1025-Urogenital bladder urothelial carcinoma definitive EBRT (with or without) chemotherapy

Indications and patient population

Bladder preservation with salvage surgery as part of protocol

Muscle invasive Urothelial Carcinoma - Stage T2a–T4a N0-2 M0
ECOG 0-2
Patients suitable for cystectomy but attempting bladder preservation
Patients medically or technically unsuitable for cystectomy but suitable for curative intent chemoradiation (optimal approach) or radiotherapy alone
Maximal transurethral resection of bladder tumour (TURBT) recommended prior to commencing EBRT - complete is not always possible.
Ideally haemoglobin level>100 g/L, preferably >120 g/L^r
Adequate bladder capacity and function preferred
Renal function satisfactory for concurrent chemotherapy

Cautions

Pacemakers and Implantable Cardioverter Defibrillators (ICDs)
Non-rheumatoid collagen vascular disorders
Inflammatory bowel disease and/or history of adhesions/bowel obstruction
Poor urinary function

Exclusions

Previous high dose radiotherapy to the pelvis

Notes

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

Risk Factors for recurrence of bladder carcinoma following EBRT:

The factors listed below increase the risk of local failure following EBRT.^r ^r ^r ^r They may be considered relative contra-indications for bladder preservation when primary cystectomy is possible:

Large tumour diameter (> 5cm)
Multifocal bladder tumours
Hydronephrosis
Incomplete TURBT
Widespread Carcinoma in situ (CIS) component

Links to other regimens

Option 1 (for patients with adequate renal function)

6 weekly cycles of cisplatin, to commence on day 1 or 2 of radiation treatment- Link to Bladder Locally Advanced Definitive cISplatin (Weekly) Chemoradiation
Delivered with a dose prescription of 64 Gy/32#

Option 2

Infusional 5FU during fractions 1 to 5 and 16 to 20 of radiotherapy and Mitomycin C on day 1^r - Bladder Mitomycin and Fluorouracil Chemoradiation
This regimen is also suitable for patients with impaired renal function
Delivered with a dose prescription of 55 Gy/20# or 64 Gy/32 #

Note:

Chemotherapy is to be given at the beginning of each week (Monday/Tuesdays), or starting within the first 2 days of radiation treatment.
On the days chemotherapy is administered, the planned radiation treatment should also be given, if possible, following the chemotherapy.

Clinical information

Pelvic floor exercises may be helpful - consider referral to continence nurse or physiotherapist.

Simulation

Simulation	Options	Notes
Position	Supine
Arm/leg/head/neck/shoulder position	Arms on chest
Immobilisation and supports	Knee supports Ankle stocks
Organ pre-requisites	Bladder empty Rectum empty	As per departmental protocol. Ask patient to empty their bladder immediately prior to commencement of simulation/treatment.
Contrast	Optional IV/oral/bladder contrast	As per department protocol. Link to Management and guidelines for the use of IV contrast for radiotherapy planning.
Radio-opaque markers	Optional use	As per departmental protocol.
Bolus	N/A
Other imaging	Optional MRI fusion Optional PET fusion (nodes)	As per departmental protocol.
CT acquisition	3DCT	Scan from L3/4 to below ischial tuberosities.
Medications	N/A

Dose prescription

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	Bladder only	64Gy	ICRU 50/62/83	Photons	6 - 18 MV	2Gy	32	1	10
NB: There is currently no high level evidence, however in certain patients these lymph node dose prescriptions may be considered.
Optional: In the setting of N1-2 disease
1	Involved nodes	60 - 64Gy	ICRU 83 (IMRT or VMAT only)	Photons	6 - 18 MV	2Gy	30 - 32	1	10
2	Uninvolved nodes	52 - 56Gy (50Gy equivalent)	ICRU 83 (IMRT or VMAT only)	Photons	6 - 18 MV	2Gy	32	1	10
OR
Single Phase 3DCRT/IMRT/VMAT
1	Bladder	55Gy	ICRU 50/62/83	Photons	6 - 18 MV	2.75Gy	20	1	10
NB:There is currently no high level evidence for treating patients with nodal disease with hypofractionation. The RCM considers conventional fractionation (2 Gy/#) to be the preferred regimen.
Two phase 3DCRT
1	Bladder	50Gy	ICRU 50/62	Photons	6 - 18 MV	2Gy	25	1	10
2	Bladder	14Gy	Individualised	Photons	6 - 18 MV	2Gy	7	1	10

Prescription notes

Treatment delays should be avoided as could impact on local control.^r
If using a 2 phased technique, consider planning phase 2 with the bladder full to assist with reducing the small bowel dose and removing some of the bladder wall (distant from the primary tumour) from the phase 2 volume.^r

Target volumes

Contouring atlases:

Clinical Target Volumes - based on FROGG 2012 Consensus Guidelines.^r

Single Phase 3DCRT/IMRT/VMAT (No nodes, N0)
GTV	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	Whole bladder (including GTV) + 0.5cm margin on gross extra-vesical extension. *In males*: If involvement of the bladder neck/trigone, CIS or multiple tumours, consider including the whole prostate in the CTV. If there is involvement at the pelviureteric junction, consider including 1-2cm of the distal ureter. In females: With bladder neck involvement, multiple tumours or CIS, consider including the proximal 1.5-2.0cm of urethra. If the anterior vaginal wall is involved, include in 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. When vagina is included, consider including proximal urethra. If there is involvement at the pelviureteric junction, consider including 1-2cm of the distal ureter.
PTV	CTV with anisotropic margin expansion: Anteriorly, posteriorly and laterally: 1.5-2.0cm, Superiorly: 2.0-2.5cm, Inferiorly: 1.0-1.5cm (inferior expansion may be reduced to 1.0cm if the prostate or urethra has been included). Smaller margins may be used if departmental set up error has been appropriately quantified.

Two Phase 3DCRT/IMRT/VMAT (No nodes, N0)
Phase 1
GTV₁	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).
CTV₁	Whole bladder (including GTV) + 0.5cm margin on gross extra-vesical extension *In males*: If involvement of the bladder neck/trigone, CIS or multiple tumours, consider including the whole prostate in the CTV. If there is involvement at the pelviureteric junction, consider including 1-2cm of the distal ureter. In females: With bladder neck involvement, multiple tumours or CIS, consider including the proximal 1.5-2.0cm of urethra. If the anterior vaginal wall is involved, include in 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. When vagina is included, consider including proximal urethra. If there is involvement at the pelviureteric junction, consider including 1-2cm of the distal ureter.
PTV₁	CTV with anisotropic margin expansion: anteriorly, posteriorly and laterally: 1.5-2.0cm superiorly: 2.0-2.5cm inferiorly: 1.0-1.5cm (inferior expansion may be reduced to 1.0cm if the prostate or urethra has been included). Smaller margins may be used if departmental set up error has been appropriately quantified.
Phase 2
Phase 2 reduced volumes should only be used at the site where the primary tumour arose if the lesion is clearly identified on imaging or documented at cystoscopy^r
GTV₂	Gross residual disease seen on cystoscopy or identified on imaging (CT, MRI) – as per Phase 1
CTV₂	GTV or site of known tumour + 0.5cm margin on extra-vesicular extension (EVE) if present
PTV₂	CTV₂ with anisotropic margin expansion: anteriorly, posteriorly and laterally: 1.5-2.0cm superiorly: 2.0-2.5cm inferiorly: 1.0-1.5cm Smaller margins may be used if departmental set up error has been appropriately quantified

Node target volumes for N1-2 disease (Optional)
GTV	Any involved nodes
CTV	Involved nodes + 0.5-1cm, cropped to anatomical boundaries AND uninvolved internal iliac, external iliac and obturator nodes^r ^r
PTV	CTV + 0.5-1cm As per department protocol

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

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 particularly 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.

Treatment timing: A study by Mangar et al^r identified that in the 20 minute time it takes to set up and deliver a radiotherapy 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 1.5cm would account of approximately 95% of bladder size/location.

Bladder IMRT / VMAT: Toxicity and outcome data for IMRT/VMAT (in form of series data) utilising various fractionation schedules, simultaneous integrated boosts and with or without nodal volumes has been published.^r ^r ^r While data remains limited, this is a field of continued interest.

Adaptive Radiation Therapy (ART) : The principle of Bladder ART is to account for daily variation in bladder volume via a selection of the appropriate “plan for the day” after daily imaging for each fraction followed by selecting a plan from a library of plans. Review of ART practices by Kibrom et al indicates a number of online / off-line; and plan of the day or daily re-planned/optimised techniques being trialled. While ART has merit it has yet to be determined how to apply it in a sustainable and safe process, utilising a process that is available and applicable to all radiotherapy centres with varying resources and skill sets.^r These challenges have been evaluated in the TROG 10.01 BOLART feasibility study,^r which demonstrated the applicability and challenges in execution of a bladder ART program.

Organs at risk

Organ	Constraints	Additional information
Small bowel	ALARA	Be aware of location of small bowel when determining volumes. Avoid dosimetric hotspots in loops of small bowel.
Rectum	V40Gy < 60% V50Gy < 50%^r V60Gy < 35%^r	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 1.5cm caudal to the inferior border of the CTV. Superiorly, the anorectal contours should extend at least 0.5cm beyond the proximal margin of the PTV. The recommended volume irradiated should not exceed these constraints (based on 2Gy/fraction). Appropriate adjustments need to be made for hypofractionated treatments.
Femoral Heads	V50Gy < 30%^r	Femurs are contoured from the acetabulum to the lower extent equal to the inferior border

Target verification

Modality	Frequency	Match point
kV or MV or Cone beam CT	Daily	Bone - review soft tissue

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

Target verification notes

Consideration should be given to dose delivered from verification imaging and whether this needs to be accounted for in treatment planning, particularly with respect to critical OARs.

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 radiotherapy (usually temporary)
Fatigue	Read more about fatigue
Irritative or obstructive urinary symptoms	Bladder spasms, dysuria, nocturia, frequency, incontinence, urgency, retention.
Toxicity relating to chemotherapy
Proctitis	Including diarrhoea, bowel frequency, rectal urgency, pain and bleeding. Read more about Proctitis
Sexual function - female	Vaginitis, vaginal mucositis, dyspareunia/stenosis.
Sexual function - male	Sexual and erectile dysfunction.

Late: Long term side effects - months post radiotherapy (may be permanent)
Fatigue	Read more about fatigue
Proctitis	Read more about proctitis
Cystitis/urethritis
Bladder dysfunction	New or ongoing.
Sexual dysfunction - female	Dyspareunia, vaginal dryness, vaginal stenosis. Read more about radiation induced vaginal stenosis Read more about radiation induced vaginal dryness
Sexual dysfunction - male	Including erectile dysfunction, impotence, dry/painful ejaculation, orgasmalgia.
Premature ovarian failure / menopause	If ovaries present.
Impaired fertility or Infertility	Read more about the effect of cancer treatment on fertility
Urinary incontinence
Faecal incontinence
Lymphoedema	Read more about lymphoedema
Radiation induced small bowel obstruction	Rare. Read more about radiation induced small bowel obstruction
Radiation induced rectourethral fistulas	Rare. Read more about radiation induced rectourethral fistulas
Second malignancy

Evidence

Source	Study & year published	Supports use Yes/No/NA	Is the radiation dose and fractionation consistent with the protocol?	Comments
Phase III trials	James et al, 2012^r	Yes	Yes	Randomised patients to RT alone or chemoRT with Mitomycin C and 5FU
Phase II trials	Gogna et al, 2006^r	Yes	Yes	Establishes tolerability and efficacy of RT with weekly cisplatin
Phase II trials	Mak et al, 2014^r	Yes	No	Combined analysis of 5 Phase II studies and one Phase III study. Generally used a low dose phase 1 ≈ 40 Gy then restaging cystoscopy before proceeding to either cystectomy (non CR) or consolidative RT (if CR).
Case series	Shipley et al, 2002^r and Efstathiou et al, 2012^r	Yes	Total dose ≈ 64 Gy if proceeded to consolidative RT after check cystoscopy	Phase 1: RT 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	Hindson et al, 2012^r	Yes	Yes
NCCN	V2, 2016^r	Yes	Yes
ASCO	Milowsky et al, 2016^r	Yes	Does not specify RT dose but endorses combined modality treatment as described in the EAU guidelines.	Endorses the 2014 EAU
European Association of Urology (EAU)	Witjes et al, 2014^r	Yes	No - Suggests 60–66 Gy followed by a further tumour boost.

Efficacy

No randomised trials comparing radical cystectomy versus bladder preservation have been undertaken. Several non-randomised prospective and retrospective studies of combined modality treatment have confirmed survival outcomes comparable to cystectomy alone.^r ^r ^r Most studies of combined modality treatment report 5-year survival rates of 50-60%.^r ^r ^r

The key evidence supporting this protocol is by James et al^r in a phase III trial of 360 patients with cT2-T4aN0MO, randomising patients to receive radiotherapy versus chemo-radiotherapy. Radiotherapy was 64 Gy in 34 fractions or or 55 Gy in 20 fractions. Chemotherapy involved Fluorouracil infusion / Mitomycin C. One-third of patients in each arm receiving discretionary neo-adjuvant chemotherapy. At a median follow-up of 70 months, the 2-year recurrence free rate was 67% in the chemo-radiotherapy arm versus 54% in the radiotherapy alone arm (HR 0.68, 95%CI 0.48 - 0.96; p=0.03). Five-year OS rates were 48% and 35% respectively (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 chemo-therapy arm. The findings suggest this chemo-radiotherapy schedule is an alternative option to cisplatin/fluorouracil.

Fig 2 - Kaplan-Meier Analysis of Survival over 72 months of follow-up
(A) locoregional recurrence free survival (B) invasive locoregional recurrence free survival (C) overall survival P values were calculated by log-rank test stratified according to the randomisation group.

Gogna et al 2006^r reported the combined analysis of two successive Phase II trials of chemo-radiotherapy (TROG 97.01 and TROG 99.06) utilising weekly cisplatin. In TROG 99.06, 43 patients received 64 Gy in 34 fractions with weekly cisplatin 35 mg/m². Completion of the TROG 99 was 80%. The complete response (CR) rate at 6 months post RT was 70%. The local control (LC) 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^r published a combined analysis of six successive RTOG trials of multimodality therapy totalling 468 patients - five Phase II and one Phase III trial. In principle these studies offered induction chemo-radiotherapy followed by re-staging cystoscopy and then proceeded to immediate cystectomy if a CR was not achieved or onto completion of chemo-radiotherapy if CT was achieved (total dose approximately 64 Gy). However there was diversity of radiotherapy and chemotherapy schedules utilised. The CR rate to induction chemoradiotherapy was 69%. At a median follow-up of 4.3 years, 5-year OS was 57%, disease specific survival was 71%, local failure rate was 43%, 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 2. Pooled Long-Term Outcomes

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

Pelvic nodal irradiation

Conformal radiotherapy 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 in the context of newer chemotherapy regimens. Pathological nodal involvement is reported in approximately 25% of patients who undergo cystectomy and lymph node dissection.^r In studies of bladder alone chemo-radiotherapy trials, pelvic nodal relapse rates of 5.5% have been reported.^r ^r A randomised single institution trial comparing chemoRT to the bladder alone versus whole pelvis plus bladder boost, showed no significant difference in rates of bladder preservation, locoregional recurrence, disease free survival (DFS) and overall survival (OS) with a rate of nodal recurrence of 15% in both arms.^r Elective nodal irradiation has been evaluated in successive RTOG bladder trials, however this remains an area of ongoing evaluation.^r

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 2006^r Huddart* et al 2013^r	43.0% 30.3 %
Genitourinary: Grade >3	Gogna et al 2006^r Huddart et al 2013^r James et al 2012^r	23.0% 16.6% 21.4%
Gastrointestinal Grade 2	Gogna et al 2006^r Huddart et al 2013^r	35.0% 27.0%
Gastrointestinal Grade ≥ 3	Huddart et al 2013^r James et al 2012^r	3.8% 2.7-9.6%
Late
Genitourinary Grade 2	Gogna et al 2006^r	27%
Genitourinary Grade ≥ 3 (RTOG/EORTC)	Gogna et al 2006^r Huddart et al 2013^r James et at 2012^r	4.0% § 11.8% 1.3 - 3.3%
Cystectomy for late GU toxicity	Gogna et al 2006^r Huddart et al 2013^r James et al 2012^r	0% < 1% 1.2%	As a percentage of all patients who underwent RT
Gastrointestinal Grade 2 (RTOG/EORTC)	Gogna et al 2006^r Huddart et al 2013^r	3.5% 3.9% ¶
Gastrointestinal Grade >3 (RTOG/EORTC)	Gogna et al 2006^r Huddart et al 2013^r James et al 2012^r	2 % 3.3% ¶ 0%

* Data from Huddart et al 2013 for all patients combined
§ In all cases of Grade 3 or 4 GU 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,^r there was a small increase in acute grade ≥ 3 toxicity for those receiving chemoradiotherapy compared to radiotherapy alone (36.0% vs. 27.5% p=0.07). This difference was primarily due to a significant increase in gastrointestinal toxicity in the chemoradiotherapy group (9.6% vs. 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 results in reduced toxicity. The combined analysis^r 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. 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.

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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. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:: 18 February 2014
Last reviewed:: 19 August 2016
Review due:: 19 August 2018

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

14 Nov 2018