Clinical trial NCT04815694: THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI Guided Radiotherapy
Official title: THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI Guided Radiotherapy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Neoadjuvant Chemoradiotherapy
Locally Advanced Rectal Cancer
Pathological Complete Response
Keywords: MRI guided radiotherapy
Early Regression Index- ERI
Lead sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Sponsor class: OTHER
Collaborators: name: Viewray Inc.
First posted: 2021-03-25
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Complete response
timeFrame: 6 months
measure: Prospective validation of delta radiomics MR-guide Radiotherapy model
timeFrame: 6 months
Secondary outcomes:
measure: 3 years Local control
timeFrame: 3 years follow up
measure: 3 years Metastasis Free Survival
timeFrame: 3 years follow up
measure: 3 years Disease Free Survival
timeFrame: 3 years follow up
measure: 3 years Overall Survival
timeFrame: 3 years follow up
measure: R0 resection rate
timeFrame: 6 months
measure: Tumor Regression Grade 2
timeFrame: 6 months
measure: Neoadjuvant rectal (NAR) score
timeFrame: 6 months
measure: Tumor Regression Grade 1
timeFrame: 6 months
measure: Sphincter preservation rate
timeFrame: 6 months
measure: Organ preservation rate
timeFrame: 3 years follow up
measure: Rectal function
timeFrame: 3 years follow up
measure: Sexual function
timeFrame: 3 years follow up
Other outcomes:
Locations:
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A.Gemelli IRCCS
Study officials:
affiliation: Fondazione Policlinico Universitario A. Gemelli, IRCCS
name: Giuditta Chiloiro, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.