Bladder Cancer
Conditions
Keywords
Adaptive radiotherapy, standard radiotherapy, Tri-Modal therapy
Brief summary
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
RADIATIONAdaptive 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 radiotherapy (alternatively : capecitabine taken twice daily at a dose of 825 per square meter per day on the days of radiotherapy)
RADIATIONstandard 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 (alternatively : capecitabine taken twice daily at a dose of 825 per square meter per day on the days of radiotherapy)
Sponsors
Ligue contre le cancer, France
Institut du Cancer de Montpellier - Val d'Aurelle
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| evaluation of the technique of adaptive radiotherapy in terms of acute Gastro-Intestinal toxicity. | from the Day 1 Radiotherapy to 3 months after the last day of Radiotherapy | rate of patients without acute diarrhea grade ≥2 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of all late toxicities | from 3 months after the last day of Radiotherapy to 5 years after the last day of Radiotherapy | description of all late toxicities according to Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0) |
| evaluation of quality of life specific to the cancer disease | 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. | Quality of life will be evaluated using European Organisation for Research and Treatment of Cancer - Quality Life Questionnaire (EORTC QLQ-C30) |
| evaluation of quality of life and of the measurements specific to the treatment of bladder cancer with muscle invasion | 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. | Quality of life will be evaluated using European Organisation for Research and Treatment of Cancer - Quality Life Questionnaire - Bladder Cancer (EORTC QLQ-BLM30) |
| evaluation of quality of life for patient ≥ 70 years old in order to establish a minimum standardized geriatric assessment | 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. | Quality of life will be evaluated using Geriatric COre DatasEt oncogeriatric (GCODE) for patient ≥ 70 years old |
| evaluation of quality of life for patient ≥ 70 years old (Specific to elderly people with cancer) | 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. | Quality of life will be evaluated using European Organisation for Research and Treatment of Cancer - Quality Life Questionnaire-Elderly (EORTC QLQ- ELD30) for patient ≥ 70 years old |
| Evaluation of all acute toxicities | from the Day 1 Radiotherapy to 3 months after the last day of Radiotherapy | description of all acute toxicities according to Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0) |
| assessment of cystectomy free survival | At 3 and 5 years after the last day of Radiotherapy | the time interval from randomization to cystectomy |
| assessment of overall survival | At 3 and 5 years after the last day of Radiotherapy | the time interval from randomization to death from any cause |
| assessment of local control rate | At 3 and 5 years after the last day of Radiotherapy | The presence of non-muscle-invasive or muscle-invasive bladder cancers evaluate by cystoscopy |
| assessment of the dosimetric results | during tthe radiotherapy for both arms | Dosimetric results in terms of treatment volume coverage and Organ At Risk protection |
| evaluation of the impact of the adaptive process on fractions execution | during tthe radiotherapy for both arms | Evaluation of duration of the treatment fractions (in minutes) in the two arms. Evaluation of the percentage of fractions fully delivered and the duration of physician/physicist mobilization for the adaptive process |
| assessment of disease free survival | At 3 and 5 years after the last day of Radiotherapy | time interval from randomization to first carcinologic event as local or distant relapse or death |
Countries
France
Contacts
Primary ContactAurore MOUSSION
Outcome results
None listed