Adjuvant Radiotherapy in Patients With Pathological High-risk Bladder Cancer (GETUG-AFU 30) (Bladder-ART)

Adjuvant Radiotherapy in Patients With Pathological High-risk Bladder Cancer: A Randomized Multicentre Phase II Study

This is a randomized multicentre study in patients with high-risk MIBC to investigate adjuvant radiotherapy after radical cystectomy and pelvic lymph node dissection.

The objective of the study is to provide evidence that adjuvant radiotherapy improves loco-regional control with potential benefits in survival. The study will also evaluate the quality of life of patients and the tolerance of the treatment.

Study Overview

• Status: Recruiting
• Conditions: Patients With High-risk MIBC
• Intervention / Treatment: Radiation: pelvic radiotherapy

Detailed Description

INDICATION:

Patients with pathological high-risk muscle invasive bladder cancer treated by radical cystectomy and pelvic lymph nodes dissection

METHODOLOGY:

Multicenter randomised phase II study in high-risk bladder cancer patients treated by radical cystectomy with pelvic lymph nodes dissection assessing :

• Experimental Arm: adjuvant pelvic radiotherapy consisting of 28 x 1.8 Gy fractions (total dose of 50.4 Gy), 5 days per week, 1 fraction /day (duration of RT is 38 days).
• Standard Arm: surveillance. Eligible patients will be randomised, in a 3:1 ratio, to receive either: adjuvant pelvic radiotherapy (Experimental Arm), or surveillance (Standard Arm).

PRIMARY OBJECTIVE:

The primary objective of the trial is to assess the efficacy of adjuvant radiotherapy in patients with high-risk bladder cancer after radical cystectomy and pelvic lymph nodes dissection. Efficacy will be assessed in terms of pelvic recurrence-free survival (PRFS) at 3 years.

SECONDARY OBJECTIVES:

For each treatment arm (adjuvant pelvic radiotherapy [Experimental Arm], or surveillance [Standard Arm]), these objectives will be evaluated independently.

• To evaluate 5-year pelvic recurrence-free survival (PRFS)
• To evaluate disease-free survival (DFS) at 3 and 5 years.
• To evaluate overall survival (OS) at 3 and 5 years.
• To evaluate metastasis-free survival (MFS) at 3 and 5 years.
• To evaluate disease-specific survival (DSS) at 3 and 5 years.
• To evaluate the tolerance and safety of each treatment strategy.
• To evaluate patients' quality of life.

Ancillary studies Objectives:

• Investigation of individual predisposition to develop radiotherapy induced late digestive toxicity using the radiation-induced lymphocyte apoptosis (RILA) assay
• The analyse of genomic and transcriptome correlation between different clusters and oncological outcomes
• Dosimetric banking to evaluate the correlation of Dose-Volume Histogram with:
• Gastrointestinal toxicity grade ≥2;
• Pelvic recurrence (radiotherapy volumes, mapping of recurrences).

• Study Type: Interventional
• Enrollment (Anticipated): 109
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mallik ZIBOUCHE; Phone Number: + 33 1 44 23 55 68; Email: m-zibouche@unicancer.fr

Study Locations

• France
  • Amiens, France, 80090
    • Withdrawn
    • Clinique de l'Europe
  • Angers, France, 49055
    • Recruiting
    • ICO Paul Papin
    • Contact: Valentine GUIMAS, MD; Phone Number: +33 2 40 67 99 00; Email: valentine.guimas@ico.unicancer.fr
  • Annecy, France, 74000
    • Withdrawn
    • Clinique Générale d'Annecy
  • Bordeaux, France, 33076
    • Recruiting
    • Institut Bergonié
    • Contact: Paul SARGOS, MD; Phone Number: + 33 5 56 33 33 76; Email: P.Sargos@bordeaux.unicancer.fr
  • Brest, France, 29200
    • Not yet recruiting
    • Clinique Pasteur Cfro
    • Contact: Ali HASBINI, MD; Phone Number: +33 2 98 31 32 00; Email: alihasbini@oncologie-brest.fr
  • Caen, France, 14000
    • Recruiting
    • Centre Francois Baclesse
    • Contact: Emmanuel MEYER, MD; Phone Number: +33 2 31 45 50 02; Email: e.meyer@baclesse.unicancer.fr
  • Clermont-Ferrand, France, 63011
    • Withdrawn
    • Centre Jean Perrin
  • Créteil, France, 94000
    • Withdrawn
    • Hopital Henri Mondor
  • Dijon, France, 21079
    • Recruiting
    • Centre Georges-Francois Leclerc
    • Contact: Etienne MARTIN, MD; Phone Number: +33 3 80 73 75 18; Email: emartin@cgfl.fr
  • Grenoble, France, 38043
    • Recruiting
    • CHU Grenoble
    • Contact: Olivier VERRY, MD; Phone Number: +33 4 76 76 54 35; Email: cverry@chu-grenoble.fr
  • Lille, France, 59000
    • Recruiting
    • Centre Oscar Lambret
    • Contact: David PASQUIER, MD; Phone Number: +33 3 20 29 51 44; Email: d-pasquier@o-lambret.fr
  • Limoges, France, 87042
    • Recruiting
    • Hôpital Universitaire Dupuytren
    • Contact: Pierre CLAVERE, Prof; Phone Number: +33 5 55 05 62 69; Email: pierre.clavere@chu-limoges.fr
  • Lorient, France, 56100
    • Recruiting
    • Groupe Hospitalier Bretagne Sud
    • Contact: Guillaume BERA, MD; Phone Number: +33 2 97 06 90 30; Email: g.bera@ghbs.bzh
  • Lyon, France, 69008
    • Recruiting
    • Centre Léon Bérard
    • Contact: Pascale POMMIER, MD; Phone Number: +33 4 78 78 51 66; Email: pascal.pommier@lyon.unicancer.fr
  • Marseille, France, 13385
    • Recruiting
    • CHU La Timone
    • Contact: Xavier MURACCIOLE, MD; Email: xavier.muracciole@ap-hm.fr
  • Montpellier, France, 34298
    • Withdrawn
    • Institut regional du Cancer Montpellier
  • Paris, France, 75015
    • Recruiting
    • Hopital Europeen Georges Pompidou
    • Contact: Catherine DURDUX, Prof; Phone Number: +33 1 56 09 34 02; Email: catherine.durdux@.aphp.fr
  • Paris, France, 75010
    • Recruiting
    • Saint Louis
    • Contact: Christophe HENNEQUIN, Prof; Phone Number: +33 1 42 49 90 24; Email: christophe.hennequin2@aphp.fr
  • Paris, France, 75651
    • Withdrawn
    • Aphp Pitie-Salpetriere
  • Pierre-Bénite, France, 69310
    • Withdrawn
    • CH Lyon sud
  • Rennes, France, 35042
    • Withdrawn
    • Centre Eugène Marquis
  • Saint Gregoire, France, 35760
    • Recruiting
    • CHP Saint-Grégoire
    • Contact: Xavier ARTIGNAN; Phone Number: +33 2 90 09 44 64; Email: xartignan@vivalto-sante.com
  • Saint-Herblain, France, 44805
    • Recruiting
    • ICO - Site René Gauducheau
    • Contact: Stéphane SUPIOT, MD; Phone Number: +33 2 40 67 99 13; Email: stephane.supiot@ico.unicacner.fr
  • Saint-Priest-en-Jarez, France, 42270
    • Recruiting
    • Institut de Cancérologie Lucien Neuwirth
    • Contact: Nicolas MAGNE, Prof; Phone Number: +33 4 77 91 71 04; Email: nicolas.magne@icloire.fr
  • Toulouse, France, 31059
    • Recruiting
    • Institut Claudius Regaud
    • Contact: Pierre GRAFF-CAILLEAUD, MD; Phone Number: +33 5 31 15 54 30; Email: graff-cailleaud.pierre@iuct-oncopole.fr
  • Toulouse, France, 31076
    • Recruiting
    • Clinique Pasteur
  • Villejuif, France, 94805
    • Suspended
    • Gustave Roussy Cancer Campus Grand Paris

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

To be eligible, the patients must fulfil all of the following inclusion criteria:

1. Patients with histologically-confirmed muscle-invasive bladder cancer, either with pure urothelial carcinomas, or dominant urothelial carcinomas (>50%) combined with other histological variants including: micropapillary, epidermoid, or adenocarcinomas, are eligible. Patients with small cell variants, pure adenocarcinomas, or pure epidermoid carcinomas are not eligible.

2. Patients with radical cystectomy and pelvic lymph nodes dissection with no microscopic residual disease (R0 and R1).

   Note that only R1 patients without urinary diversion as orthotropic neo-bladder replacement are eligible for the study, to limit cystectomy bed radiation induced toxicities.

3. Patients with tumours of TNM staging: pN0-2, M0 by imagery, and pT3a, pT3b, pT4a, and pT4b, as well as, pTX-pN1-2, pTX-NX-R1 are eligible.
4. Patients having received neo-adjuvant or adjuvant chemotherapy treatment are eligible. Randomization is allowed only if AE due to chemotherapy are ≤grade 2 at randomization.
5. Patients ≥18 years old.
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
7. Absolute neutrophil count (ANC) ≥1500 cells/mm³.
8. Platelets ≥100000 cells/mm³.
9. Haemoglobin ≥8 g/dL (Note: following a blood transfusion or another intervention if required).
10. Adequate hepatic function: aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤2.5 x upper limit of normal (ULN); or ≤3.5 x ULN in the case of concurrent disease with known etiology and for which a corrective treatment is possible.
11. Adequate renal function: clearance >30 mL/min (MDRD).
12. Patients having provided written informed consent prior to any study-related procedures.
13. Patients affiliated to the social security scheme.
14. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol.

Exclusion Criteria:

Patient must not be enrolled if he/she fulfils any of the following non-inclusion criteria:

1. Patients with R1 resection and with orthotropic neo-bladder reconstruction as urinary diversion are not eligible.
2. Patients with clinical or radiological evidence of metastases or N3 staged bladder cancer are not eligible.

3. Prior invasive solid tumours or haematological malignancies unless disease free for a minimum of 3 years prior to randomisation except:

   • skin basal cell carcinoma,
   • in situ epithelioma of the cervix,
   • or prostate cancer: incidentally discovered during cystoprostatectomy and pelvic lymph node dissection and with a good prognosis (T stage <pT3b and/or Gleason <8 and pN- and/or post-operative prostate-specific antigen (PSA) <0.1 nanogram/mL),
4. Prior pelvic radiotherapy.
5. Patients with active inflammatory bowel disease.
6. Patients who required surgical treatment for bowel obstruction before bladder cancer diagnosis or after cystectomy.
7. Prior chemotherapy for other malignant diseases within the previous 5 years, except for neoadjuvant pre-cystectomy chemotherapy or adjuvant chemotherapy which are permitted.

8. Patients with the following severe acute co-morbidity are not eligible:

   • Unstable angina or congestive heart failure that required hospitalization in the 6 months before randomisation.
   • Transmural myocardial infarction in the 6 months prior to randomisation.
   • Acute bacterial or fungal infection requiring intravenous antibiotics at randomisation.
   • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of randomisation.
   • Severe hepatic disease: Child-Pugh Class B or C hepatic disease.
   • Known acquired immune deficiency syndrome (AIDS); the study treatment could impact blood count.
9. Patients with any other disease or illness which requires hospitalization or is incompatible with the study treatment are not eligible.
10. Patients unable to comply with study obligations for geographic, social, or physical reasons, or who are unable to understand the purpose and procedures of the study.
11. Patients enrolled in another therapeutic study within 30 days prior of randomisation.
12. Person deprived of their liberty or under protective custody or guardianship.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Experimental Arm; adjuvant pelvic radiotherapy consisting of 28 x 1.8 Gy fractions (total dose of 50.4 Gy), 5 days per week, 1 fraction / day (duration of RT is 38 days).	Radiation: pelvic radiotherapy; adjuvant pelvic radiotherapy consisting of 28 x 1.8 Gy fractions (total dose of 50.4 Gy), 5 days per week, 1 fraction / day (duration of RT is 38 days).
NO_INTERVENTION: Standard Arm; Surveillance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pelvic recurrence-free survival (PRFS)	The PRFS is defined as the delay between randomization and pelvic recurrence or death, whichever occurs first. The pelvic recurrence will be evaluated according to RECIST V1.1 criteria.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pelvic recurrence-free survival (PRFS)	The PRFS is defined as the delay between randomization and pelvic recurrence or death, whichever occurs first. The pelvic recurrence will be evaluated according to RECIST V1.1 criteria.	5 years
Disease-free survival (DFS)	DFS is defined as the delay between randomization and tumor progression (local, regional, or distant) or death of any cause, whichever occurs first.	3 years
Disease-free survival (DFS)	DFS is defined as the delay between randomization and tumor progression (local, regional, or distant) or death of any cause, whichever occurs first.	5 years
Overall Survival (OS)	OS is defined as the delay between randomization and death, of any cause.	3 years
Overall Survival (OS)	OS is defined as the delay between randomization and death, of any cause.	5 years
Metastasis-free survival (MFS)	MFS is defined as the delay between randomization, and metastasis (clinical or radiological) or death of any cause whichever occurs first.	3 years
Metastasis-free survival (MFS)	MFS is defined as the delay between randomization, and metastasis (clinical or radiological) or death of any cause whichever occurs first.	5 years
Disease-specific survival (DSS)	DSS is defined as the delay between randomization and death due to bladder cancer.	3 years
Disease-specific survival (DSS)	DSS is defined as the delay between randomization and death due to bladder cancer.	5 years
Tolerance will be evaluated by toxicity: acute (<6 months after RT) and late (≥6 months after RT), assessed using the NCI CTCAE Version N°4.0	The tolerance will be evaluated by toxicity: acute (<6 months after RT) and late (≥6 months after RT), assessed using the NCI CTCAE Version N°4.0.	5 years
Patients' quality of Life	EORTC QLQ-C30	5 years
Patient quality of Life	The Bladder Cancer Index (BCI)	5 years
Evaluation of acute and late toxicities	The safety will be evaluated by toxicity: acute (<6 months after RT) and late (≥6 months after RT), assessed using the NCI CTCAE Version N°4.0.	5 years

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Paul SARGOS, MD, Institut Bergonié; Principal Investigator: Stéphane LARRE, Prof, CHU Robert Debré; Principal Investigator: Géraldine PIGNOT, MD, Institut Paoli-Calmettes

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 19, 2018
• Primary Completion (ANTICIPATED): December 1, 2027
• Study Completion (ANTICIPATED): December 1, 2027

Study Registration Dates

• First Submitted: October 30, 2017
• First Submitted That Met QC Criteria: November 3, 2017
• First Posted (ACTUAL): November 6, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 25, 2022
• Last Update Submitted That Met QC Criteria: October 24, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms
• Other Study ID Numbers: UC-0160/1617; 2016-A01535-46 (REGISTRY: ANSM)

Drug and device information, study documents

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