Sequential Chemotherapy Followed by Ultrahypofractionated Radiotherapy for Muscle-Invasive Bladder Cancer

Muscle-invasive bladder cancer (MIBC) is a potentially lethal disease for which radical cystectomy with appropriate systemic therapy remains a standard curative approach in medically fit patients. However, Half of bladder cancer cases are diagnosed in patients aged over 75 years, many of whom are not fit for major surgery owing to their performance status and comorbidities .

A substantial proportion of bladder cancer cases occur in older adults (there is no single universal age cutoff for the term older adults, but several commonly used definitions exist: WHO: generally refers to people aged 60 years or older, particularly in low- and middle-income countries, while in clinical and research settings: ≥65 years is frequently used as the operational definition of older adults, especially in oncology and geriatric medicine), and advanced age is frequently accompanied by comorbidities and frailty that may limit eligibility for radical surgery or multimodality treatment. Bladder-preserving treatment incorporating maximal transurethral resection of bladder tumor (TURBT) and definitive radiotherapy is therefore an important treatment option in selected patients.

Most established bladder-preservation protocols use concurrent chemoradiotherapy. Nevertheless, sequential treatment-systemic chemotherapy followed by definitive radiotherapy-may be attractive in selected patients . Published data support bladder-preserving radiotherapy in older adults, although the literature is heterogeneous and most contemporary series evaluate concurrent rather than purely sequential treatment . In Older adults, concurrent chemoradiotherapy has been associated with improved survival, while hypofractionated bladder radiotherapy schedules have demonstrated acceptable tolerability in selected older populations .

These observations provide the rationale for prospectively evaluating a sequential approach in patients who are not ideal candidates for concurrent chemoradiotherapy. A number of small single-centre studies using the higher biological dose of 30-36 Gy in 6 Gy per fraction suggest acceptable acute and late toxicity with local control achieved in over of 60% patients at 3 months . Prospective multicentre assessment of this radiotherapy schedule has not yet been performed. The proposed study will evaluate the feasibility, efficacy, treatment completion, and toxicity of a sequential strategy in older adults with non-metastatic MIBC.

• Transurethral Resection of Bladder Tumor (Procedure): All patients should undergo maximal safe TURBT before systemic treatment. The objective is maximal tumor debulking while preserving bladder function and obtaining adequate tissue for pathological diagnosis and staging. A second-look TURBT may be considered, especially when the initial resection was incomplete (tumors ≥3 cm, no evaluation of muscle involvement in spite of radiological evidence).
• Sequential Systemic Chemotherapy (Drug): Systemic chemotherapy will be administered before radiotherapy. The preferred regimen should be selected according to renal function, performance status, comorbidities, and multidisciplinary assessment. Suggested protocol options: * Cisplatin-eligible patients: Gemcitabine + cisplatin may be used commonly for 3-4 cycles. * Cisplatin-ineligible patients: Gemcitabine + carboplatin may be considered where appropriate . Radiotherapy should commence after adequate recovery from chemotherapy, provided there is no evidence of progression and the patient remains suitable for local treatment. A practical interval is approximately 3-6 weeks after the final chemotherapy cycle.
• radiotherapy (Radiation): Three-dimensional conformal radiotherapy planning is recommended using three or four fields; however, use of static 5-7-field IMRT or volumetric modulated arc radiotherapy treatment is permitted. Three-dimensional dose distributions will be produced for the overall prescribed dose of 36 Gy in six fractions. The dose distribution will be assessed for coverage of the PTV and normal tissues sparing using appropriate transverse sagittal and coronal views. All plans will be created to ensure that at least 98% of the PTV (PTV D98%) receives >90% (ideally >95%) of the prescribed dose, the median PTV dose (PTV D50%) is within 1% of the prescription dose and the near maximum (PTV D2%) is <107% (ideally <105%) of the prescribed dose. To minimize unexpected high dose outside the PTV, it is required that 1 cm3 of normal tissue outside the PTV should be <110% of the prescribed dose.

Primary outcomes

• Assessment of objective Response rate (ORR) and Disease control rate (DCR) [4-6 weeks after completion of RT]: Evaluate the Clinical efficacy including Objective Response rate (ORR) and Disease control rate (DCR) at 4-6 weeks after finishing RT.
• Assessment of Toxicity of Treatment [Baseline]: Evaluate Toxicity of Treatment using Common Terminology Criteria for Adverse Events (CTCAE V.5)
• Assessment of Toxicity of Treatment [Baseline]: Assessment of treatment-related toxicity according to health-related quality of life using the EQ-5D questionnaire

Secondary outcomes

• Assess the Time to local disease progression [From treatment initiation until the end of the follow up ( 12 months follow up )]: Time from the date of treatment initiation to the date of documented local disease progression
• Assess the Time to EFS [From treatment initiation until progression or death]: Time from the date of treatment initiation to Event free survival

Sex: All, ages: 65 Years to any

Inclusion Criteria:

1. Histologically confirmed urothelial carcinoma of the urinary bladder
2. Muscle-invasive disease, preferably clinical stage cT2-T4a, N0, according to TNM staging system.
3. No evidence of distant metastatic disease (M) .
4. Age ≥65 years including medically unfit patients for radical cystectomy or radical daily radiotherapy for any reason including but not limited to performance status, comorbidity or patient preferance .
5. ECOG performance status 0_ 3.
6. Patients must have undergone maximal safe TURBT, with documentation of detrusor muscle in the specimen whenever technically feasible.
7. _Creatinine clearance (CrCl) ≥30 mL/min for patients receiving a carboplatin-based regimen.

CrCl ≥40 mL/min for patients receiving fractionated cisplatin-based chemotherapy.

8- Eligible patients would have an expected survival of greater than 6 months, be willing to accept assessment with cystoscopy following radiotherapy completion and be able to attend for follow-up

Exclusion Criteria:

1. Nodal disease and distant metastatic disease (M1).
2. Previous radiotherapy to the pelvis or any contraindication for pelvic RT including IBD.
3. Previous systemic chemotherapy for the current MIBC.
4. Uncontrolled active infection, moderate to severe hydronephrosis, invasion of prostatic urethra, diffuse TIS throughout the bladder, tumor size >6 cm.
5. Active or history of other malignancy within 2 years of recruitment except for non-melanomatous skin carcinoma, previous non-muscle invasive bladder tumors and low-risk prostate cancer (as defined by NCCN risk stratification as T1/T2a, Gleason 6, PSA <10) will be excluded.
6. _ Active Hepatitis B and Hepatitis C.