imaging device to detect viable residual disease at cervix during brachytherapy with greater accuracy.

|Objectives and Endpoints

1. Primary: To compare the specificity and sensitivity of far-infrared imaging device along with clinical examination versus MRI at the time of brachytherapy.

2. Secondary:

3. To determine the prognostic impact of the volume of residual abnormality in MRI (GTres) on:

4. The clinical complete response rate on MRI at 3 months post-treatment

5. Disease-Free survival.

6. Quantification of Tumor Infiltrating Lymphocytes in the biopsy specimens and PD-L1 expression in the tumor and immune cells.

7. Determine the prognostic impact of the above parameters on disease-free survival

|Population & setting

Patient diagnosed with Carcinoma Cervix, who will undergo definitive concurrent chemoradiation followed by brachytherapy with curative intent. Patients with MRI non-compatible implants, cochlear implants, bleeding or platelet disorders will be excluded.

|Intervention

Image guided biopsies will be obtained from the cervix at the time of first brachytherapy. Biopsy locations will be determined by the areas of abnormality noted on the pre-brachytherapy MRI imaging as well as the clinical findings combined with far-infrared imaging. Biopsy specimens would be analyzed for the tumor infiltrating lymphocytes and PD-L1 expression.

|Study Design

Single arm, prospective, cohort study.

|Outcome & Measures

1. Sensitivity, Specificity and Accuracy of MRI as compared to Clinical examination combined with infrared imaging. The gold standard will be presence of viable tumor in the biopsy sample obtained from the area.
2. The adjusted odds ratio of having a complete response at 3 months per unit change in the volume of GTres.
3. The adjusted hazard ratio of the disease free survival per unit change in the volume of GTres
4. Counts of the TIL expressed in number / mm2 as well as percentage of cells in the biopsy specimen.
5. PD-L1 expression in terms of percentage of cells staining in IHC.

|Study Procedures

Pre-brachytherapy MRI will be done as per usual institutional protocol and the GTres will be mapped on the diagram. GTres volume will also be calculated. During brachytherapy, patients will be examined clinically and will undergo far-infrared imaging which will be again used to map the areas of residual abnormality. Biopsies will be taken from the abnormal area as well as from a normal area.

|Statistical Consideration

A sample size of 135 biopsies is required to detect an absolute difference of 15% in the specificity as compared to the specificity of MRI (assumed to be 60%) with a two-sided Type I error of 5% and a power of 80%. This corresponds to a sample size of 54 patients, as patients will have multiple biopsies. An interim analysis will be planned after 54 patients have been accrued and the obtained sensitivity and specificity parameters will be refined to calculate the final sample size which is currently estimated to be 150 patients.

|Feasibility

Annually about 100 patients of carcinoma cervix undergo this form of treatment in our center. We expect a further increase in the numbers with the increase in the machine availability in the department.

|Significance

In addition to the obvious advantage that this non-invasive imaging device has in terms of use during follow up, we will be able to use the results of the study to prospectively quantitate the prognostic impact of the residual abnormality as well as find out the association between the prognosis and the patterns of viable disease and tumor infiltrating lymphocytes. If the method of biopsy acquisition proves successful in identifying viable disease in a large majority of patients, then we can design further studies where the adjuvant therapy is tailored based on the nature of the disease.