THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI Guided Radiotherapy (THUNDER2)

• ClinicalTrials.gov Identifier: NCT04815694
• Recruitment Status: Unknown
• First Posted: March 25, 2021
• Last Update Posted: March 25, 2021
• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Collaborator: Viewray Inc.
• Information provided by (Responsible Party): Giuditta Chiloiro, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Study Description

Brief Summary:

Neoadjuvant chemoradiation therapy (nCRT) is the standard treatment modality in locally advanced rectal cancer (LARC) and patients achieving complete response to treatment (CR) usually have a better prognosis in terms of local control (LC), metastases-free survival (MFS) and overall survival (OS).

Recently, an early tumour regression index (ERITCP) was introduced, to predict pathological CR (pCR) after nCRT in LARC patients. In particular, the authors found that the patients with ERITCP <13.1 show a strong response during therapy and have a lower probability to experience distant relapses.

Aim of this clinical trial is to investigate the impact of dose escalation in rectal cancer, identifying the poor responder cases using the ERI index during the course of radiotherapy and increasing the prescribed dose in these patients.

Adopting this boosting protocol, an increase of 10% of CR (clinical and pathological) rate is expected.

For patients enrolled in the trial, chemoradiotherapy (CRT) will be administered using the MRI guided Radiotherapy (MRgRT) machine available in our institution.

If ERI will be inferior than 13.1 the patient will continue the original treatment. Patients with complete clinical response will go through wait and see approach.

If ERI will be higher than 13.1 the treatment plan will be reoptimized considering the residual tumor at fraction 10 as new therapy volume, where the dose will be intensified to reach 60.1 Gy.

The number of cases to be enrolled will be 63. The primary endpoints will be complete response considered as: ypT0N0 in case of Total Mesorectal Excision (TME), ypT0ycN0 in case of LE, ycT0N0 in case of WW; prospective validation of delta radiomics MR-guide Radiotherapy model.

Condition or disease	Intervention/treatment	Phase
Neoadjuvant Chemoradiotherapy; Locally Advanced Rectal Cancer; Pathological Complete Response	Radiation: RT Dose escalation in LARC patients with an Early Regression Index > 13.1 at second week on nCRT	Not Applicable

Detailed Description:

Neoadjuvant chemoradiation therapy (nCRT) is the standard treatment modality in locally advanced rectal cancer (LARC) and patients achieving complete response to treatment (CR) usually have a better prognosis in terms of local control (LC), metastases-free survival (MFS) and overall survival (OS).

Since response to radiotherapy is dose dependent in rectal cancer, dose escalation may lead to higher complete response rates. The possibility to predict patients who will achieve CR before surgery or during nCRT is of crucial importance. Recently, an early tumour regression index (ERITCP) was introduced, to predict pathological CR (pCR) after nCRT in LARC patients. In particular, the authors found that the patients with ERITCP <13.1 show a strong response during therapy and have a lower probability to experience distant relapses.

Aim of this clinical trial is to investigate the impact of dose escalation in rectal cancer, identifying the poor responder cases using the ERI index during the course of radiotherapy and increasing the prescribed dose in these patients.

Adopting this boosting protocol, an increase of 10% of CR (clinical and pathological) rate is expected.

For patients enrolled in the trial, chemoradiotherapy (CRT) will be administered using the MRI guided Radiotherapy (MRgRT) machine available in our institution.

The initial radiotherapy treatment will consist in delivering 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum of 45Gy in 25 fractions on the whole pelvis. Chemotherapy with 5-fluorouracil(5-FU) or oral capecitabine will be administered continuously.

A 0.35 Tesla Magnetic Resonance image will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated.

If ERI will be inferior than 13.1 the patient will continue the original treatment. Patients with complete clinical response will go through wait and see approach.

If ERI will be higher than 13.1 the treatment plan will be reoptimized considering the residual tumor at fraction 10 as new therapy volume, where the dose will be intensified to reach 60.1 Gy.

After the end of CRT, the clinical response will be evaluated 8-10 weeks using high tesla MR and CT images or FDGPET-CT image 8-10 weeks after the end of nCRT. Surgery will be performed 12-16 weeks after the end of the CRT in case of partial or stable or progression disease, while in case of major or complete clinical response at restaging imaging, a Watch and Wait (W&W) or local excision (LE) approach should be followed. Late toxicity and quality of life (QoL) will be scored at first follow-up (FUP) and at 1 and 2 years of FUP according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 scale, functional scales and QoL questionnaires (LARS and SEXUAL questionnaires, at the start of treatment, after surgery and at 1 and 2 years of FUP), respectively.

The number of cases to be enrolled will be 63: all the patients will be treated at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. All the cases will be discussed in weekly multidisciplinary tumor board to share the best therapeutic options, both at the diagnosis and at presurgical restaging.

. The primary endpoints will be complete response considered as: ypT0N0 in case of Total Mesorectal Excision (TME), ypT0ycN0 in case of LE, ycT0N0 in case of WW; prospective validation of delta radiomics MR-guide Radiotherapy model.

The secondary endpoints will be:3 years LC, MFS, Disease Free Survival (DFS), OS; R0 resection rate; Tumor Regression Grade (TRG) 1, TRG 2, Neoadjuvant Rectal (NAR) score; Sphincter preservation rate; Organ preservation rate; Rectal and sexual functions.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 63 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: The initial radiotherapy treatment will consist in delivering 55 Gy in 25 fractions on GTV plus the corresponding mesorectum of 45Gy in 25 fractions on the whole pelvis. Chemotherapy with 5-fluorouracil (5-FU) or oral capecitabine will be administered continuously. A 0.35 Tesla Magnetic resonance image will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated. If ERI will be inferior than 13.1 the patient will continue the original treatment. If ERI will be higher than 13.1 the treatment plan will be reoptimized considering the residual tumor at fraction 10 as new therapy volume, where the dose will be intensified to reach 60.1 Gy.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI Guided Radiotherapy
• Actual Study Start Date: March 17, 2021
• Estimated Primary Completion Date: March 30, 2022
• Estimated Study Completion Date: September 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: LARC patients treated by MRgRT with Early Regression Index (ERI) at 10th fraction >13.1; All patients will be treated on MRgRT, at the second week , patients with an ERI > 13.1 will underwent RT dose intensification on GTV + 3 mm to 60.1 Gy with a Simultaneous Integrated Boost (SIB).	Radiation: RT Dose escalation in LARC patients with an Early Regression Index > 13.1 at second week on nCRT; The initial radiotherapy treatment will consist in delivering 55 Gy in 25 fractions on GTV plus the corresponding mesorectum of 45Gy in 25 fractions on the whole pelvis. Chemotherapy with 5-fluorouracil (5-FU) or oral capecitabine will be administered continuously. A 0.35 Tesla Magnetic resonance image will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated. If ERI will be inferior than 13.1 the patient will continue the original treatment. If ERI will be higher than 13.1 the treatment plan will be reoptimized considering the residual tumor at fraction 10 as new therapy volume, where the dose will be intensified to reach 60.1 Gy.
No Intervention: LARC patients treated by MRgRT with Early Regression Index (ERI) at 10th fraction < 13.1; All patients will be treated on MRgRT, at the second week , patients with an ERI < 13.1 will underwent standard RT dose of 55Gy on tumor and corresponding mesorectum

Outcome Measures

Primary Outcome Measures :

1. Complete response [ Time Frame: 6 months ]
   ypT0N0 in case of TME, ypT0ycN0 in case of LE, ycT0N0 in case of WW
2. Prospective validation of delta radiomics MR-guide Radiotherapy model [ Time Frame: 6 months ]
   correlation between response prediction and clinical or pathological response

Secondary Outcome Measures :

1. 3 years Local control [ Time Frame: 3 years follow up ]
   survival outcomes
2. 3 years Metastasis Free Survival [ Time Frame: 3 years follow up ]
   survival outcomes
3. 3 years Disease Free Survival [ Time Frame: 3 years follow up ]
   survival outcomes
4. 3 years Overall Survival [ Time Frame: 3 years follow up ]
   survival outcomes
5. R0 resection rate [ Time Frame: 6 months ]
   percentage of surgical intervention with negative margins
6. Tumor Regression Grade 2 [ Time Frame: 6 months ]
   surgical outcomes
7. Neoadjuvant rectal (NAR) score [ Time Frame: 6 months ]
   surgical outcomes
8. Tumor Regression Grade 1 [ Time Frame: 6 months ]
   surgical outcomes
9. Sphincter preservation rate [ Time Frame: 6 months ]
   percentage of surgical intervention without the positioning of permanent stomia
10. Organ preservation rate [ Time Frame: 3 years follow up ]
    percentage of patients underwent conservative approaches (WW or EL)
11. Rectal function [ Time Frame: 3 years follow up ]
    impact of therapy on rectal functions by MSKCC questionnaire (from always to never with 5 items)
12. Sexual function [ Time Frame: 3 years follow up ]
    impact of therapy on sexual function by IIEF and FSFI questionnaires (from 1 worst to 5 better)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histological proven adenocarcinoma of the rectum cT2-3, N0-2 or cT4 for anal sphincter involvement N0-2a, M0
• No prior radiotherapy in pelvic region;
• Tumour located between 0 and 15 cm above the anal verge;
• Not mesorectal fascia involvement for tumor
• No extramesorectal nodes involvement
• No extramural venous invasion (EMVI)
• No rectal mucinous adenocarcinoma histology
• No contra-indications for MRI
• Eastern Cooperative Oncology Group (ECOG) 0-1
• Age over 18 years
• Adequate hematological function: granulocyte count > 1500/microl; Hemoglobin level > 10 g/dl; Platelet count > 100000/microl; Alanine Aminotransferase/ aspartate aminotransferase (ALT/AST): 7-45 UI/L;
• No other malignancies in the previous history (except skin and initial cervical cancer);
• Absence of important comorbidities: severe cardiac or coagulative disease, moderate or severe; restrictive/obstructive lung deficit, severe cognitive impairment, moderate and severe renal and hepatic impairment.
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial;
• Absence of pregnancy or lactating female patients;
• Written informed consent

Exclusion Criteria: not defined

Contacts and Locations

Contacts

Contact: Giuditta Chiloiro, MD PhD; + 39 3934360389; giuditta.chiloiro@policlinicogemelli.it

Locations

Italy

Fondazione Policlinico Universitario A.Gemelli IRCCS; Recruiting

Roma, Italy, 00168

Contact: Margherita Zona +39 0630156261 margherita.zona@policlinicogemelli.it

Sponsors and Collaborators

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Viewray Inc.

Investigators

• Principal Investigator: Giuditta Chiloiro, MD PhD; Fondazione Policlinico Universitario A. Gemelli, IRCCS

  Study Documents (Full-Text)

Documents provided by Giuditta Chiloiro, Fondazione Policlinico Universitario Agostino Gemelli IRCCS:

Study Protocol and Statistical Analysis Plan  [PDF] November 3, 2020

Informed Consent Form  [PDF] November 3, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Chiloiro G, Cusumano D, Boldrini L, Romano A, Placidi L, Nardini M, Meldolesi E, Barbaro B, Coco C, Crucitti A, Persiani R, Petruzziello L, Ricci R, Salvatore L, Sofo L, Alfieri S, Manfredi R, Valentini V, Gambacorta MA. THUNDER 2: THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI guided radiotherapy. BMC Cancer. 2022 Jan 15;22(1):67. doi: 10.1186/s12885-021-09158-9.

• Responsible Party: Giuditta Chiloiro, Principal Investigator, Medical Doctor PhD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• ClinicalTrials.gov Identifier: NCT04815694
• Other Study ID Numbers: 3460
• First Posted: March 25, 2021
• Last Update Posted: March 25, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Giuditta Chiloiro, Fondazione Policlinico Universitario Agostino Gemelli IRCCS:

MRI guided radiotherapy; Early Regression Index- ERI

Additional relevant MeSH terms:

Neoplasms