A multicentre phase II study of hypofractionated conformal radiotherapy with concurrent gemcitabine...

$: A multicentre phase II study of hypofractionated conformal radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer$
The Christie NHS Foundation Trust

A multicentre phase II study of hypofractionated conformal radiotherapy with concurrent

gemcitabine in muscle-invasive bladder cancer

A. Choudhury*, R. Swindell*, J. P. Logue*, P. A. Elliott*, J.E. Livsey*, P. Symonds#, J. P. Wylie*, N.W. Clarke*, A.

E. Kiltie$, R.A. Cowan*

*The Christie, Wimslow Road, Manchester M20 4BX, #Leicester Royal Infirmary, Leicester LE1 5WW, $The Gray Institute, Oxford OX3 7DQ

J Clin Oncol. 2011 Feb 20;29(6):733-8. Epub 2011 Jan 4.


Outline

• Background

• Results of phase II GemX study

• Future directions


Introduction

• Radical treatment for MIBC can be radiotherapy or surgery

• Survival is ~50% at 5 years for either modality.


Comparison of RT and surgery: Disease-specific survival

Kotwal et al: Int. J. Radiation Oncology Biol. Phys., Vol. 70, No. 2, pp. 456–463, 2008


Prognostic factors

• Age/performance status

• Stage

• Renal function

• Hydronephrosis

• Unifocal disease – no widespread CIS


Patient selection for radical radiotherapy treatment

• Localised-disease muscle-invasive cancer

• Maximal Trans-Urethral Resection of Bladder

• Good bladder function

• WHO PS ≤3


Conventional whole bladder RT-The Christie1

• Maximal TURBT

• Staged using MRI pelvis and CXR

• Whole Bladder RT: 52.5 Gy/20# n=60

(1) Cowan et al. Int. J. Radiation Oncology Biol. Phys., Vol. 59, No. 1, pp. 197–207, 2004


Christie series

Cowan. R, McBain. C. et al. Int. J. Radiation Oncology Biol. Phys., Vol. 59, pp. 197-207, 2004

5yr Survival

OS: 58%

DSS: 65%


Chemoradiation

• Chemoradiation increases the rate of bladder preservation and local control compared to radiotherapy alone

• Effect on survival is unclear, although no detriment

• The optimal chemotherapy regimen is unknown


Results of Canadian Trial

Pelvic-recurrence free survivalOverall survival

Coppin et al: Journal of Clinical Oncology, Vol 14, No 11 (November), 1996: pp 2901-2907


Summary of bladder preservation studies to 2010

Rene et al. Curr Oncol > v.16(4); Aug 2009


Rationale for GemX

• Gemcitabine is effective in bladder cancer and is a potent radiosensitizer in vitro (1).

• Christie phase I study found acceptable toxicity when combined with hypofractionation (2)

(1) Sangar et al. Br J Cancer. 2004 Jan 26;90(2):542-8. (2) Sangar et al. Int. J. Radiation Oncology Biol. Phys., Vol. 61, No. 2, pp. 420–425, 2005


Christie phase I GemX study

• 3+3 design• 8 patients• T2=4, T3=4• Dose-limiting toxicity grade 3+ (RTOG)• All 8 completed RT• 6/8 completed chemoradiotherapy• G3 toxicity at 150mg/m2

• 100mg/m2 taken forward to phase II

Sangar et al: Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):420-5.


Phase II methods

• Phase II study• T2/3 N0 M0 bladder cancer• PS 0-2• 52.5 Gy/20#: CT and conformal planning• Gem 100mg/m2 weekly during RT

• Median FUp: 36 months (16-62 months)

Choudhury et al. J Clin Oncol. 2011 Feb 20;29(6):733-8. Epub 2011 Jan 4.


Centres

Manchester 31

Leeds 10

Preston 2

Leicester 7


Preliminary results compared to conventional

Age Median 67yrs

(48-84yrs)

Median 67yrs

(40-82yrs)

Gender M: 39

F: 11

M: 44

F: 16

WHO PS 0: 25

1: 19

2: 1

Not known: 5

≤1: 53

>1: 7

Histology TCC: 47

Mixed: 3

TCC: 55

Grade II: 3

III: 47

II: 8

III: 51

CIS 12

T stage T2: 40

T3: 8

T2: 17

T3: 42

Hydronephrosis 5 18


Treatment

• All patients completed RT

• 46 patients completed 4 cycles of Gem

• 2 patients had 2 courses and 2 patients had 3 courses – all four stopped due to G3 GI toxicity.


Check cystoscopy

• Median time from start of RT:• 135 days (72-248 days)

GemX Standard RT

CR 44

88%

45

75%

Superficial 3

6%

7

12%

Muscle-invasive 0 3

4%

Not done 3

6%

5

8%


Outcomes

• Median follow up: 36 months (15-61 months)

• 2 intercurrent deaths within 90 days of treatment (one MI and one pneumonia)

• 7 deaths from disease

• 5 intercurrent deaths

• 36 currently alive: 2 with metastatic disease and 5 with local superficial disease


Cystectomy post GemX

• 4 cystectomies post RT:• 8 months, 17 months, 30 months, 45 months

• Three due to recurrent disease and one due to toxicity

• One patient had a bowel resection only due to late toxicity.


Survival

• Survival calculated from start of RT

• Overall survival and disease-specific survival determined.

• 32 alive with an intact bladder


Overall survival

• 3yr overall survival: 75%; 5yr OS: 65% • Conventional RT: 3yr overall survival: 65%; 5yr OS: 58%


Disease-specific survival

• 3yr disease-specific survival: 82%; 5yr DSC: 78%• Conventional RT: 5yr disease-specific survival: 65%


Patient-reported late toxicity


Bladder preservation 2011

• BC2001: 360 pts RT v CRT: reported in abstract form

• BCON: 333 pts RT v RT+CN: ↑13% OS @ 3yrs (p=0.04)


Cause-specific survival of patients with primary v secondary cystectomy

Addla et al. The Journal of Urology Vol. 181, Issue 4, Supplement, Page 633 0 2 4 6 8 10

Years from cystectomy

0

20

40

60

80

100

Canc

er-sp

ecific

survi

val (%

)

Primary (145/313)Salvage (118/239)

p=0.39, log-rank test

313 190 118 82 52 42239 130 100 83 63 45


Where do we go from here?

• Lower T3/hydronephrosis incidence may reflect more recent surgical policy of treating poor prognosis patients?

• Where does GemX fit in?

• Role of neoadjuvant chemotherapy?

• Now giving neoadjuvant Gem/Cis with GemX and collecting toxicity data

A multicentre phase II study of hypofractionated conformal radiotherapy with concurrent gemcitabine...

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