Evaluation of the Clinical Utility of Online Adaptive Radiotherapy in Bladder Cancer (BLADAPT-GETUG V11)

Official title

Randomized Open Phase II Multienter Study Evaluating the Clinical Utility of Online Adaptive Radiotherapy in Bladder Cancer

Overview

Trimodal therapy (TMT) consisting of transurethral resection of bladder tumors followed by radiotherapy and chemotherapy is a therapeutic alternative in patients with Muscle-Infiltrating Bladder Cancer who are inoperable or refuse surgery. One of the main challenges of TMT is the planning and delivery of radiation therapy. Indeed, the bladder is a mobile hollow organ subject to repletion, with variations in size and shape during and between radiotherapy sessions. Standard radiotherapy techniques require large planning target volume margins around the bladder, which can be responsible for irradiation of a large volume of large and small bowel with grade 2 and 3 toxicities. Adaptive radiotherapy allows for the generation of a treatment fraction personalized to a patient's anatomical modification with margin reduction and improves the dosimetric quality of the delivered plans. The hypothesis is that this improvement results in radiation-induced toxicity improvement.

Detailed description

In 2023, the incidence of muscle-infiltrating bladder cancer (MIBC) in France was 14062 cases, 81% of which were in men.

The standard treatment for MIBC is cystectomy preceded by neoadjuvant chemotherapy. Trimodal therapy (TMT), consisting of transurethral resection of bladder tumors (TURBT) followed by radiotherapy (RT) and chemotherapy (CT), has emerged as a valuable therapeutic de-escalation alternative in patients who are inoperable or refuse surgery with its physical and psychological sequelae. TMT provides survival outcomes identical to cystectomy in selected patients and allows for bladder preservation in successful cases. TMT is an effective potential alternative to radical cystectomy for recurrent high-grade T1 urothelial cancer of the bladder who failed intravesical therapy.

One of the main challenges of TMT is the planning and delivery of radiation therapy. Indeed, the bladder is a mobile hollow organ subject to repletion, with variations in size and shape during radiotherapy sessions (intra-fractional movement) and between sessions (inter-fractional movement). To take into account these movements, standard radiotherapy techniques require large planning target volume (PTV) margins around the bladder, which can be responsible for irradiation of a large volume of large and small bowel with grade 2 and 3 toxicities up to 42% and 17% respectively.

Adaptive radiotherapy (ART) allows for the generation of a treatment fraction personalized to a patient's anatomical modification. While it was until recently only performed "offline", i.e. between two radiotherapy sessions, it is now possible to perform a daily customization of the radiotherapy session ("online") for a given patient to ensure optimal coverage of the target with minimized margins. ART allows PTV margins reduction for MIBC and improves therefore the dosimetric quality of the delivered plans.

The hypothesis is that the dosimetric improvement induced by ART results in radiation-induced toxicity improvement.

Interventions

• Radiation Adaptive radiotherapy
  Patient will be treated by concomitant: * adaptive radiotherapy 5 days a week for 4 weeks with hypofractionated irradiation 55 Gy / 20 fractions +/- pelvic inclusion 44 Gy/20 fractions (SIB). * chemotherapy if not contraindicated : * Cisplatin : 20 mg/m2/day on day 1 to day 4 and day 22 to day 25 (or 80 mg/m2 during week 1 and 4 of radiotherapy) Or * Gemcitabine: 80 to 100 mg/m2/week Or * Mitomycin C: 12 mg/m2 on day 1 only + 5FU infusion 500 mg/m2/day during 5 days on week 1 and 4 of ra
• Radiation standard radiotherapy
  Patient will be treated by concomitant: * standard 5 days a week for 4 weeks with hypofractionated irradiation 55 Gy / 20 fractions +/- pelvic inclusion 44 Gy/20 fractions (SIB). * chemotherapy if not contraindicated : * Cisplatin : 20 mg/m2/day on day 1 to day 4 and day 22 to day 25 (or 80 mg/m2 during week 1 and 4 of radiotherapy) Or * Gemcitabine: 80 to 100 mg/m2/week Or * Mitomycin C: 12 mg/m2 on day 1 only + 5FU infusion 500 mg/m2/day during 5 days on week 1 and 4 of radiotherapy (a

Primary outcome measures

• evaluation of the technique of adaptive radiotherapy in terms of acute Gastro-Intestinal toxicity. [Time frame: from the Day 1 Radiotherapy to 3 months after the last day of Radiotherapy]

Secondary outcome measures (12)

• Evaluation of all acute toxicities [Time frame: from the Day 1 Radiotherapy to 3 months after the last day of Radiotherapy]
• Evaluation of all late toxicities [Time frame: from 3 months after the last day of Radiotherapy to 5 years after the last day of Radiotherapy]
• evaluation of quality of life specific to the cancer disease [Time frame: at baseline, the last day of radiotherapy, every 3 months after the last day of radiotherapy, during first year and every 6 months then after until 3 years.]
• evaluation of quality of life and of the measurements specific to the treatment of bladder cancer with muscle invasion [Time frame: at baseline, the last day of radiotherapy, every 3 months after the last day of radiotherapy, during first year and every 6 months then after until 3 years.]
• evaluation of quality of life for patient ≥ 70 years old in order to establish a minimum standardized geriatric assessment [Time frame: at baseline, the last day of radiotherapy, every 3 months after the last day of radiotherapy, during first year and every 6 months then after until 3 years.]
• evaluation of quality of life for patient ≥ 70 years old (Specific to elderly people with cancer) [Time frame: at baseline, the last day of radiotherapy, every 3 months after the last day of radiotherapy, during first year and every 6 months then after until 3 years.]
• assessment of disease free survival [Time frame: At 3 and 5 years after the last day of Radiotherapy]
• assessment of cystectomy free survival [Time frame: At 3 and 5 years after the last day of Radiotherapy]
• assessment of overall survival [Time frame: At 3 and 5 years after the last day of Radiotherapy]
• assessment of local control rate [Time frame: At 3 and 5 years after the last day of Radiotherapy]
• assessment of the dosimetric results [Time frame: during tthe radiotherapy for both arms]
• evaluation of the impact of the adaptive process on fractions execution [Time frame: during tthe radiotherapy for both arms]

Eligibility criteria

Inclusion criteria

• Histologically proven muscle-infiltrating bladder cancer (de novo MIBC or after a history of non-muscle-invasive bladder cancer) or patients with initial high-grade T1 tumor showing Ta or T1 recurrence, or those with high-grade T1 after a course of intravesical biological therapy or chemotherapy;
• Age ≥ 18 years;
• Urothelial carcinoma (transitional cell carcinoma of the bladder, micropapillary, microcystic with trophoblastic differenciation) and squamous cell histological types are allowed;
• Stage T1-T4aN0M0
• TransUrethral Resection of Bladder Tumor (TURBT) and Position Emission Tomography- scanner and X-ray Computed Tomography (PET-CT) or Computed Tomography scan of thorax/abdomen/pelvis (without carcinological anomaly) within 8 weeks prior to the start of radiation therapy (if TURBT was performed more than 6 weeks before the inclusion visit, a new TURBT or, at least, a cystoscopy showing no progression, no residual tumour or regrowth must be done);
• Suitable for radiotherapy;
• Eastern Cooperative Oncology Group/World Human Organisation (ECOG/WHO) performance status from 0 to 2
• Negative pregnancy test (blood or urine), for women of childbearing age only;
• If the patient is sexually active, he/she must agree to use contraception deemed adequate and appropriate by the investigator throughout the period of study drug administration and 6 months after the end of treatment for both men and women.
• Affiliation to the French Social Security System;
• Dated, written and signed Informed consent

Exclusion criteria

• Prior pelvic radiation therapy;
• Patients with previous or concomitant other malignancy within the past 5 years EXCEPT adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix. Patients who have had a previous other malignancy must have been disease free for at least five years;
• Presence of endopenic stent;
• Inability to comply with the protocol;
• Grade 1 or greater baseline diarrhea;
• Uncontrolled inflammatory bowel disease (ulcerative colitis or Crohn's disease);
• Uncontrolled immune or cardiac or pulmonary disease;
• Patients whose regular follow-up is impossible for psychological, family, social or geographical reasons;
• Legal incapacity or physical, psychological or mental status interfering with the patient's ability to sign the informed consent or to terminate the study;
• Pregnant or breast-feeding subjects

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 11 centers

• Centre Georges François Leclerc — Dijon
• Institut du Cancer de Montpellier — Montpellier
• Centre Eugène Marquis — Rennes
• Institut de Cancérologie de l'Ouest — Saint-Herblain
• Centre Oscar Lambret — Lille
• Centre de radiothérapie Bayard — Villeurbanne
• Centre Henri Becquerel — Rouen
• Institut Sainte Catherine — Avignon
• … and 3 more centers

Publications

• Cabaille M, Khalifa J, Tessier AM, Belhomme S, Crehange G, Sargos P. [A review of adaptive radiotherapy for bladder cancer]. Cancer Radiother. 2021 May;25(3):271-278. doi: 10.1016/j.canrad.2020.08.046. Epub 2021 Jan 2. French. PMID 33402293
• Fahmy O, Khairul-Asri MG, Schubert T, Renninger M, Malek R, Kubler H, Stenzl A, Gakis G. A systematic review and meta-analysis on the oncological long-term outcomes after trimodality therapy and radical cystectomy with or without neoadjuvant chemotherapy for muscle-invasive bladder cancer. Urol Oncol. 2018 Feb;36(2):43-53. doi: 10.1016/j.urolonc.2017.10.002. Epub 2017 Nov 6. PMID 29102254
• Huddart R, Hafeez S, Omar A, Alonzi R, Birtle A, Cheung KC, Choudhury A, Foroudi F, Gribble H, Henry A, Hilman S, Hindson B, Lewis R, Muthukumar D, McLaren DB, McNair H, Nikapota A, Olorunfemi A, Parikh O, Philipps L, Rimmer Y, Syndikus I, Tolentino A, Varughese M, Vassallo-Bonner C, Webster A, Griffin C, Hall E. Acute Toxicity of Hypofractionated and Conventionally Fractionated (Chemo)Radiotherap PMID 37225552
• Hafeez S, Lewis R, Hall E, Huddart R; RAIDER Trial Management Group. Advancing Radiotherapy for Bladder Cancer: Randomised Phase II Trial of Adaptive Image-guided Standard or Dose-escalated Tumour Boost Radiotherapy (RAIDER). Clin Oncol (R Coll Radiol). 2021 Jun;33(6):e251-e256. doi: 10.1016/j.clon.2021.02.012. Epub 2021 Mar 23. No abstract available. PMID 33766502
• Kool R, Dragomir A, Kulkarni GS, Marcq G, Breau RH, Kim M, Busca I, Abdi H, Dawidek M, Uy M, Fervaha G, Cury FL, Alimohamed N, Izawa J, Jeldres C, Rendon R, Shayegan B, Siemens R, Black PC, Kassouf W. Benefit of Neoadjuvant Cisplatin-based Chemotherapy for Invasive Bladder Cancer Patients Treated with Radiation-based Therapy in a Real-world Setting: An Inverse Probability Treatment Weighted Analys PMID 38326142
• Dahl DM, Rodgers JP, Shipley WU, Michaelson MD, Wu CL, Parker W, Jani AB, Cury FL, Hudes RS, Michalski JM, Hartford AC, Song D, Citrin DE, Karrison TG, Sandler HM, Feng FY, Efstathiou JA. Bladder-Preserving Trimodality Treatment for High-Grade T1 Bladder Cancer: Results From Phase II Protocol NRG Oncology/RTOG 0926. J Clin Oncol. 2024 Dec;42(34):4095-4102. doi: 10.1200/JCO.23.02510. Epub 2024 Sep PMID 39226514
• de Haar-Holleman A, van Hoogstraten LMC, Hulshof MCCM, Tascilar M, Bruck K; BlaZIB study group; Meijer RP, Alfred Witjes J, Kiemeney LA, Aben KKH. Chemoradiation for muscle-invasive bladder cancer using 5-fluorouracil versus capecitabine: A nationwide cohort study. Radiother Oncol. 2023 Jun;183:109584. doi: 10.1016/j.radonc.2023.109584. Epub 2023 Mar 1. PMID 36863459
• Hall E, Hussain SA, Porta N, Lewis R, Crundwell M, Jenkins P, Rawlings C, Tremlett J, Sreenivasan T, Wallace J, Syndikus I, Sheehan D, Lydon A, Huddart R, James N; BC2001 Investigators. Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial. Eur Urol. 2022 Sep;82(3):273-279. doi: 10.1016/j.eururo.2022.04.017. Epub 2022 May 14. PMID 35577644

Identifiers

NCT: NCT07043543 · PROICM 2024-02 BLA

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗