a multicentre phase ii study of hypofractionated conformal radiotherapy with concurrent gemcitabine...

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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.

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Outline

• Background

• Results of phase II GemX study

• Future directions

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Introduction

• Radical treatment for MIBC can be radiotherapy or surgery

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

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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

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Prognostic factors

• Age/performance status

• Stage

• Renal function

• Hydronephrosis

• Unifocal disease – no widespread CIS

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Patient selection for radical radiotherapy treatment

• Localised-disease muscle-invasive cancer

• Maximal Trans-Urethral Resection of Bladder

• Good bladder function

• WHO PS ≤3

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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

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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%

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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

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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

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Summary of bladder preservation studies to 2010

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

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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

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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.

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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.

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Centres

Manchester 31

Leeds 10

Preston 2

Leicester 7

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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

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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.

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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%

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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

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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.

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Survival

• Survival calculated from start of RT

• Overall survival and disease-specific survival determined.

• 32 alive with an intact bladder

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Overall survival

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

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Disease-specific survival

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

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Patient-reported late toxicity

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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)

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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

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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