Dr JOY NARAYAN CHAKRABORTY

MS, DNB Urology, DNB Surgery, FRCS Edinburgh.

Vi v a To p i c
FRCS England, FRCS Urology, FHEA Bladder Cancer 6
Postgraduate Tutor in Surgical & Urological
Sciences, Edinburgh University, UK

Trimodality Therapy in MIBC

CONTACT
urologicacademy@gmail.com
A 62 year old woman presents to your haematuria clinic with visible haematuria and significant lower urinary tract
symptoms. She is on medication for hypertension. At cystoscopy she has a large 4 x 4 cm solid bladder tumour at the
left lateral wall.

An urgent staging CT scan (chest / abdomen / pelvis), MRI pelvis and TURBT are arranged. Pathology following TURBT
confirms G3pT2a at least bladder cancer. MRI scan shows organ confined disease and her CT scan shows no distant
disease.

Her case is reviewed at the specialist bladder cancer MDM.

She returns to the specialist bladder cancer clinic and is seen jointly by a urologist, oncologist and specialist nurse.

Would you offer her chemotherapy?

If so, would you recommend neoadjuvant or adjuvant? Why?
What is the evidence?
What are the regimens and common side effects / complications?
Although this lady chose to have a RC, she discussed a bladder sparing approach with the oncologist.
What are the important steps of a bladder sparing approach? Is it effective? How would you counsel this lady?
What are the important steps of a bladder sparing approach? Is it effective? How would you counsel this lady?

The steps are as follows

• Complete/ Maximal TURBT

• Chemotherapy
• RT

At present, concurrent Chemoradiotherapy using MMC & 5-FU as a standard of care for patients opting for organ-
preservation surgery for MIBC

What is the Rationale of TMT ?

MULTIMODAL THERAPY (TRIMODAL THERAPY) (3)

Maximal TURBT
The first step of multimodal treatment is a “maximal TURBT”, where as much tumour as possible is resected. The aim of
therapy is to remove all visible disease without compromising the safety of the surgery.

Chemotherapy
It acts as a sensitizer to radiation by increasing the cell kill in a synergistic fashion and it can potentially improve loco-
regional control, because half of the population of patients with MIBC may have occult metastases.

Radiotherapy
A standard regimen will involve "EBRT to the bladder and pelvic lymph nodes for an initial dose of 40 Gy, followed by
additional boost to the bladder to 54 Gy and a final boost to the tumour to a total of 64–65 Gy"
Rationale of TMT

The rationale of TMT is

• TURBT and RT will achieve local tumour control in the bladder and adjacent nodes.

• Chemotherapy will act as ‘radiosensitiser’ and target ‘micro metastasis’. It acts as a sensitizer to radiation by
increasing the cell kill in a synergistic fashion and it can potentially improve loco-regional control, because half of
the population of patients with MIBC may have occult metastases

• Preservation of the bladder will improve QoL without compromising oncological outcome.

There are no successfully completed RCTs comparing the outcome of TMT with RC, but TMT using chemoradiation has
been shown to be superior to RT alone.

Who are the ideal candidates for bladder preservation?

Ideal candidates for bladder preservation

Ideal candidates for TMT should have the following criteria:

1. Adequate renal function to allow Cisplatin-based chemotherapy (although alternative regimens such as 5-FU or
MMC or low-dose Gemcitabine have shown good activity)
2. Adequate bladder capacity and function
3. Motivated patient without history of pelvic radiation who is willing to forgo an ileal neobladder upon recurrence
4. Organ-confined tumour (cT2) and small tumour size in the absence of a palpable mass
5. Ability to safely perform a resection of all visible tumour with TURBT
6. Absence of any tumour-associated Hydronephrosis or Lymphadenopathy
7. Absence of extensive CIS
8. Absence of diffuse, multifocal disease.

Is there any role of Neoadjuvant or adjuvant Chemotherapy with TMT as we give before RC ?
Is there any role of Neoadjuvant or adjuvant Chemotherapy with TMT as we give before RC ?

To date, no level 1 evidence exists to support the use of either neoadjuvant or adjuvant chemotherapy towards
improving local control or survival in the setting of TMT.

What do you mean by the term “maximal TURBT”?

Maximal TURBT

Maximal TURBT means: Complete TURBT + EUA

Maximal TUR-BT is defined as macroscopically complete resection of visible bladder tumour without safety violation.
Maximal TURBT purposes is to debulk gross tumour and so that adjuvant radiation can damage any minimal residual
macroscopic and microscopic disease that may persist after complete TURBT.

How will you proceed for Radiation therapy in Trimodality Therapy (TMT)
Radiation therapy in Trimodality Therapy (TMT)

It is categorized into 2 types while are split treatment and continuous treatment.

• Split treatment composed of induction RT and consolidation RT. The split regimen is aim to evaluate response of
trimodal therapy and select the unresponsive cases to perform salvage cystectomy.
Induction to a dose of 40Gy followed by a Consolidation radiation to a full dose of 65Gy.

• Continuous treatment is aim to increase chance of bladder preservation and increase time for response.
Meta-analysis shows that the OS of these 2 techniques is not different.

The current Radiation protocol for Bladder preservation is:

• EBRT (either one daily or twice daily) to the bladder

• Limited PLND to an initial dose of 40Gy
• Boost to the whole bladder to 54 Gy
• A further tumour boost (incorporating all TUR & radiographic information) to a total dose of 64-65Gy.

What is the rationale of Chemotherapy ? What should be the usual Chemotherapy Regimen in TMT ?
Rationale of Chemotherapy in TMT

Chemotherapy in TMT is applied for two reasons:

• ‘Enhance radiosensitivity’
• ‘Treat micro-metastasis’.

Chemotherapy regimen in TMT that are usually used are

1.Cisplatin 35 mg/m2, weekly up to 6 weeks

2.Cisplatin-based regimens with 5-FU (fluorouracil 400 mg/m2 on days 1–3 and 8–10 with cisplatin 15 mg/m2 on days
1,2, 8, and 9) or paclitaxel (paclitaxel 50 mg/m2 on days 1 and 8 and cisplatin 15 mg/m2 on days 1, 2, 8, and 9)

3. 5-FU/mitomycin-C (500 mg/m2 5-FU days 1–5 and 16–20 with mitomycin-C 12 mg/m2 on day 1)

4. Gemcitabine 27 mg/m2, twice weekly up to 6 weeks “ [1]

 Two main courses of TMT are
Split & Continuous

The Cystoscopic assessment is

performed after TMT completion
(Continuous course) or after TMT
induction and before consolidation
(Split course)

# Ploussard G, Daneshmand S, Efstathiou JA, Herr HW, James ND, Rödel CM, Shariat SF, Shipley WU, Sternberg CN, Thalmann GN, Kassouf
W. Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review. European urology.
2014 Jul 1;66(1):120-37.

How would you counsel this lady for TMT?

How would you counsel this lady for TMT?

• I would counsel this lady that the best option in terms of malignancy control is RC with urinary diversion. The
benefit of the best oncologic aim must be weighted with poorer quality of life, operation and anaesthetic
complications and mortality risk.

• Most of studies that compared Trimodal therapy and radical cystectomy showed better oncologic outcomes for
radical cystectomy. Therefore, Radical cystectomy remains the gold standard for MIBC treatment. Meta-analysis by
Wettstein et al. showed that RC had better disease specific survival and overall survival than trimodal therapy.

• Trimodal therapy is an alternatives option especially in high operative risk patients and patients who strongly desire
bladder sparing approach; however, strict criteria should be followed at the time of option selection, treatment and
follow up.

• If trimodal therapy is chosen, there would be some risk of further salvage radical cystectomy and lifelong
cystoscopies; and these should form part of the pre-treatment patient discussions.

[# Wettstein, M.S., et al., Systematic review and meta-analysis on trimodal therapy versus radical cystectomy for muscle-invasive
bladder cancer: Does the current quality of evidence justify definitive conclusions? PLoS One, 2019. 14(4): p. e0216255.
How would you counsel this lady for TMT?

Before any Bladder preserving protocol is employed shared decision making is necessary regarding
• Efficacy
• Potential side effects
• Benefit in terms of recurrence rate and survival
• Need for Salvage radical cystectomy.
• Need for follow up.
• Cost effectiveness
• Quality of life.

• The average 5-year CSS and OS is reported to be 71% and 57% respectively with 21% rate of salvage radical
cystectomies.
• Overall improved survival benefit of 27% and reduction in salvage radical cystectomy rate of 13% was observed with
ideal candidate.
• There are no published RCT comparing outcomes between trimodal therapy and radical cystectomy. A good review of
TMT is by Ploussard G et al, Eur Urol 2014; 66: 120-37. They conclude that the 5-year CSS ranges from 50-82%, 5-year
OS from 36-74%. Salvage cystectomy rates are 25-30%. Patient selection is key -> including small, solitary muscle
invasive tumours, no hydronephrosis and minimal/no CIS
What should be the Radiation Dose for TMT ?
Radiation Dose for TMT

• Both 64 Gy in 32 fractions and a hypofractionated schedule of 55 Gy in 20 fractions are used as standard treatment in
the UK and were part of the protocols in the BC2001 and BCON

• Hypofractionated radiotherapy with 55 Gy in 20 fractions is non-inferior to 64 Gy in 32 fractions in relation to both

invasive locoregional control and late bladder and rectum toxicity, and is superior with regard to invasive locoregional
control.

• 55 Gy in 20 fractions over 4 weeks should be considered as the new standard of care for bladder preservation
therapy in patients with muscle-invasive bladder cancer.

[# Choudhury A, Porta N, Hall E, Song YP, Owen R, MacKay R, West CM, Lewis R, Hussain SA, James ND, Huddart R. Hypofractionated
radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and BCON trials. The Lancet
Oncology. 2021 Feb 1;22(2):246-55.]

Are there any pathological or radiological features of bladder cancer or patient factors which make cystectomy or
chemoradiotherapy the favoured management option in muscle invasive bladder cancer?
Are there any pathological or radiological features of bladder cancer or patient factors which make cystectomy or
chemoradiotherapy the favoured management option in muscle invasive bladder cancer?

These factors need to be considered while offering TMT over cystectomy.

Pathological
Muscle invasive disease
No CIS
No LVI
No Variant histology

Radiological
Absence of hydronephrosis
Absence of visible metastatic disease.
Radiological stage <T3b

Patient Factors
1. Patient preference
2. Good renal function
3. Good Bladder function
4. Suitable candidate- Good performance status Advantages of RC over TMT ?
Advantages of RC over TMT ?

Pathological features that TMT can handle suitably are UC stage cT2-T3a and no extensive CIS while RC can be
performed in every pathological T stage (. +- T4b). Moreover, partial cystectomy is first line treatment option of urachal
adenocarcinoma ; this might be because its origination and disease nature. For radiological features, if the patient has
hydronephrosis or clinically T3b or T4a , RC is favoured treatment option.

TMT is currently considered as a curative alternative to RC in selected MIBC cases.

TMT have advantage of

• Low risk of adverse outcomes and mortality

• Maintain or improve quality of life.
• Provide non inferior oncological outcomes to RC.

• However, TMT can be employed in carefully selected, informed, and motivated patients with MIBC and in them who
are unfit for RC . The selection criteria as mentioned by Tholomier et al. (2) are categorized into ideal and high risk
candidates (2)
• Moreover, RC specimens allow pathological staging whereas Radical RT relies on clinical staging which often results
in understaging and suggests that tumours being treated with Radical RT are actually more advanced.

• A good review of TMT is by Ploussard G et al, Eur Urol 2014; 66: 120-37. They conclude that the 5-year cancer-
specific survival ranges from 50-82%, 5-year overall survival from 36-74%. Salvage cystectomy rates are 25-30%.
Patient selection is key - including small, solitary muscle invasive tumours, no hydronephrosis and minimal/no CIS.

In summary, non randomised comparisons of RC and TMT (after complete TURBT +/- neoadjuvant/adjuvant
chemotherapy) are comparable for solitary T2 tumours without widespread CIS or hydronephrosis in terms of
oncological outcome and survival.

Those patients that recur after chemoradiotherapy and require a salvage cystectomy may do worse in terms of
morbidity and mortality. Chemoradiotherapy may also effect bladder function post treatment but most studies report
good bladder function.

Can TMT be extended to non-ideal MIBC patients?

The extended criteria for TMT with high-risk features also called as Non-ideal TMT patients that have worse outcomes.

• cT3-T4a disease
• Inability to perform complete TURBT.
• Presence of Hydronephrosis
• Presence of extensive CIS
• Diffuse and multifocal disease

Comparison: Ideal TMT patient*

• cT2
• Complete TURBT
• No hydronephrosis
• No CIS
• Unifocal tumour
• Good bladder function and capacity

Is Partial cystectomy is regarded a standard ‘Bladder preserving’ tool compared to Maximal TURBT ?
Is Partial cystectomy is a standard Bladder preserving tool?

• The treatment is alternative option for MIBC patients, but the selection should be strict criteria. The ideal case
should be small size solitary lesion, no CIS, tumour position should be complete resection with margin 2 cm and the
residual bladder capacity should be adequate for functional voiding. Moreover, random bladder and prostatic
urethral biopsy should be performed prior to partial cystectomy to ensure no other concomitant diseases. Partial
cystectomy had 5-year OSS approximately 70 %, and a quarter of the patients undergone partial cystectomy
needed salvage radical cystectomy due to recurrent disease. [1]

• I would be careful recommending partial cystectomy in MIBC. It is not usually recommended for MIBC as bladder
cancer is often associated with a field change and there will be potential for cancer in the remaining parts of the
bladder.

• I would like to make it clear that this is not standard practice and TMT with maximal TURBT followed by
chemoradiotherapy is the standard way of trying to deliver a bladder sparing treatment.

• Partial cystectomy is not a standard treatment for bladder cancer, with the one exception being for
adenocarcinoma in a urachal remnant.

Some surgeons treat bladder cancers truly confined to a diverticulum (ie with negative mapping biopsies in the rest of
the bladder) with a diverticulectomy (Voskuilen CS et al, Eur Urol Focus 2020;6:1226-1232). However, there is a
concern about tumour cell spillage with such an approach.
BC2001 Trial

• Largest RCT of Bladder sparing treatment for MIBC. It was designed to assess whether radiosensitisation using chemo-
RT with 5-FU and MMC improved outcomes compared with RT alone; and also to compare standard and reduced high-
dose-volume RT (RHDVRT).
• BC2001 trial confirms the improved locoregional control reported previously for Chemoradiotherapy over RT alone.

* 10-yr OS survival rate 30%

[# James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R. Radiotherapy
with or without chemotherapy in muscle-invasive bladder cancer. New England Journal of Medicine. 2012 Apr 19;366(16):1477-88

# Hall E, Hussain SA, Porta N, Lewis R, Crundwell M, Jenkins P, Rawlings C, Tremlett J, Sreenivasan T, Wallace J, Syndikus I.
Chemoradiotherapy in muscle-invasive bladder cancer: 10-yr follow-up of the phase 3 randomised controlled BC2001 trial. European
Urology. 2022 Sep 1;82(3):273-9.].
BCON Trial (Bladder Carbogen Nicotinamide), 2010

• It compares Radical RT with and without carbogen (gas containing 90% O2 & 10% CO2) and Nicotinamide in locally
advanced BCa.

• An alternative approach testing hypoxic sensitisation was tested in a second UK trial (BCON, multicentre randomised
trial of radical radiotherapy with carbogen ((hypoxia-modifying agents)) in the radical treatment of locally advanced
bladder cancer), which enrolled similar locally advanced bladder cancer patients for RT alone (either 55 Gy in 20
fractions in 4 wk. or 64 Gy in 32 fractions in 6.5 wk.) or synchronous radiosensitisation (carbogen and nicotinamide).

* 10-yr OS rate 30%

[# Hoskin PJ, Rojas AM, Bentzen SM, Saunders MI. Radiotherapy with concurrent carbogen and nicotinamide in bladder
carcinoma. J Clin Oncol 2010;28:4912–8].

• a nonrandomised UK trial showed that synchronous weekly gemcitabine 100 mg/m2 with 52.5 Gy in 20 fractions for
whole bladder RT could achieve an 88% complete response rate at post-treatment cystoscopy [20].
The ”Chemo" in Chemoradiotherapy is used as a tumour sensitiser based on the key BC2001 trial (James ND et al, N
Engl J Med 2012; 366: 1477-88). Radiosenstisers have improved the effectiveness of Radiotherapy.

In the BC2001 trial they used mitomycin and 5FU, which resulted in better local control when compared to
radiotherapy alone - 67% vs 54% recurrence free rates at 2 years. However, there was no overall survival benefit at 5
years and an increase in acute GI toxicity.

Carbogen and nicotinamide have also shown benefit as radiosensitisers (BCON - Hoskin PJ et al, Radiother Oncol
2009;91:120-5).

If salvage RC is required after TMT, what type of diversion would you suggest ?
If salvage RC is required after TMT, what type of diversion would you suggest ?

I will suggest an ileal conduit diversion.

Importantly, during patient counselling, I will not recommend ortho- topic neobladder reconstruction (although
feasible) after pelvic radiation because of significantly higher risk of functional complications and incontinence rates.

This risk is confirmed within the published literature, as most patients who underwent a cystectomy following TMT
received an ileal conduit diversion.
This lady underwent RC and agreed for adjuvant chemotherapy.

Q1. Prior to starting adjuvant chemotherapy, this lady’s tumour is sequenced and found to be luminal papillary.
What does this mean? Does this result influence her treatment?

Q2. She has been reading about immunotherapy and asks you whether she should have immunotherapy instead of
chemotherapy.
What do you advise?
What is the role of systemic immunotherapy in muscle invasive bladder cancer?
Would you manage bladder small cell cancer, squamous cell cancer or adenocarcinoma differently to urothelial cell
bladder cancer?

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