12Radiotherapy dose fractionation Third edition
2.
Bladder cancer
Radical treatment
Conventional fractionation (dose per fraction 1.8–2.0 Gray [Gy])
The radiotherapeutic regimens used in studies comparing radiotherapy and surgery for
bladder cancer have been delivered using either a conventional regimen of 60–64 Gy in
30–32 fractions over 6–6.5 weeks or hypofractionated radiotherapy of 52.5–55 Gy in 20
fractions (Level 2b).
1–5
Hyperfractionation
Two published trials compare hyperfractionation with doses of 1–1.2 Gy per fraction to
conventionally fractionated treatment.
6,7
Pooled analysis suggests a signicant benet from
hyperfractionation with a 17% (95% condence interval, 6–27%) improvement in the rate
of local control.
8
However, the regimens in both arms of these studies used split courses
with overall treatment times of eight weeks. This approach would no longer be considered
acceptable in a control arm (Level 1b).
5
Accelerated fractionation
There was no evidence of clinical benet from 60.8 Gy in 32 fractions given using two
fractions per day of 1.9 Gy over a treatment time of 26 days when compared to a standard
regime of 64 Gy in 32 fractions over 45 days.
9
The shorter regimen was associated with a
higher rate of intestinal toxicity (Level 1b).
5
Hypofractionation
The two UK-based randomised controlled trials published in the last ve years allowed the
use of both conventional (60 Gy in 30 fractions) and hypofractionated radiotherapy (55 Gy
in 20 fractions).
10,11
Although neither study was powered to detect a dierence in outcome
based on dose and fractionation, there was no dierence seen between conventional and
hypofractionated radiotherapy (Level 2b).
5
Partial bladder irradiation
Partial bladder radiotherapy has been studied in two UK-based trials. A trial from
Manchester compared whole bladder radiotherapy 52.5 Gy in 20 fractions with partial
bladder irradiation of 57.5 Gy in 20 fractions and 55 Gy in 16 fractions.
12
There was no
signicant dierence in local control at ve years between the three groups, and late toxicity
was similar in all three arms. The BC2001 sub-study compared whole bladder high-dose
irradiation with reduced high-dose volume radiation therapy.
13
There was no dierence in
locoregional recurrence, late toxicity or overall survival between the two groups (Level 1b).
5
Radical radiotherapy with radiosensitisation
Two UK-based randomised control trials have demonstrated that radical radiotherapy with a
radiosensitiser improves outcomes compared to radiotherapy alone.
10,11
BC2001 compared
radical radiotherapy alone with radical radiotherapy given concurrently with mitomycin
C and 5-uorouracil (5-FU), with the chemoradiotherapy arm showing signicantly better
two-year locoregional recurrence rates of 67% versus 54% (Level 1b).
5,10
The Bladder
Carbogen Nicotinamide (BCON) investigators compared radical radiotherapy alone to
radical radiotherapy given concurrently with carbogen and nicotinamide with a signicant
improvement in three-year overall survival of 13% in the experimental arm (Level 1b).
5,11
Some centres within the UK use a weekly gemcitabine chemoradiation protocol based on a
multicentre phase II study which has shown acceptable toxicity and comparable outcomes
13Radiotherapy dose fractionation Third edition
to those in the literature with a three-year overall survival of 75% and 88% achieving a
complete endoscopic response at rst check cystoscopy (Level 2b).
5,14
Treatment technique
The size of the planning target volume (PTV) is critical to any discussion of dose and
fractionation.
15,16
Some centres use a two-phase (large pelvic volume/small bladder volume)
approach, although there is no robust evidence for this approach improving survival
outcomes for patients (Level 5).
5
There is no published evidence using fraction sizes other
than 1.8–2 Gy for this approach. All of the dose-fractionation regimens discussed below are
based on the assumption that the PTV is <1,000 mililitres (ml) and that three-dimensional
(3-D) image-based planning techniques are used. There is also increasing use of adaptive
radiotherapy techniques for bladder treatment using a ‘plan of the day’ based on imaging
prior to delivery of each fraction. The fractionation evidence has not been tested in this
setting, but there is no reason to believe that the recommendations below do not apply to
the adaptive setting also.
Recommendations
For radical radiotherapy to the bladder:
52.5–55 Gy in 20 fractions over 4 weeks
60–64 Gy in 30–32 fractions over 6–6.5 weeks (Grade B)
There is robust evidence that radiotherapy with a radiosensitiser using carbogen and
nicotinamide or chemotherapy improves outcomes for patients with organ-conned
muscle-invasive bladder cancer (Grade A)
10,11
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based medicine.
5
Palliative radiotherapy
The Medical Research Council (MRC) randomised trial BA09 clearly established that 21 Gy
in three fractions on alternate weekdays in one week (4–6 elapsed days) is as eective as
35 Gy in ten fractions in two weeks in palliating symptoms in patients with bladder cancer.
17
There was no statistically signicant dierence in the rate of symptom relief (64% versus
71%; p=0.192; 95% condence interval for the 7% rate dierence, –2% to +13%), nor was
there any signicant dierence in the duration of symptomatic relief (Level 1b).
5
Other
palliative regimes which are in use in the UK are 20 Gy in ve fractions and 30–36 Gy in 5–6
fractions over 5–6 weeks (Level 2-).
5
These regimes are also used for frail patients not t for
radical radiotherapy treatment.
In the hypofractionated bladder radiotherapy with or without image-guided adaptive
planning (HYBRID) trial, a dose of 30–36 Gy in 5–6 fractions given weekly has beenused.
For very frail patients, a 6–8 Gy single fraction of pelvic radiotherapy often provides
symptomatic relief (Level 4).
5
14Radiotherapy dose fractionation Third edition
Recommendations
For the palliation of local symptoms from bladder cancer:
21 Gy in 3 fractions on alternate days in 1 week is the regimen of choice (Grade A)
30–36 Gy in 5-6 fractions weekly has also been used in this setting (Grade D)
A single fraction of 6–8 Gy may provide useful palliation in patients who are unt for the
recommended regimen (Grade D)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based medicine.
5
References
15Radiotherapy dose fractionation Third edition
1. Shelley MD, Barber J, Mason MD. Surgery versus radiotherapy for muscle invasive bladder cancer.
Cochrane Database Syst Rev 2001; 2001(3): CD002079.
2. Booth CM, Siemens DR, Li G et al. Curative therapy for bladder cancer in routine clinical practice: a
population-based outcomes study. Clin Oncol (R Coll Radiol) 2014; 26(8): 506–514.
3. Gray PJ, Fedewa SA, Shipley WU et al. Use of potentially curative therapies for muscle-invasive
bladder cancer in the United States: results from the National Cancer Data Base. Eur Urol 2013; 63(5):
823–829.
4. Kotwal S, Choudhury A, Johnston C, Paul AB, Whelan P, Kiltie AE. Similar treatment outcomes for
radical cystectomy and radical radiotherapy in invasive bladder cancer treated at a United Kingdom
specialist treatment center. Int J Radiat Oncol Biol Phys 2008; 70(2): 456–463.
5. www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009
(last accessed 22/9/16)
6. Edsmyr F, Andersson L, Esposti PL, Littlebrand B, Nilsson B. Irradiation therapy with multiple small
fractions per day in urinary bladder cancer. Radiother Oncol 1985; 4(3): 197–203.
7. Näslund I, Nilsson B, Littbrand B. Hyperfractionated radiotherapy of bladder cancer. A ten-year follow-
up of a randomized clinical trial. Acta Oncol 1994; 33(4): 397–402.
8. Goldobenko GV, Matveev BP, Shipilov VI, Kilmakov BD, Tkachev S. Radiation treatment of bladder
cancer using dierent fractionation regimens. Med Radiol (Mosk) 1991; 36(5): 14–16.
9. Horwich A, Dearnaley D, Huddart R et al. A randomised trial of accelerated radiotherapy for localised
invasive bladder cancer. Radiother Oncol 2005; 75(1): 34–43.
10. James ND, Hussain SA, Hall E et al. Radiotherapy with or without chemotherapy in muscle-invasive
bladder cancer. N Engl J Med 2012; 366(16): 1477–1488.
11. Hoskin PJ, Rojas AM, Bentzen SM, Saunders MI. Radiotherapy with concurrent carbogen and
nicotinamide in bladder carcinoma J Clin Oncol 2010; 28(33): 4912–4918.
12. Cowan RA, McBain CA, Ryder WD et al. Radiotherapy for muscle-invasive carcinoma of the bladder:
results of a randomized trial comparing conventional whole bladder with dose-escalated partial
bladder radiotherapy. Int J Radiat Oncol Biol Phys 2004; 59(1): 197–207.
13. Huddart RA, Hall E, Hussain SA et al. 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 2013; 87(2): 261–269.
14. Choudhury A, Swindell R, Logue JP et al. Phase II study of conformal hypofractionated radiotherapy
with concurrent gemcitabine in muscle-invasive bladder cancer. J Clin Oncol 2011; 29(6): 733–738.
15. Muren LP, Ekerold R, Kvinnsland Y, Dahl O. On the use of margins for geometrical uncertainties around
the rectum in radiotherapy planning. Radiother Oncol 2004; 70(1): 11–19.
16. Muren LP, Smaaland R, Dahl O. Conformal radiotherapy of urinary bladder cancer. Radiother Oncol
2004; 73(3): 387–398.
17. Duchesne GM, Bolger JJ, Griths GO et al. A randomized trial of hypofractionated schedules of
palliative radiotherapy in the management of bladder carcinoma: results of medical research council
trial BA09. Int J Radiat Oncol Biol Phys 2000; 47(2): 379–388.
