1025-Bladder carcinoma definitive EBRT with or without chemotherapy

An adaptive radiation therapy (ART) treatment approach is an option for this treatment protocol. ART should only be used in centres with the additional quality assurance, training, experience and protocols required to safely deliver this treatment approach. There are various approaches to delivering ART in the published literature. The RAIDER trial is one example and comprehensive information on this trial’s requirements are available here opens in a new tab or window.

Indications and patient population

Muscle-invasive urothelial carcinoma.
T2a–T4a, N0-2, M0.

Patients with increased perioperative mortality and morbidity risk.
Patients medically or technically unsuitable for cystectomy, but suitable for curative intent chemoradiation (optimal approach) or radiation therapy alone.
Patients suitable for cystectomy, but with a preference for bladder preservation.

Ideally haemoglobin level >100g/L, preferably >120 g/L.
Renal function satisfactory for concurrent chemotherapy.

ECOG 0-2.

Cautions

Previous high dose radiation to the pelvis.

Poor urinary and bowel function.

Widespread carcinoma in situ (CIS), multifocal tumours, or gross residual macroscopic disease following a transurethral resection of bladder tumour (TURBT).

When primary cystectomy is possible, consider these factors which increase the risk of local failure following EBRT: ¹^,²^,³^,⁴
- large tumour diameter (>5 cm)
- multifocal bladder tumours
- hydronephrosis
- incomplete TURBT
- widespread CIS component.

Inflammatory bowel disease and/or history of adhesions/bowel obstruction.

Non-rheumatoid collagen vascular disorders.

Cardiac implantable electronic devices (CIEDs).

Indications notes

This treatment is a trimodality bladder preservation approach comprising of a combination of maximal transurethral resection of bladder tumour (TURBT), followed by radiation therapy with concurrent chemotherapy.

Maximal TURBT is recommended prior to commencing radiation therapy. Complete resection is not always possible. Consider proceeding directly to bladder preservation, if macroscopic clearance is not anticipated.

Clinical information

Suitable patients should be considered for salvage surgery in the event of a recurrence or incomplete response.
When attempting bladder preservation, long term surveillance is recommended.
Consider stenting for hydronephrosis prior to radiation treatment.

Timing of chemotherapy

Chemotherapy is used as a radiosensitiser and is administered on the same day as radiation therapy. To minimise the risk of a geographic miss caused by changes in bladder size due to fluid loading or diuretic effects, it is preferred to administer chemotherapy after radiation therapy has been delivered.

Simulation

Simulation	Options	Notes
Position	Supine.
Arm/leg/head/neck/shoulder position	Arms on chest.
Immobilisation and supports	Neck support. Knee supports. Ankle supports. Vacbag (optional).
Organ pre-requisites	Bladder filling as per requirements for target volumes and treatment delivery e.g. bladder empty and bladder partially full. Rectum empty.	As per departmental protocol. To improve bladder size reproducibility, consider: decreased fluid intake prior to simulation and treatment avoiding chemotherapy with fluid loading or diuretic therapy immediately prior to planning and treatment. Note, bladder and rectal volume should be consistent between CT simulation and daily treatment delivery. Refer to eviQ Preparing your bladder and bowel for pelvic radiation therapy patient information sheet.
Contrast	Optional IV/oral/bladder contrast.	As per department protocol. Refer to eviQ Contrast administration resources.
Radiopaque markers	Fiducials (optional).	As per department protocol. Can be used to assist with target volume delineation and image guided radiation therapy.
Bolus	N/A
Other imaging	MRI (optional). PET (optional).
CT acquisition	3D CT.	Scan from L3/L4 to 1.5 cm below ischial tuberosities.
Medications	N/A

Simulation notes

For adaptive radiation therapy, simulation should be based on the relevant adaptive approach e.g. RAIDER protocol opens in a new tab or window.⁵

Dose prescription

Bladder only

Single phase

3DCRT/IMRT/VMAT
Phase	Target area	Dose prescription	Prescription point/ volume	Beam type	Beam energy	Dose/#	Fractions	Scheduling
Phase	Target area	Dose prescription	Prescription point/ volume	Beam type	Beam energy	Dose/#	Fractions	#/day	#/fortnight
1	PTV_Primary	55 Gy	ICRU 50/62/83	Photons	6-18 MV	2.75 Gy	20	1	10
OR
1	PTV_Primary	64 Gy	ICRU 50/62/83	Photons	6-18 MV	2 Gy	32	1	10

Simultaneous integrated boost (SIB)

IMRT/VMAT
Phase	Target area	Dose prescription	Prescription point/ volume	Beam type	Beam energy	Dose/#	Fractions	Scheduling
Phase	Target area	Dose prescription	Prescription point/ volume	Beam type	Beam energy	Dose/#	Fractions	#/day	#/fortnight
SIB	PTV_{Primary_low dose}	46 Gy	ICRU 50/62/83	Photons	6-18 MV	2.3 Gy	20	1	10
SIB	PTV_{Primary_high dose}	55 Gy	ICRU 50/62/83	Photons	6-18 MV	2.75 Gy	20	1	10

Sequential boost

IMRT/VMAT
Phase	Target area	Dose prescription	Prescription point/ volume	Beam type	Beam energy	Dose/#	Fractions	Scheduling
Phase	Target area	Dose prescription	Prescription point/ volume	Beam type	Beam energy	Dose/#	Fractions	#/day	#/fortnight
1	PTV_{Primary_low dose}	50 Gy	ICRU 50/62/83	Photons	6-18 MV	2 Gy	25	1	10
2	PTV_{Primary_high dose}	14 Gy	ICRU 50/62/83	Photons	6-18 MV	2 Gy	7	1	10

Dose escalated

The delivery of dose escalated radiation therapy requires an adaptive radiation therapy (ART) approach.

IMRT/VMAT
Phase	Target area	Dose prescription*	Prescription point/ volume	Beam type	Beam energy	Dose/#	Fractions	Scheduling
Phase	Target area	Dose prescription*	Prescription point/ volume	Beam type	Beam energy	Dose/#	Fractions	#/day	#/fortnight
1	PTV_{Primary_low dose}	52 Gy	ICRU 50/62/83	Photons	6-18 MV	1.63 Gy	32	1	10
1	PTV_{Primary_high dose}	70 Gy	ICRU 50/62/83	Photons	6-18 MV	2.19 Gy	32	1	10
OR
1	PTV_{Primary_low dose}	46 Gy	ICRU 50/62/83	Photons	6-18 MV	2.3 Gy	20	1	10
1	PTV_{Primary_high dose}	60 Gy	ICRU 50/62/83	Photons	6-18 MV	3 Gy	20	1	10

* Acceptable dose variation of ± 5%⁶

Bladder and lymph nodes

While there is currently no high-level evidence, in certain patients with N1-2 disease these lymph node dose prescriptions may be considered.

Simultaneous integrated boost (SIB)

IMRT/VMAT
Phase	Target area	Dose prescription	Prescription point/ volume	Beam type	Beam energy	Dose/#	Fractions	Scheduling
Phase	Target area	Dose prescription	Prescription point/ volume	Beam type	Beam energy	Dose/#	Fractions	#/day	#/fortnight
SIB	PTV_Primary	64 Gy	ICRU 50/62/83	Photons	6-18 MV	2 Gy	32	1	10
	PTV_{Involved_l}_ymph_nodes	60-64 Gy				1.88-2 Gy
	PTV_{Elective_l}_ymph_nodes	52-56 Gy (50 Gy EQD2)				1.63-1.75 Gy

Prescription notes

Treatment delays could impact on local control and should be avoided.⁷

If using a two phase technique, consider:
- planning phase 2 with the bladder full to assist with reducing the small bowel dose
- removing some of the bladder wall (distant from the primary tumour) from the phase 2 volume.⁸

Consider adaptive radiation therapy, particularly in the setting of higher prescription doses.⁹

Dose escalated adaptive radiation therapy has been shown to be feasible and safe.⁶

There are dose prescriptions that use adaptive radiation therapy and do not involve dose escalation. For example prescriptions see RAIDER protocol opens in a new tab or window.

Target volumes

Bladder target volumes

Single dose level

Volume	Description
GTV_Primary	Gross residual disease seen on cystoscopy or identified on imaging (CT, MRI) post-TURBT + gross extra-vesical spread (previous site of tumour if complete TURBT).
CTV_Primary	Whole bladder (including GTV) + 0.5 cm margin on gross extra-vesical extension. *In male pelvis*: For involvement of the bladder neck/trigone the proximal 1 cm of the prostatic urethra should be included in the CTV_Primary. If proximal prostatic urethra biopsies positive then the whole prostatic urethra should be included in the CTV_Primary. If there is involvement at the vesicoureteric junction, consider including 1-2 cm of the distal ureter. In female pelvis: With bladder neck involvement, multiple tumours or CIS, consider including the proximal 1.5-2.0 cm of the urethra. If the anterior vaginal wall is involved, include in the GTV. Any remaining uninvolved anterior vaginal wall to be included in the CTV. For posterior tumours, the anterior vaginal wall can be included in the CTV_Primary. If the vagina is included, consider including the proximal urethra. If there is involvement at the vesicoureteric junction, consider including 1-2 cm of the distal ureter.
PTV_Primary	CTV_Primary with anisotropic margin expansion: Anteriorly, posteriorly and laterally: 1.5-2.0 cm Superiorly: 2.0-2.5 cm Inferiorly: 1.0-1.5 cm (inferior expansion may be reduced to 1.0 cm if the prostate or urethra has been included). Smaller margins may be used if departmental set up error has been appropriately quantified using an image-guided radiation therapy (IGRT) specific anisotropic margin expansion.

Sequential boost or simultaneous integrated boost (SIB)

Boost/reduced volumes should only be used at the site where the primary tumour arose, if the lesion is clearly identified on imaging and/or documented at cystoscopy.⁸

Volume	Description
GTV_{Primary_low dose}	As per single phase GTV above
CTV_{Primary_low dose}	As per single phase CTV above
PTV_{Primary_low dose}	As per single phase CTV above
GTV_{Primary_high dose}	As per single phase GTV above.
CTV_{Primary_high dose}	GTV or site of known tumour + 0.5 cm margin on extra-vesicular extension (EVE) if present.
PTV_{Primary_high dose}	CTV_{Primary_high}_dosewith anisotropic margin expansion: Anteriorly, posteriorly and laterally: 1.5-2.0 cm Superiorly: 2.0-2.5 cm Inferiorly: 1.0-1.5 cm. Smaller margins may be used if departmental set up error has been appropriately quantified using an image-guided radiation therapy (IGRT) specific anisotropic margin expansion.

Lymph node target volumes

Involved nodes

Volume	Description
GTV_{Involved_}_{lymph nodes}	Any involved nodes
CTV_{Involved_}_{lymph nodes}	GTV_{Involved_}_{lymph nodes} + 0.5-1.0 cm margin (cropped to anatomical boundaries).¹⁰^,¹¹
PTV_{Involved_}_{lymph nodes}	CTV_{Involved_}_{lymph nodes} + 0.5-1 cm. As per department protocol.

Elective lymph nodes

Volume	Description
CTV_{Elective_}_{lymph nodes}	Includes the following nodal areas: pre-sacral chain external iliac nodes internal iliac nodes, including the obturator nodes.
PTV_{Elective_}_{lymph nodes}	CTV_{Elective_}_{lymph nodes} + 0.5-1 cm. As per department protocol.

Margin ranges have been agreed by the Radiation Oncology reference committee and reflect safe clinical practice.

Adaptive radiation therapy

Target volumes should be based on the relevant adaptive approach e.g RAIDER protocol opens in a new tab or window.

Target volume notes

Due to variable bladder filling and the potential for geographical miss, lesions positioned in the dome of the bladder should be treated using a single phased approach. The two-phased approach may be suitable in cases where the tumour is well-lateralised or situated over the trigone, with good evidence of absence of CIS away from the index lesion.

Target volume guides

FROGG consensus guidelines for muscle invasive bladder cancer.⁸

Taylor et al. 2007 provide guidelines for defining nodal regions in the pelvis.¹²

Organs at risk

Organ	Constraints		Additional information
Organ	20 fractions	32 fractions	Additional information
Small bowel	ALARA⁸	ALARA⁸	Be aware of location of small bowel when determining volumes. Consider the presence of overlap between the small bowel and the treatment PTV.⁸ Avoid dosimetric hotspots in loops of small bowel.⁸
Rectum	V44 Gy <50%⁸	V50 Gy <50%⁸	The outer wall of the rectum is contoured superiorly from the recto-sigmoid junction (where the rectum turns horizontally into the sigmoid, usually at the caudal border of the sacro-iliac joint) to 1.5 cm caudal to the inferior border of the CTV. Superiorly, the anorectal contour should extend at least 0.5 cm beyond the proximal margin of the PTV.
Femoral Heads	V44 Gy <10%⁸	V50 Gy <10%⁸	Femurs are contoured from the acetabulum to the inferior field borders.

Adaptive radiation therapy

Table 2: Summary of organ at risk dose constraints guide for 32 and 20 fraction cohorts - RAIDER trial.

Target verification

Modality	Frequency	Match point
CBCT.	Daily.	Soft tissue.

Target verification recommendations reflect the minimum imaging required for the safe delivery of this protocol.

Adaptive radiation therapy

Target verification should be based on the relevant adaptive approach. The RAIDER protocol opens in a new tab or window is an example.

Side effects

The side effects listed below are not a complete list of all possible side effects for this treatment and should only be used as a guide.

Acute: Short term side effects during or within a few weeks post radiation therapy (usually temporary)
Fatigue	Read more about fatigue.
Irritative or obstructive urinary symptoms	Bladder spasms, dysuria, nocturia, frequency, incontinence, urgency, retention.
Proctitis	Including diarrhoea, increased bowel frequency, rectal urgency, pain and bleeding. Read more about proctitis. Read more about treatment induced diarrhoea.
Enteritis	Abdominal discomfort.
Sexual function	Sexual and erectile dysfunction. Vaginitis, vaginal mucositis, dyspareunia/stenosis. Read more about vaginal dryness. Read more about vaginal stenosis.

Late: Long term side effects - months to years post radiation therapy (may be permanent)
Fatigue	Read more about fatigue.
Cystitis/urethritis	Includes haematuria. Read more about cystitis.
Urinary incontinence
Bladder dysfunction	Rarely need for temporary or permanent catheterisation.
Bowel toxicity	Including stricture, obstruction, bleeding, diarrhoea, fistula and perforation. Read more about treatment induced diarrhoea.
Radiation induced small bowel obstruction	Rare.
Proctitis	Read more about proctitis.
Faecal incontinence
Radiation induced rectourethral fistulas	Rare.
Rectovaginal/vesicovaginal fistula
Lymphoedema	Read more about lymphoedema.
Sexual function	Including erectile dysfunction, impotence, dry and/or painful ejaculation, haematospermia and reduction in ejaculate. Patients should be offered sexual counselling to manage potential late effects related to sexual function. Vaginitis, vaginal mucositis, dyspareunia/stenosis. Read more about vaginal dryness. Read more about vaginal stenosis.
Premature ovarian failure/menopause	If ovaries present. Read more about fertility preservation for people with cancer opens in a new tab or window.
Impaired fertility or infertility	Fertility preservation should be discussed prior to commencement of treatment. Read more about fertility preservation for people with cancer opens in a new tab or window.
Second malignancy

Evidence

Source	Study & year published	Supports use Yes/No/NA	Is the radiation dose and fractionation consistent with the protocol?	Comments
Meta-analysis	Choudhury et al. 2021¹³	Yes	Yes	An individual patient data meta-analysis of the BCT2001 and BCON randomised controlled trials demonstrated that delivering 55 Gy in 20 fractions is non-inferior to 64 Gy in 32 fractions in terms of invasive locoregional control and toxicity and superior regarding invasive locoregional control.
Phase III trials	James et al. 2012¹⁴	Yes	Yes	Randomised patients to radiation therapy alone or chemoradiation with mitomycin and 5FU.
Phase II trials	RAIDER Huddart et al. 2025⁶	Yes	Yes	Shows safety and feasibility of dose escalated adaptive radiation therapy (ART) for bladder cancer.
	Mak et al. 2014⁴	Yes	No	Combined analysis of five phase II studies and one phase III study. Phase 1 treatment included radiation therapy to approximately 40 Gy, then re-staged patients with cystoscopy before proceeding to either cystectomy (non-complete response) or phase 2 consolidative radiation therapy up to 64 Gy (if complete response).
	Gogna et al. 2006¹⁵	Yes	Yes	Establishes tolerability and efficacy of radiation therapy with weekly cisplatin.
Case series	Shipley et al. 2002² and Efstathiou et al. 2012¹⁶	Yes	Total dose approximately 64 Gy if proceeded to consolidative radiation therapy after check cystoscopy.	Phase 1 treatment: radiation therapy to 40 Gy then reassess response.
Guidelines	Date published/revised	Supports use Yes/No/NA	Is the dose and regimen consistent with the protocol?	Comments
FROGG	Cardoso et al. 2020⁸	Yes	Yes
NCCN	V4. 2024¹⁷	Yes	Yes
ASCO	Milowsky et al. 2016¹⁸	Yes	Does not specify radiation dose, but endorses combined modality treatment as described in the EAU guidelines.
European Association of Urology (EAU)	Witjes et al. 2014¹⁹	Yes	No Suggests 60–66 Gy followed by a further tumour boost.

Efficacy

Chemoradiation vs radiation therapy alone

The key evidence supporting this protocol is from a phase III trial by James et al. (n = 360).¹⁴ Patients with muscle-invasive bladder cancer, cT2-T4a, N0, M0, were randomised to receive chemoradiation or radiation therapy alone. Chemotherapy involved fluorouracil infusion and mitomycin, with one-third of patients in each arm receiving discretionary neoadjuvant chemotherapy. Radiation therapy was 64 Gy in 32 fractions or 55 Gy in 20 fractions. At a median follow-up of 70 months, the 2-year recurrence-free rate was 67% in the chemoradiation arm versus 54% in the radiation therapy alone arm (HR = 0.68, 95% CI:0.48-0.96, p = 0.03). Five-year overall survival rates were 48% with chemoradiation arm versus 35% with radiation alone (HR = 0.82, 95% CI:0.63-1.09, p = 0.16). A trend towards reduced cystectomy rates of 11.4% versus 16.8% (p = 0.07) at 2 years was observed in the chemotherapy arm. The findings suggest this chemoradiation schedule is an alternative option to cisplatin.

Fig 1. Kaplan-Meier analysis of survival over 72 months of follow-up

(A) locoregional disease-free survival; (B) invasive locoregional disease-free survival; (C) overall survival p-values were calculated by log-rank test stratified according to the randomisation group.

Radical cystectomy vs trimodality bladder preservation

No randomised trials comparing radical cystectomy versus trimodality bladder preservation have been completed. Several non-randomised prospective and retrospective studies of combined modality treatment have confirmed survival outcomes comparable to cystectomy alone.²^,³^,¹⁵ Most studies of combined modality treatment report 5-year survival rates of 50-60%.³^,¹⁴^,²⁰

Gogna et al. 2006 reported the combined analysis of two successive phase II trials of chemoradiation utilising weekly cisplatin (TROG 97.01 and TROG 99.06).¹⁵ In TROG 99.06, 43 patients received 64 Gy in 32 fractions with weekly cisplatin 35 mg/m². Completion of the planned treatment protocol with minor deviations was 80% (40 out of 43 patients). The complete response rate at 6 months post-radiation therapy completion was 70%. The local control rate (free of both superficial and invasive recurrence) at 5 years was 45%. At 5 years, 61% had retained a functional bladder. Within 12 months, 13% of patients had salvage surgery, of which 8% was for progressive/persistent or recurrent disease.

Mak et al. 2014 published a combined analysis of six successive multimodality RTOG trials 468 patients in total; one phase III trial and five phase II trials.⁴ In principle, these studies offered induction chemoradiation followed by re-staging cystoscopy, and then proceeded to immediate cystectomy if a complete response was not achieved, or onto completion of chemoradiation if a complete response was achieved (total dose of approximately 64 Gy). However, a diverse range of radiation therapy and chemotherapy schedules were used. The complete response rate to induction chemoradiation was 69%. At a median follow-up of 4.3 years, 5-year overall survival was 57%, disease-specific survival was 71%, local failure rate was 43%, and intact bladder rate was 80%. The 10-year outcomes are presented in table 2. Of the 100 patients who underwent cystectomy, 62% were for incomplete response to induction, and 36% for salvage after delayed recurrence (5-year survival for this group was 45%).

Table 1. Pooled Long-Term Outcomes

Fig 2. Kaplan-Meier analysis of overall and disease-specific survival

(A) Overall survival in all patients; (E) Disease-specific survival in patients with a complete response after combined-modality therapy compared with patients who were non-responders.

Hypofractionation

An individual patient data meta-analysis by Choudhury et al. (2021) of two randomised controlled trials (RCT), BCT2001 and BCON analysed locoregional control and toxicity between two fractionation schedules: 64 Gy in 32 fractions over 6.5 weeks or 55 Gy in 20 fractions over 4 weeks (hypofractionation).¹³

In the meta-analysis, individual data from a total of 782 patients enrolled in either the BCT2001 or BCON trials were analysed. BCT2001 was an RCT with a two-by-two factorial design comparing radiation therapy alone versus chemoradiation therapy, as well as standard whole-bladder radiation therapy versus reduced high-dose radiation therapy with tumour boost. BCON compared whole-bladder radiation therapy with or without hypoxia modification (carbogen and nicotinamide).²¹

Co-primary endpoints at three years were the rate of control of invasive locoregional recurrence (defined as invasive bladder recurrence or recurrence in pelvic nodes) and late rectum or bladder toxicity.

The meta-analysis demonstrated non-inferiority of the hypofractionated schedule (55 Gy in 20 fractions) compared to the 64 Gy in 32 fractions schedule in terms of invasive locoregional control and toxicity. Additionally, the hypofractionated schedule was reported to be superior for invasive locoregional control, with patients receiving the hypofractionated schedule having a lower risk of invasive locoregional recurrence (adjusted hazard ratio [HR] 0.71 [95% CI 0.52–0.96]). No significant differences were observed in late toxicity between the fractionation regimens (adjusted risk difference [RD] –3.37% [95% CI –11.85 to 5.10]).

The analysis was limited in assessing acute toxicities due to differences in data collection between the two trials. Data from the BCT2001 trial suggested worse health-related quality of life (HRQOL) at treatment completion with the hypofractionated schedule; however, this did not result in excess treatment interruptions. After six months, no differences in HRQOL were observed between the two fractionation schedules.

Based on this analysis, the authors recommended adopting the hypofractionation schedule as a standard of care for these patients. However, they acknowledged limitations, including differing primary RCT endpoints, variations in data collection (particularly toxicity data), and the fact that the meta-analysis was not pre-planned. Fractionation schedules were also driven by institutional policies rather than randomisation. Given these limitations and the unlikelihood of a future randomised trial on fractionation, the authors noted that hypofractionated radiation therapy offers advantages in terms of patient preference, logistics, and health resource utilisation.

Pelvic nodal irradiation

Conformal radiation therapy techniques are allowing re-evaluation of tolerance, toxicity and efficacy of pelvic nodal irradiation. This is in the context of treating elective pelvic nodes or node positive disease at diagnosis, and of newer chemotherapy regimens. Pathological nodal involvement is reported in approximately 25% of patients who undergo cystectomy and lymph node dissection.⁸ In studies of bladder only chemoradiation trials, pelvic nodal relapse rates of 5.5% have been reported.¹⁴^,¹⁵ A randomised single institution trial which compared chemoradiation to the bladder alone versus whole pelvis plus bladder boost, showed no significant difference in rates of bladder preservation, locoregional recurrence, disease-free survival, or overall survival, and a rate of nodal recurrence of 15% in both arms.²² For clinically node negative patients, elective nodal irradiation increases toxicity and there is no evidence that elective nodal irradiation improves outcomes.²²

Intrafraction bladder filling

A study by Mangar et al. identified that in the 20 minute period it takes to set-up and deliver a radiation fraction, the bladder filling was 0.16ml/min in a linear fashion for the first 150 ml, indicating that a CTV to PTV expansion of 1.5 cm would account for approximately 95% of bladder expansion and location.²³

Adaptive Radiation Therapy

The principle of bladder adaptive radiation therapy (ART) is to account for daily variation in bladder volume. Immediately following pre-treatment imaging and assessment, a 'plan of the day' is selected from a library of plans and used for treatment. Review of ART practices by Kibrom et al. indicates a number of techniques being trialled including online/off-line imaging, 'plan of the day', or daily re-planned/optimised techniques.²⁴ While ART has merit and can be considered at sites with relevant training, experience and protocols, it remains to be determined whether it is applicable to all radiation oncology centres, taking into account varying resources, staffing and skill sets. These challenges have been evaluated in the TROG 10.01 BOLART feasibility study, which demonstrated both the applicability and challenges in the execution of a bladder ART program.²⁵

RAIDER (Radiotherapy and Imaging with Dose Escalation for Bladder Cancer) was an international multicentre, multi-arm, two-stage, phase 2 parallel cohort randomised trial of adaptive, dose-escalated, tumour-focused radiation therapy.²⁶ It was conducted by the Institute of Cancer Research (ICR) internationally and the Trans-Tasman Radiation Oncology Group (TROG) in Australia and New Zealand. The trial aimed to investigate the feasibility of ART, minimise excess toxicity from a dose-escalated treatment approach, and provide initial efficacy data. The investigators hypothesised that improved targeting could enable focusing the full dose of radiation therapy on the gross tumour, reduce margins, and maximise bladder sparing by treating with a full bladder, thereby reducing toxicity. This mitigation of toxicity could allow for routine dose escalation and potentially improve tumour control.

In this phase 2 trial, 345 patients with T2-T4aN0M0 unifocal muscle-invasive bladder cancer (MIBC) were randomised (1:1:2) to receive either standard whole-bladder single-plan radiation therapy (WBRT), standard-dose adaptive tumour-focused radiation therapy (SART), or dose-escalated adaptive tumour-focused radiation therapy (DART). The doses for WBRT and SART were 55 Gy in 20 fractions or 64 Gy in 32 fractions, while the doses for DART were 60 Gy in 20 fractions or 70 Gy in 32 fractions. Patients receiving SART or DART had three treatment plans prepared (small, medium, and large) to account for daily variations in bladder size. A pre-treatment cone beam computed tomography (CBCT) scan was acquired before each treatment fraction. This was reviewed in real-time, and the smallest plan that provided coverage of the planning target volumes (PTV) was selected for treatment on that fraction.

The radiation therapy planning and delivery protocol includes details on the treatment approach and quality assurance requirements and is available here opens in a new tab or window.

The recently published results of this trial reported the two-year locoregional disease control rates for WBRT, SART, and DART as 66%, 66%, and 74%, respectively. The two-year bladder-intact event-free survival estimates were 67% for WBRT and SART, and 72% for DART. The study reported a low salvage cystectomy rate and overall survival rates comparable to those observed in patients undergoing cystectomy.

Additionally, the results indicated that toxicity rates for grades ≥2 and ≥3 were low in both adaptive radiation therapy groups. Refer Table 2.

Table 2. Any grade ≥3 treatment-emergent radiotherapy-related, any grade ≥3 treatment-emergent, and any grade ≥2 treatment-emergent CTCAE toxicity (occurring 6–18 months after completing radiotherapy) in the evaluable patient population

Overall, RAIDER showed that despite dose escalation, toxicity was limited, and that DART is both feasible and safe to deliver. The study supports the need for adaptive approaches to bladder radiation therapy to optimise target coverage, with most participants having received treatment with all three plans. The authors also noted for wide-spread introduction there is a need for clear guidelines and ongoing quality assurance (QA) of this treatment approach.

Toxicity

A summary of the most clinically significant toxicities associated with this protocol are included in the table below:

Toxicity	Study/Year	Incidence of event or %	Comment
Acute
Genitourinary: Grade 2	Gogna et al. 2006¹⁵ *Huddart et al. 2013²⁷	43.0% 30.3 %
Genitourinary: Grade >3	Gogna et al. 2006¹⁵ Huddart et al. 2013²⁷ James et al. 2012¹⁴	23.0% 16.6% 21.4%
Gastrointestinal Grade 2	Gogna et al. 2006¹⁵ Huddart et al. 2013²⁷	35.0% 27.0%
Gastrointestinal Grade ≥ 3	Huddart et al. 2013²⁷ James et al. 2012¹⁴	3.8% 2.7-9.6%
Late
Genitourinary: Grade 2	Gogna et al. 2006¹⁵	27%
Genitourinary: Grade ≥ 3 (RTOG/EORTC)	Gogna et al. 2006¹⁵ Huddart et al. 2013²⁷ James et al. 2012¹⁴	4.0%^§ 11.8% 1.3-3.3%
Cystectomy for late GU toxicity	Gogna et al. 2006¹⁵ Huddart et al. 2013²⁷ James et al. 2012¹⁴	0% <1% 1.2%	As a percentage of all patients who received radiation therapy.
Gastrointestinal: Grade 2 (RTOG/EORTC)	Gogna et al. 2006¹⁵ Huddart et al. 2013²⁷	3.5% 3.9%^#
Gastrointestinal: Grade >3 (RTOG/EORTC)	Gogna et al. 2006¹⁵ Huddart et al. 2013²⁷ James et al. 2012¹⁴	2 % 3.3%^# 0%

* Data from Huddart et al. for all patients combined.²⁷
^§ In all cases of grade 3 or 4 genitourinary toxicity, the patient was later found to have persistent/recurrent superficial or invasive disease and subsequently underwent salvage cystectomy.
^# Incidence of late-toxicity reported at any time during follow-up

In the James trial, there was a small increase in acute grade 3 or > grade 3 toxicity for those receiving chemoradiation, compared to radiation alone (36.0% versus 27.5%, p=0.07).¹⁴ This difference was primarily due to a significant increase in gastrointestinal toxicity in the chemoradiation group (9.6% versus 2.7%, p=0.007). There was no significant difference in late toxicity or bladder volume between the two groups.

To date, there is no evidence that using a reduced high dose volume reduces toxicity. The combined analysis of both phase II TROG studies found no difference in acute toxicity for those who received the full dose to the bladder, compared with the cone down boost.¹⁵ The larger randomised trial by Huddart et al. also found no difference in acute or late toxicity when comparing a reduced volume high dose boost compared to a single phase whole bladder technique.²⁷

References References

1: Milosevic, M., M. Gospodarowicz, A. Zietman, et al. 2007. "Radiotherapy for bladder cancer." Urology 69(1 Suppl):80-92.

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The radiotherapy panel met to develop international consensus about the optimal use of radiotherapy, alone or in combination with surgery and chemotherapy, in the radical treatment of patients with bladder cancer. A consensus meeting of experts in the treatment of bladder cancer was convened by the Societe Internationale d'Urologie (SIU). The radiotherapy committee, which had international representation from 6 countries, performed a critical review of the English-language literature and developed evidence-based guidelines for the use of radiotherapy in the treatment of patients with bladder cancer. The strength of the evidence supporting each recommendation was ranked according to a 4-point scale. Consensus statements were developed that address (1) the effectiveness of radiotherapy in the treatment of bladder cancer, (2) the most appropriate patients for curative treatment with radiotherapy, (3) the optimal method of delivery of radiotherapy, (4) the best radiation prescription for treating bladder cancer, and (5) optimal management of the patient's condition after radiotherapy has been provided. Radiotherapy is effective treatment for selected patients with bladder cancer; it produces long-term disease control with preservation of normal bladder function. Modern radiotherapy treatment techniques offer the potential to improve cure rates and reduce adverse effects. All patients in whom the condition is newly diagnosed should be assessed in a multidisciplinary setting, where the relative merits of surgery, radiotherapy, and chemotherapy can be considered on an individual basis with the aim of optimizing overall outcomes.
2: Shipley, W. U., D. S. Kaufman, E. Zehr, et al. 2002. "Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer." Urology 60(1):62-67; discussion 67-68.

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OBJECTIVES: To evaluate the outcomes of patients with muscle-invasive Stage T2-4a bladder carcinoma managed by transurethral surgery and concurrent chemoradiation. METHODS: A total of 190 patients were treated on institutional prospective protocols using concurrent cisplatin-containing chemotherapy and radiotherapy after rigorous transurethral resection of the bladder tumor. Patients were re-evaluated by repeated biopsy and urine cytologic analysis after 40 Gy, with the initial tumor response guiding subsequent therapy. One hundred twenty-one patients with a complete response by cytologic and histologic examination and those medically unfit for cystectomy received boost chemoradiation to 64 to 65 Gy. Those patients without a complete response were advised to undergo radical cystectomy. A total of 66 patients (35%) ultimately underwent radical cystectomy; 41 for less than a complete response and an additional 25 for recurrent invasive tumors. The median follow-up was 6.7 years for all surviving patients. RESULTS: The 5 and 10-year actuarial overall survival rate was 54% and 36%, respectively (Stage T2, 62% and 41%; Stage T3-T4a, 47% and 31%, respectively). The 5 and 10-year disease-specific survival rate was 63% and 59% (Stage T2, 74% and 66%; Stage T3-T4a, 53% and 52%), respectively. The 5 and 10-year disease-specific survival rate for patients with an intact bladder was 46% and 45% (Stage T2, 57% and 50%; Stage T3-T4a, 35% and 34%), respectively. The pelvic failure rate was 8.4%. No patient required cystectomy because of bladder morbidity. CONCLUSIONS: The 10-year overall survival and disease-specific survival rates are comparable with the results reported for contemporary radical cystectomy for patients of similar clinical and pathologic stage. One third of patients treated on protocol with the goal of bladder sparing ultimately required a cystectomy. A trimodality approach with bladder preservation based on the initial tumor response is, therefore, safe, with most long-term survivors retaining functional bladders.
3: Rodel, C., G. G. Grabenbauer, R. Kuhn, et al. 2002. "Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results." J Clin Oncol 20(14):3061-3071.

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PURPOSE: To evaluate our long-term experience with combined modality treatment and selective bladder preservation and to identify factors that may predict treatment response, risk of relapse, and survival. PATIENTS AND METHODS: Between 1982 and 2000, 415 patients with bladder cancer (high-risk T1, n = 89; T2 to T4, n = 326) were treated with radiotherapy (RT; n = 126) or radiochemotherapy (RCT; n = 289) after transurethral resection (TUR) of the tumor. Six weeks after RT/RCT, response was evaluated by restaging-TUR. In case of complete response (CR), patients were observed at regular intervals. In case of persistent or recurrent invasive tumor, salvage-cystectomy was recommended. Median follow-up was 60 months (range, 6 to 199 months). RESULTS: CR was achieved in 72% of patients. Local control after CR without muscle-invasive relapse was maintained in 64% of patients at 10 years. Distant metastases were diagnosed in 98 patients with an actuarial rate of 35% at 10 years. Ten-year disease-specific survival was 42%, and more than 80% of survivors preserved their bladder. Early tumor stage and a complete TUR were the most important factors predicting CR and survival. RCT was more effective than RT alone in terms of CR and survival. Salvage cystectomy for local failure was associated with a 45% disease-specific survival rate at 10 years. Cystectomy because of a contracted bladder was restricted to 2% of patients. CONCLUSION: TUR with RCT is a reasonable option for patients seeking an alternative to radical cystectomy. Ideal candidates are those with early-stage and unifocal tumors, in whom a complete TUR is accomplished.
4: Mak, R. H., D. Hunt, W. U. Shipley, et al. 2014. "Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233." J Clin Oncol 32(34):3801-3809.

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PURPOSE: Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder cancer (MIBC), reserving cystectomy for salvage treatment. We performed a pooled analysis of long-term outcomes in patients with MIBC enrolled across multiple studies. PATIENTS AND METHODS: Four hundred sixty-eight patients with MIBC were enrolled onto six RTOG bladder-preservation studies, including five phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903). Overall survival (OS) was estimated using the Kaplan-Meier method, and disease-specific survival (DSS), muscle-invasive and non-muscle-invasive local failure (LF), and distant metastasis (DM) were estimated by the cumulative incidence method. RESULTS: The median age of patients was 66 years (range, 34 to 93 years), and clinical T stage was T2 in 61%, T3 in 35%, and T4a in 4% of patients. Complete response to CMT was documented in 69% of patients. With a median follow-up of 4.3 years among all patients and 7.8 years among survivors (n = 205), the 5- and 10-year OS rates were 57% and 36%, respectively, and the 5- and 10-year DSS rates were 71% and 65%, respectively. The 5- and 10-year estimates of muscle-invasive LF, non-muscle-invasive LF, and DM were 13% and 14%, 31% and 36%, and 31% and 35%, respectively. CONCLUSION: This pooled analysis of multicenter, prospective RTOG bladder-preserving CMT protocols demonstrates long-term DSS comparable to modern immediate cystectomy studies, for patients with similarly staged MIBC. Given the low incidence of late recurrences with long-term follow-up, CMT can be considered as an alternative to radical cystectomy, especially in elderly patients not well suited for surgery.
5: Hafeez, S., A. Webster, V. N. Hansen, et al. 2020. "Protocol for tumour-focused dose-escalated adaptive radiotherapy for the radical treatment of bladder cancer in a multicentre phase II randomised controlled trial (RAIDER): radiotherapy planning and delivery guidance." BMJ Open 10(12):e041005.

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Abstract

Introduction Daily radiotherapy delivered with radiosensitisation offers patients with muscle invasive bladder cancer (MIBC) comparable outcomes to cystectomy with functional organ preservation. Most recurrences following radiotherapy occur within the bladder. Increasing the delivered radiotherapy dose to the tumour may further improve local control. Developments in image-guided radiotherapy have allowed bladder tumour-focused ‘plan of the day’ radiotherapy delivery. We aim to test within a randomised multicentre phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity.

Methods and analysis Patients with T2-T4aN0M0 unifocal MIBC will be randomised (1:1:2) between standard/control whole bladder single plan radiotherapy, standard dose adaptive tumour-focused radiotherapy or dose-escalated adaptive tumour-focused radiotherapy (DART). Adaptive tumour-focused radiotherapy will use a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment will be used to visualise the anatomy and inform selection of the most appropriate plan for treatment.

Two radiotherapy fractionation schedules (32f and 20f) are permitted. A minimum of 120 participants will be randomised in each fractionation cohort (to ensure 57 evaluable DART patients per cohort).

A comprehensive radiotherapy quality assurance programme including pretrial and on-trial components is instituted to ensure standardisation of radiotherapy planning and delivery.

The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late Common Terminology Criteria for Adverse Events grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes.
6: Huddart, R., S. Hafeez, C. Griffin, et al. 2025. "Dose-escalated Adaptive Radiotherapy for Bladder Cancer: Results of the Phase 2 RAIDER Randomised Controlled Trial." Eur Urol 87(1):60-70.

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Abstract

Background and objective: Delivering radiotherapy to the bladder is challenging as it is a mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule.

Methods: RAIDER is an international phase 2 noncomparative randomised controlled trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary endpoint was the proportion of patients with radiotherapy-related late Common Terminology Criteria for Adverse Events grade ≥3 toxicity; the trial was designed to rule out >20% toxicity with DART.

Key findings and limitations: A total of 345 patients were randomised between October 2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52% had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants planned for DART met the mandatory medium plan dose constraints. Radiotherapy-related grade ≥3 toxicity was reported in one of 58 patients (90% confidence interval [CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall survival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage cystectomy.

Conclusions and clinical implications: Grade ≥3 late toxicity was low. DART was safe and feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are promising for dose-escalated treatments, with a low salvage cystectomy rate and overall survival similar to that seen in cystectomy cohorts.

Keywords: Adaptive radiotherapy; Image-guided radiotherapy; Muscle-invasive bladder cancer; Radiotherapy; Randomised controlled trial.
7: Moonen, L., H. vd Voet, R. de Nijs, et al. 1998. "Muscle-invasive bladder cancer treated with external beam radiation: influence of total dose, overall treatment time, and treatment interruption on local control." Int J Radiat Oncol Biol Phys 42(3):525-530.

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PURPOSE: To evaluate and eventually quantify a possible influence of tumor proliferation during the external radiation course on local control in muscle invasive bladder cancer. METHODS AND MATERIALS: The influence of total dose, overall treatment time, and treatment interruption has retrospectively been analyzed in a series of 379 patients with nonmetastasized, muscle-invasive transitional cell carcinoma of the urinary bladder. All patients received external beam radiotherapy at the Netherlands Cancer Institute between 1977 and 1990. Total dose varied between 50 and 75 Gy with a mean of 60.5 Gy and a median of 60.4 Gy. Overall treatment time varied between 20 and 270 days with a mean of 49 days and a median of 41 days. Number of fractions varied between 17 and 36 with a mean of 27 and a median of 26. Two hundred and fourty-four patients had a continuous radiation course, whereas 135 had an intended split course or an unintended treatment interruption. Median follow-up was 22 months for all patients and 82 months for the 30 patients still alive at last follow-up. A stepwise procedure using proportional hazard regression has been used to identify prognostic treatment factors with respect to local recurrence as sole first recurrence. RESULTS: One hundred and thirty-six patients experienced a local recurrence and 120 of these occurred before regional or distant metastases. The actuarial local control rate was 40.3% at 5 years and 32.3% at 10 years. In a multivariate analysis total dose showed a significant association with local control (p = 0.0039), however in a markedly nonlinear way. In fact only those patients treated with a dose below 57.5 Gy had a significant higher bladder relapse rate, whereas no difference in relapse rate was found among patients treated with doses above 57.5 Gy. This remained the case even after adjustment for overall treatment time and all significant tumor and patient characteristics. The Normalized Tumor Dose (NTD) (alpha/beta = 10) and NTD (alpha/beta = 15) were not significantly related to local control (p = 0.96 and p = 0.053, respectively). Only weak evidence was found for an association between local control and overall treatment time (p = 0.067). No difference in bladder relapse rate was found among patients treated with a continuous course and patients who had treatment interruptions (p = 0.099). Neither the length of the interruption, nor the actual number of treatment days has a significant influence on local control (p = 0.04 and p = 0.09, respectively). CONCLUSION: In contrast to two earlier, but smaller reports, in this study no significant effect of treatment prolongation on outcome after radiotherapy could be demonstrated and thus no support was found for an important role for tumor proliferation as the cause of treatment failure in muscle-invasive bladder cancer. Results of large-sized phase III trials will have to be awaited to show any benefit from reduction of the overall treatment time and to quantify the potential effect of tumor proliferation.
8: Cardoso, M., A. Choudhury, D. Christie, et al. 2020 "FROGG patterns of practice survey and consensus recommendations on radiation therapy for muscle invasive bladder cancer". J Med Imaging Radiat Oncol. Vol 64(6):882-893.

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9: Hafeez, S., F. McDonald, S. Lalondrelle, et al. 2017. "Clinical Outcomes of Image Guided Adaptive Hypofractionated Weekly Radiation Therapy for Bladder Cancer in Patients Unsuitable for Radical Treatment." Int J Radiat Oncol Biol Phys 98(1):115-122.

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PURPOSE AND OBJECTIVES: We report on the clinical outcomes of a phase 2 study assessing image guided hypofractionated weekly radiation therapy in bladder cancer patients unsuitable for radical treatment. METHODS AND MATERIALS: Fifty-five patients with T2-T4aNx-2M0-1 bladder cancer not suitable for cystectomy or daily radiation therapy treatment were recruited. A "plan of the day" radiation therapy approach was used, treating the whole (empty) bladder to 36 Gy in 6 weekly fractions. Acute toxicity was assessed weekly during radiation therapy, at 6 and 12 weeks using the Common Terminology Criteria for Adverse Events version 3.0. Late toxicity was assessed at 6 months and 12 months using Radiation Therapy Oncology Group grading. Cystoscopy was used to assess local control at 3 months. Cumulative incidence function was used to determine local progression at 1 at 2 years. Death without local progression was treated as a competing risk. Overall survival was estimated using the Kaplan-Meier method. RESULTS: Median age was 86 years (range, 68-97 years). Eighty-seven percent of patients completed their prescribed course of radiation therapy. Genitourinary and gastrointestinal grade 3 acute toxicity was seen in 18% (10/55) and 4% (2/55) of patients, respectively. No grade 4 genitourinary or gastrointestinal toxicity was seen. Grade ≥3 late toxicity (any) at 6 and 12 months was seen in 6.5% (2/31) and 4.3% (1/23) of patients, respectively. Local control after radiation therapy was 92% of assessed patients (60% total population). Cumulative incidence of local progression at 1 year and 2 years for all patients was 7% (95% confidence interval [CI] 2%-17%) and 17% (95% CI 8%-29%), respectively. Overall survival at 1 year was 63% (95% CI 48%-74%). CONCLUSION: Hypofractionated radiation therapy delivered weekly with a plan of the day approach offers good local control with acceptable toxicity in a patient population not suitable for radical bladder treatment.
10: Baumann, B. C., W. R. Bosch, A. Bahl, et al. 2016. "Development and Validation of Consensus Contouring Guidelines for Adjuvant Radiation Therapy for Bladder Cancer After Radical Cystectomy." Int J Radiat Oncol Biol Phys 96(1):78-86.

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PURPOSE: To develop multi-institutional consensus clinical target volumes (CTVs) and organs at risk (OARs) for male and female bladder cancer patients undergoing adjuvant radiation therapy (RT) in clinical trials. METHODS AND MATERIALS: We convened a multidisciplinary group of bladder cancer specialists from 15 centers and 5 countries. Six radiation oncologists and 7 urologists participated in the development of the initial contours. The group proposed initial language for the CTVs and OARs, and each radiation oncologist contoured them on computed tomography scans of a male and female cystectomy patient with input from >/=1 urologist. On the basis of the initial contouring, the group updated its CTV and OAR descriptions. The cystectomy bed, the area of greatest controversy, was contoured by another 6 radiation oncologists, and the cystectomy bed contouring language was again updated. To determine whether the revised language produced consistent contours, CTVs and OARs were redrawn by 6 additional radiation oncologists. We evaluated their contours for level of agreement using the Landis-Koch interpretation of the kappa statistic. RESULTS: The group proposed that patients at elevated risk for local-regional failure with negative margins should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac, obturator, and presacral), whereas patients with positive margins should be treated to the pelvic nodes and cystectomy bed. Proposed OARs included the rectum, bowel space, bone marrow, and urinary diversion. Consensus language describing the CTVs and OARs was developed and externally validated. The revised instructions were found to produce consistent contours. CONCLUSIONS: Consensus descriptions of CTVs and OARs were successfully developed and can be used in clinical trials of adjuvant radiation therapy for bladder cancer.
11: RTOG 0926. 2015. "Phase II protocol for patients with stage T1 bladder cancer to evaluate selective bladder preserving treatment by radiation therapy concurrent with radiosensitizing chemotherapy following a thorough transurethral surgical re-staging".

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12: Taylor, A., A. G. Rockall and M. E. B. Powell. 2007. "An Atlas of the Pelvic Lymph Node Regions to Aid Radiotherapy Target Volume Definition." Clinical Oncology 19(7):542-550.

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13: Choudhury, A., N. Porta, E. Hall, et al. 2021. "Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and BCON trials." Lancet Oncol 22(2):246-255.

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Summary

Background

Two radiotherapy fractionation schedules are used to treat locally advanced bladder cancer: 64 Gy in 32 fractions over 6·5 weeks and a hypofractionated schedule of 55 Gy in 20 fractions over 4 weeks. Long-term outcomes of these schedules in several cohort studies and case series suggest that response, survival, and toxicity are similar, but no direct comparison has been published. The present study aimed to assess the non-inferiority of 55 Gy in 20 fractions to 64 Gy in 32 fractions in terms of invasive locoregional control and late toxicity in patients with locally advanced bladder cancer.

Methods

We did a meta-analysis of individual patient data from patients (age ≥18 years) with locally advanced bladder cancer (T1G3 [high-grade non-muscle invasive] or T2–T4, N0M0) enrolled in two multicentre, randomised, controlled, phase 3 trials done in the UK: BC2001 (NCT00024349; assessing addition of chemotherapy to radiotherapy) and BCON (NCT00033436; assessing hypoxia-modifying therapy combined with radiotherapy). In each trial, the fractionation schedule was chosen according to local standard practice. Co-primary endpoints were invasive locoregional control (non-inferiority margin hazard ratio [HR]=1·25); and late bladder or rectum toxicity, assessed with the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic tool (non-inferiority margin for absolute risk difference [RD]=10%). If non-inferiority was met for invasive locoregional control, superiority could be considered if the 95% CI for the treatment effect excluded the null effect (HR=1). One-stage individual patient data meta-analysis models for the time-to-event and binary outcomes were used, accounting for trial differences, within-centre correlation, randomised treatment received, baseline variable imbalances, and potential confounding from relevant prognostic factors.

Findings

782 patients with known fractionation schedules (456 from the BC2001 trial and 326 from the BCON trial; 376 (48%) received 64 Gy in 32 fractions and 406 (52%) received 55 Gy in 20 fractions) were included in our meta-analysis. Median follow-up was 120 months (IQR 99–159). Patients who received 55 Gy in 20 fractions had a lower risk of invasive locoregional recurrence than those who received 64 Gy in 32 fractions (adjusted HR 0·71 [95% CI 0·52–0·96]). Both schedules had similar toxicity profiles (adjusted RD −3·37% [95% CI −11·85 to 5·10]).

Interpretation

A hypofractionated schedule of 55 Gy in 20 fractions is non-inferior to 64 Gy in 32 fractions with regard to both invasive locoregional control and toxicity, and is superior with regard to invasive locoregional control. 55 Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer.
14: James, N.D., S.A. Hussain, E. Hall, et al. 2012. Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer.N Engl J Med; 366;16: 1477-88.

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BACKGROUND: Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone. METHODS: In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects. RESULTS: At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P=0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P=0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P=0.07) but not during follow-up (8.3% vs. 15.7%, P=0.07). CONCLUSIONS: Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. (Funded by Cancer Research U.K.; BC2001 Current Controlled Trials number, ISRCTN68324339.).
15: Gogna, N. K., J. H. Matthews, S. L. Turner, et al. 2006. "Efficacy and tolerability of concurrent weekly low dose cisplatin during radiation treatment of localised muscle invasive bladder transitional cell carcinoma: a report of two sequential Phase II studies from the Trans Tasman Radiation Oncology Group." Radiother Oncol 81(1):9-17.

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BACKGROUND AND PURPOSE: To determine the feasibility, toxicity, and clinical effectiveness of concurrent weekly cisplatin chemotherapy in conjunction with definitive radiation in the treatment of localised muscle invasive bladder cancer. PATIENTS AND METHODS: In January 1997 the Trans Tasman Radiation Oncology Group embarked on a Phase II study (TROG 97.01) of weekly cisplatin (35 mg/m(2) x 7 doses) plus radiation to a dose of 63 Gy over 7 weeks. Following an interim toxicity analysis, the dose intensity of cisplatin was reduced to 6 cycles and the radiation schedule changed to 64 Gy over 6.5 weeks leading to the second study (TROG 99.06). A total of 113 patients were enrolled. RESULTS: Acute grade 3 urinary toxicity occurred in 23% of the patients. Acute grade 4 pelvic toxicity was not seen. Thirty-eight patients (33%) experienced grade 3 or 4 cisplatin related toxicities with 15 patients (12%) requiring significant dose modification. The reduced dose intensity in Study 99.06 improved tolerability. Incidence of significant late morbidity was low (6%). Seventy-nine patients (70%) achieved complete remission at the 6 month cystoscopic assessment. Local invasive recurrence was seen in 11 of the 79 patients (14%). In 18 patients (16%) isolated superficial TCC/CIS were detected (6 months and beyond). The local control rate was 45% with a functional bladder being retained in 69 of the 113 patients (61%). RFS and DSS at 5 years were 33% and 50%, respectively. CONCLUSION: Our two sequential Phase II studies have shown that concurrent chemoradiation using weekly cisplatin in the management of localised invasive bladder TCC is feasible and reasonably well tolerated. This approach is currently being investigated further in a randomised study.
16: Efstathiou, J. A., D. Y. Spiegel, W. U. Shipley, et al. 2012. "Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience." Eur Urol 61(4):705-711.

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BACKGROUND: Whether organ-conserving treatment by combined-modality therapy (CMT) achieves comparable long-term survival to radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) is largely unknown. OBJECTIVE: Report long-term outcomes of patients with muscle-invasive BCa treated by CMT. DESIGN, SETTING, AND PARTICIPANTS: We conducted an analysis of successive prospective protocols at the Massachusetts General Hospital (MGH) treating 348 patients with cT2-4a disease between 1986 and 2006. Median follow-up for surviving patients was 7.7 yr. INTERVENTIONS: Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy (RT) after maximal transurethral resection of bladder tumor (TURBT) plus neoadjuvant or adjuvant chemotherapy. Repeat biopsy was performed after 40 Gy, with initial tumor response guiding subsequent therapy. Those patients showing complete response (CR) received boost chemotherapy and RT. One hundred two patients (29%) underwent RC-60 for less than CR and 42 for recurrent invasive tumors. MEASUREMENTS: Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method. RESULTS AND LIMITATIONS: Seventy-two percent of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% (T2=74%, 67%, and 63%; T3-4=53%, 49%, and 49%), respectively. Five-, 10-, and 15-yr OS rates were 52%, 35%, and 22% (T2: 61%, 43%, and 28%; T3-4=41%, 27%, and 16%), respectively. Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. Among patients undergoing visibly complete TURBT, only 22% required cystectomy (vs 42% with incomplete TURBT; log-rank p <0.001). In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. Use of neoadjuvant chemotherapy did not improve outcomes. No patient required cystectomy for treatment-related toxicity. CONCLUSIONS: CMT achieves a CR and preserves the native bladder in >70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients.
17: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)Version 4.2024 - Bladder Cancer. www.nccn.org

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18: Milowsky, M. I., R. B. Rumble, C. M. Booth, et al. 2016. "Guideline on Muscle-Invasive and Metastatic Bladder Cancer (European Association of Urology Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement." J Clin Oncol 34(16):1945-1952.

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PURPOSE: To endorse the European Association of Urology guideline on muscle-invasive (MIBC) and metastatic bladder cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS: The guideline on MIBC and metastatic bladder cancer was reviewed for developmental rigor by methodologists. The ASCO Endorsement Panel then reviewed the content and recommendations. RESULTS: The ASCO Endorsement Panel determined that the recommendations from the European Association of Urology guideline on MIBC and metastatic bladder cancer, published online in March 2015, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses the guideline on MIBC and metastatic bladder cancer and has added qualifying statements, including highlighting the use of chemoradiotherapy for select patients with MIBC and recommending a preference for clinical trials in the treatment of metastatic disease in the second-line setting. RECOMMENDATIONS: Multidisciplinary care for patients with MIBC and metastatic bladder cancer is critical. The standard treatment of MIBC (cT2-T4a N0M0) is neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy. In cisplatin-ineligible patients, radical cystectomy alone is recommended. Adjuvant cisplatin-based chemotherapy may be offered to high-risk patients who have not received neoadjuvant therapy. Chemoradiotherapy may be offered as an alternative to cystectomy in appropriately selected patients with MIBC and in some patients for whom cystectomy is not an option. Metastatic disease should be treated with cisplatin-containing combination chemotherapy or with carboplatin combination chemotherapy or single agents in patients ineligible for cisplatin.Additional information is available at http://www.asco.org/endorsements/MIBC and www.asco.org/guidelineswiki.
19: Witjes, J. A., E. Comperat, N. C. Cowan, et al. 2014. "EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines." Eur Urol 65(4):778-792.

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The European Association of Urology (EAU) guidelines panel on Muscle-invasive and Metastatic bladder cancer (BCa) updates its guidelines yearly. This updated summary provides a synthesis of the 2013 guidelines document, with emphasis on the latest developments. OBJECTIVE: To provide graded recommendations on the diagnosis and treatment of patients with muscle-invasive BCa (MIBC), linked to a level of evidence. EVIDENCE ACQUISITION: For each section of the guidelines, comprehensive literature searches covering the past 10 yr in several databases were conducted, scanned, reviewed, and discussed both within the panel and with external experts. The final results are reflected in the recommendations provided. EVIDENCE SYNTHESIS: Smoking and work-related carcinogens remain the most important risk factors for BCa. Computed tomography (CT) and magnetic resonance imaging can be used for staging, although CT is preferred for pulmonary evaluation. Open radical cystectomy with an extended lymph node dissection (LND) remains the treatment of choice for treatment failures in non-MIBC and T2-T4aN0M0 BCa. For well-informed, well-selected, and compliant patients, however, multimodality treatment could be offered as an alternative, especially if cystectomy is not an option. Comorbidity, not age, should be used when deciding on radical cystectomy. Patients should be encouraged to actively participate in the decision-making process, and a continent urinary diversion should be offered to all patients unless there are specific contraindications. For fit patients, cisplatinum-based neoadjuvant chemotherapy should always be discussed, since it improves overall survival. For patients with metastatic disease, cisplatin-containing combination chemotherapy is recommended. For unfit patients, carboplatin combination chemotherapy or single agents can be used. CONCLUSIONS: This 2013 EAU Muscle-invasive and Metastatic BCa guidelines updated summary aims to increase the quality of care and outcome for patients with muscle-invasive or metastatic BCa. PATIENT SUMMARY: In this paper we update the EAU guidelines on Muscle-invasive and Metastatic bladder cancer. We recommend that chemotherapy be administered before radical treatment and that bladder removal be the standard of care for disease confined to the bladder.
20: Coen, J. J., A. L. Zietman, D. S. Kaufman, et al. 2007. "Benchmarks achieved in the delivery of radiation therapy for muscle-invasive bladder cancer." Urol Oncol 25(1):76-84.

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Radiation therapy has a multifaceted role in the treatment of muscle-invasive bladder cancer, from being a component of bladder sparing regimens to adjuvant therapy for patients after partial cystectomy, to palliative treatment in patients with metastatic disease. Here, we review the techniques currently used and the settings in which these techniques are applied. Advances in imaging and radiation delivery have allowed for definition of more precise treatment volumes, permitting the delivery of higher tumor doses and lesser doses to critical targets. Better tumor control, fewer therapeutic complications, and better quality of life outcomes are anticipated. In the United States, the most rapidly growing use of radiation in the treatment of bladder cancer is as a component of selective bladder conservation. It uses trimodality therapy, consisting of a maximal transurethral resection followed by concurrent chemotherapy and radiation. Careful cystoscopic surveillance by an experienced urologist ensures a prompt cystectomy at the fist sign of treatment failure. The majority of patients retain a well-functioning bladder with no survival decrement. Radiation therapy is also used as adjuvant therapy after partial cystectomy in select patients. In this setting, it decreases the risk of local or incisional recurrence. It is also used in patients with pelvic recurrences after cystectomy, often combined with concurrent chemotherapy. Radiation is a very effective palliative agent for patients with locally advanced or metastatic disease. It can palliate bleeding and pain for patients with local progression or alleviate pain from bony metastases.
21: Hoskin, P. J., A. M. Rojas, S. M. Bentzen, et al. 2010. "Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma." J Clin Oncol 28(33):4912-4918.

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Abstract

Purpose: Phase II clinical studies suggest that hypoxic modification with carbogen and nicotinamide (CON) may increase the efficacy of radiotherapy (RT).

Patients and methods: Three hundred thirty-three patients with locally advanced bladder carcinoma were randomly assigned to RT alone versus RT with CON. A schedule of either 55 Gy in 20 fractions in 4 weeks or 64 Gy in 32 fractions in 6.5 weeks was used. The primary end point was cystoscopic control at 6 months (CC(6m)) and secondary end points were overall survival (OS), local relapse-free survival (RFS), urinary and rectal morbidity.

Results: CC(6m) was 81% for RT + CON and 76% for RT alone (P = .3); however, just more than half of patients underwent cystoscopy at that time. Three-year estimates of OS were 59% and 46% (P = .04) and 3-year estimates of RFS were 54% and 43% (P = .06) for RT + CON versus RT alone. Risk of death was 14% lower with RT + CON (P = .04). In multivariate comparison, RT + CON significantly reduced the risk of relapse (P = .05) and death (P = .03). There was no evidence that differences in late urinary or GI morbidity between treatment groups or between fractionation schedules were significant.

Conclusion: RT + CON produced a small nonsignificant improvement in CC(6m). Differences in OS, risk of death, and local relapse were significantly in favor of RT + CON. Late morbidity was similar in both trial arms. Results indicate a benefit of adding CON to radical RT.
22: Tunio, M. A., A. Hashmi, A. Qayyum, et al. 2012. "Whole-pelvis or bladder-only chemoradiation for lymph node-negative invasive bladder cancer: single-institution experience." Int J Radiat Oncol Biol Phys 82(3):e457-462.

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PURPOSE: Whole-pelvis (WP) concurrent chemoradiation (CCRT) is the standard bladder preserving option for patients with invasive bladder cancer. The standard practice is to treat elective pelvic lymph nodes, so our aim was to evaluate whether bladder-only (BO) CCRT leads to results similar to those obtained by standard WP-CCRT. METHODS AND MATERIALS: Patient eligibility included histopathologically proven muscle-invasive bladder cancer, lymph nodes negative (T2-T4, N-) by radiology, and maximal transurethral resection of bladder tumor with normal hematologic, renal, and liver functions. Between March 2005 and May 2006, 230 patients were accrued. Patients were randomly assigned to WP-CCRT (120 patients) and BO-CCRT (110 patients). Data regarding the toxicity profile, compliance, initial complete response rates at 3 months, and occurrence of locoregional or distant failure were recorded. RESULTS: With a median follow-up time of 5 years (range, 3-6), WP-CCRT was associated with a 5-year disease-free survival of 47.1% compared with 46.9% in patients treated with BO-CCRT (p = 0.5). The bladder preservation rates were 58.9% and 57.1% in WP-CCRT and BO-CCRT, respectively (p = 0.8), and the 5-year overall survival rates were 52.9% for WP-CCRT and 51% for BO-CCRT (p = 0.8). CONCLUSION: BO-CCRT showed similar rates of bladder preservation, disease-free survival, and overall survival rates as those of WP-CCRT. Smaller field sizes including bladder with 2-cm margins can be used as bladder preservation protocol for patients with muscle-invasive lymph node-negative bladder cancer to minimize the side effects of CCRT.
23: Mangar, S. A., N. R. Miller, V. S. Khoo, et al. 2008. "Evaluating inter-fractional changes in volume and position during bladder radiotherapy and the effect of volume limitation as a method of reducing the internal margin of the planning target volume." Clin Oncol (R Coll Radiol) 20(9):698-704.

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AIMS: To quantify the inter-fractional variation in bladder volume and position during a course of bladder radiotherapy, and to assess the feasibility of reducing the planning target volume (PTV) internal margin using an empty bladder protocol. MATERIALS AND METHODS: Weekly computed tomography scans were taken immediately after micturition on 15 patients undergoing radical radiotherapy for bladder cancer. Bladder volume and positional variation were compared by co-registration of the serial computed tomography scans with the initial planning scan and a single 'full' scan at the onset of treatment for each patient. A PTV was generated on the initial planning scan using both our departmental standard of 1.5cm and a reduced 1cm isotropic internal margin around the target (whole bladder) and the relative proportion of the bladder breaching the PTV using both margins compared. RESULTS: The mean post void residual volume from the planning scan was 112cm(3) (standard deviation 42cm(3)). The mean weekly variation in bladder volume relative to the planning volume was 0-12% (standard deviation 20-34%) with no observable trends over time. No statistically significant differences were seen in the proportion of bladder breaching the 1.5 and 1cm internal margin (P=0.18). Regression analysis showed that it is possible to ensure complete coverage of the bladder with a 1cm margin, providing the volume did not exceed over 50% of the initial planning scan volume. CONCLUSION: Using an empty bladder protocol and where on-line imaging is available it is feasible to reduce the internal margin of the PTV from 1.5 to 1cm, providing the volumes do not exceed >50% of the planning scan volume.
24: Kibrom, A.Z., K.A. Knight. 2015. "Adaptive radiation therapy for bladder cancer: a review of adaptive techniques used in clinical practice." Journal of Medical Radiation Sciences 62(4):277-285.

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Significant changes in the shape, size and position of the bladder during radiotherapy (RT) treatment for bladder cancer have been correlated with high local failure rates; typically due to geographical misses. To account for this, large margins are added around the target volumes in conventional RT; however, this increases the volume of healthy tissue irradiation. The availability of cone beam computed tomography (CBCT) has not only allowed in-room volumetric imaging of the bladder, but also the development of adaptive radiotherapy (ART) for modification of plans to patient-specific changes. The aim of this review is to: (1) identify and explain the different ART techniques being used in clinical practice and (2) compare and contrast these different ART techniques to conventional RT in terms of target coverage and dose to healthy tissue: A literature search was conducted using EMBASE, MEDLINE and Scopus with the key words ‘bladder, adaptive, radiotherapy/radiation therapy’. 11 studies were obtained that compared different adaptive RT techniques to conventional RT in terms of target volume coverage and healthy tissue sparing. All studies showed superior target volume coverage and/or healthy tissue sparing in adaptive RT compared to conventional RT. Cross-study comparison between different adaptive techniques could not be made due to the difference in protocols used in different studies. However, one study found daily re-optimisation of plans to be superior to plan of the day technique. The use of adaptive RT for bladder cancer is promising. Further study is required to assess adaptive RT versus conventional RT in terms of local control and long-term toxicity.
25: Foroudi, F., D. Pham, A. Rolfo, et al. 2014. "The outcome of a multi-centre feasibility study of online adaptive radiotherapy for muscle-invasive bladder cancer TROG 10.01 BOLART." Radiother Oncol 111(2):316-320.

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PURPOSE: To assess whether online adaptive radiotherapy for bladder cancer is feasible across multiple Radiation Oncology departments using different imaging, delivery and recording technology. MATERIALS AND METHODS: A multi-centre feasibility study of online adaptive radiotherapy, using a choice of three "plan of the day", was conducted at 12 departments. Patients with muscle-invasive bladder cancer were included. Departments were activated if part of the pilot study or after a site-credentialing visit. There was real time review of the first two cases from each department. RESULTS: 54 patients were recruited, with 50 proceeding to radiotherapy. There were 43 males and 7 females with a mean age of 78 years. The tumour stages treated included T1 (1 patient), T2 (35), T3 (10) and T4 (4). One patient died of an unrelated cause during radiotherapy. The three adaptive plans were created before the 10th fraction in all cases. In 8 (16%) of the patients, a conventional plan using a 'standard' CTV to PTV margin of 1.5cm was used for one or more fractions where the pre-treatment bladder CTV was larger than any of the three adaptive plans. The bladder CTV extended beyond the PTV on post treatment imaging in 9 (18%) of the 49 patients. CONCLUSIONS: From a technical perspective an online adaptive radiotherapy technique can be instituted in a multi-centre setting. However, without further bladder filling control or imaging, a CTV to PTV margin of 7mm is insufficient.
26: Huddart, R., S. Hafeez, C. Griffin, et al. 2025. "Dose-escalated Adaptive Radiotherapy for Bladder Cancer: Results of the Phase 2 RAIDER Randomised Controlled Trial." Eur Urol 87(1):60-70.

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Abstract

Background and objective: Delivering radiotherapy to the bladder is challenging as it is a mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule.

Methods: RAIDER is an international phase 2 noncomparative randomised controlled trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary endpoint was the proportion of patients with radiotherapy-related late Common Terminology Criteria for Adverse Events grade ≥3 toxicity; the trial was designed to rule out >20% toxicity with DART.

Key findings and limitations: A total of 345 patients were randomised between October 2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52% had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants planned for DART met the mandatory medium plan dose constraints. Radiotherapy-related grade ≥3 toxicity was reported in one of 58 patients (90% confidence interval [CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall survival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage cystectomy.

Conclusions and clinical implications: Grade ≥3 late toxicity was low. DART was safe and feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are promising for dose-escalated treatments, with a low salvage cystectomy rate and overall survival similar to that seen in cystectomy cohorts.

Keywords: Adaptive radiotherapy; Image-guided radiotherapy; Muscle-invasive bladder cancer; Radiotherapy; Randomised controlled trial.
27: Huddart, R. A., E. Hall, S. A. Hussain, et al. 2013. "Randomized noninferiority trial of reduced high-dose volume versus standard volume radiation therapy for muscle-invasive bladder cancer: results of the BC2001 trial (CRUK/01/004)." Int J Radiat Oncol Biol Phys 87(2):261-269.

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PURPOSE: To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer. METHODS AND MATERIALS: In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 x 2 factorial design. The primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years). RESULTS: Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT - sRT) was 6.4% (95% confidence interval -7.3%, 16.8%) under an intention to treat analysis and 2.6% (-12.8%, 14.6%) in the "per-protocol" population. CONCLUSIONS: In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.
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History

Version 6

Date	Summary of changes
11/04/2025	Reviewed at the radiation oncology urogenital reference committee meeting on 07/11/2024. Summary of changes: Flag: Added note that adaptive radiation therapy (ART) is an option where practical but not required for standard treatment. ART requires additional QA, training, experience, and protocols. Clinical information: Updated trimodality bladder preservation description. Clarified chemotherapy timing—given as a radiosensitiser on the same day as radiation therapy, preferably after treatment. Simulation: Added bladder and rectal volume consistency requirement and link to patient information sheet. Dose prescription: Reformatted table. Added simultaneous integrated boost option (46 Gy/20# to whole bladder, 55 Gy/20# to GTV). Included dose-escalated prescription requiring ART. Updated lymph node prescription wording and fractionation details. Added RAIDER trial reference for dose-escalated ART feasibility. Target volumes: Reformatted tables. Updated CTVp male pelvis description. Separated nodal target volumes into "involved" and "elective" tables. Added Taylor et al. 2007 guidelines for nodal regions. Organs at risk: Reformatted table. Removed redundant rectum constraint notes. Added RAIDER protocol organ-at-risk dose constraints table. Target verification: Removed daily CBCT requirement. Updated verification approach to align with ART protocols (e.g. RAIDER). Side effects: Removed chemotherapy toxicity. Included acute enteritis, late bowel toxicity and rectovaginal fistula (late) as side effects. Updated terminology for inclusivity and added direct hyperlinks to relevant resources. Evidence: Added meta-analysis (Choudhury et al. 2021) and RAIDER trial. Updated NCCN guidelines (Version 4, 2024). Added headings for efficacy section. Included hypofractionation discussion, removed IMRT/VMAT discussion, expanded ART evidence with RAIDER data. Review in 2 years.

Date

Summary of changes

11/04/2025

Reviewed at the radiation oncology urogenital reference committee meeting on 07/11/2024.
- Summary of changes:
  - Flag: Added note that adaptive radiation therapy (ART) is an option where practical but not required for standard treatment. ART requires additional QA, training, experience, and protocols.
  - Clinical information: Updated trimodality bladder preservation description. Clarified chemotherapy timing—given as a radiosensitiser on the same day as radiation therapy, preferably after treatment.
  - Simulation: Added bladder and rectal volume consistency requirement and link to patient information sheet.
  - Dose prescription:
    - Reformatted table.
    - Added simultaneous integrated boost option (46 Gy/20# to whole bladder, 55 Gy/20# to GTV).
    - Included dose-escalated prescription requiring ART.
    - Updated lymph node prescription wording and fractionation details.
    - Added RAIDER trial reference for dose-escalated ART feasibility.
  - Target volumes:
    - Reformatted tables.
    - Updated CTVp male pelvis description.
    - Separated nodal target volumes into "involved" and "elective" tables.
    - Added Taylor et al. 2007 guidelines for nodal regions.
  - Organs at risk:
    - Reformatted table.
    - Removed redundant rectum constraint notes.
    - Added RAIDER protocol organ-at-risk dose constraints table.
  - Target verification:
    - Removed daily CBCT requirement.
    - Updated verification approach to align with ART protocols (e.g. RAIDER).
  - Side effects:
    - Removed chemotherapy toxicity.
    - Included acute enteritis, late bowel toxicity and rectovaginal fistula (late) as side effects.
    - Updated terminology for inclusivity and added direct hyperlinks to relevant resources.
  - Evidence:
    - Added meta-analysis (Choudhury et al. 2021) and RAIDER trial.
    - Updated NCCN guidelines (Version 4, 2024).
    - Added headings for efficacy section.
    - Included hypofractionation discussion, removed IMRT/VMAT discussion, expanded ART evidence with RAIDER data.
  - Review in 2 years.

Version 5

Date	Summary of changes
19/07/2022	Target volumes: CTV description "pelviureteric junction" changed to "vesicoureteric junction".
22/02/2024	Minor correction to '3DCRT - Two phase - Bladder only' dose prescription table. First column 4th row 'Phase' corrected to read '2' for the 14 Gy dose prescription. No other changes.

Version 4

Date	Summary of changes
16/04/2021	Reviewed online for urogenital RCM held on 15/10/2020. Protocol updates published to eviQ. Review in 2 years at next urogenital RCM.

Version 3

Date	Summary of changes
18/02/2014	Approved and published to eviQ. Review Group 2.
31/03/2017	Full protocol review at August 2016 RCM Approved and published to eviQ Review group 2
31/05/2017	Transferred to new eviQ website.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:: 18 February 2014
Last reviewed:: 7 November 2024
Review due:: 31 December 2026

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1025

11 May 2025

Bladder carcinoma definitive EBRT with or without chemotherapy

Cautions

Indications notes

Timing of chemotherapy

Simulation notes

Bladder only

Single phase

Simultaneous integrated boost (SIB)

Sequential boost

Dose escalated

Bladder and lymph nodes

Simultaneous integrated boost (SIB)

Prescription notes

Bladder target volumes

Single dose level

Sequential boost or simultaneous integrated boost (SIB)

Lymph node target volumes

Involved nodes

Elective lymph nodes

Adaptive radiation therapy

Target volume notes

Target volume guides

Adaptive radiation therapy

Adaptive radiation therapy

Efficacy

Chemoradiation vs radiation therapy alone

Radical cystectomy vs trimodality bladder preservation

Hypofractionation

Pelvic nodal irradiation

Intrafraction bladder filling

Adaptive Radiation Therapy

Toxicity

References References

Abstract

Abstract

Summary

Background

Methods

Findings

Interpretation

Abstract

Abstract

Version 6

Version 5

Version 4

Version 3