The evidence for dose The evidence for dose escalation in prostate escalation in prostate

cancercancer

A. Choudhury

SpR, Clinical Oncology

OutlineOutline

• Radiobiology

• Evidence for dose escalation

• The CHHiP trial

Action of radiotherapyAction of radiotherapy

• DNA damage• Most lethal damage is

DNA DSB• Normal and cancer

cells

Factors affecting radiosensitivityFactors affecting radiosensitivity

Intrinsic Factors

• DNA repair

• Repopulation

• Redistribution

Extrinsic Factors

• Micro-environment

• Blood supply

αβαβ ratios and radiosensitivity ratios and radiosensitivity

2Spinal cord

5Squamous cell carcinoma

Low

10Mucosa

10Lymphoma

High

αβ ratio

Effe

ct

Tumour Dose

Tumour control

The therapeutic ratioThe therapeutic ratio

normal tissue damage

Maximum tumour kill with minimum normal tissue toxicity

Normal tissue constraintsNormal tissue constraints

• Rectum:

30% <70Gy and mean dose <50 Gy

• Bladder:

50% <70Gy

• Femoral heads:

50% <50Gy

Dose volume histogramsDose volume histograms

Radiation Dose Escalation Radiation Dose Escalation improves biochemical controlimproves biochemical control

64% vs. 80% bPFS at 5 years

55Gy/20 vs. 35.75Gy/13 + HDR 8.5Gy x 2220Hoskin

(Mt Vernon)

2007

60% vs. 71% bPFS at 5 years

64Gy/32 vs. 74Gy/37843Dearnaley

(RTO1)

2007

54% vs. 64% FFF at 5 years

68Gy/34 vs. 78Gy/39664Peeters

(Dutch)

2006

61% vs. 80% bPFS at 5 years

70.2Gy vs. 79.2Gy (proton boost)393Zietman

2005

59% vs. 78% bPFS at 5 years

70Gy/35 vs. 78Gy/39301Pollack

(MDA)

2007 update

ResultComparisonNRCT

bPFS=biochemical progression free survival FFF= freedom from failure

RT01 trialRT01 trial

• UK-based trial – largest phase III study• Compared 64Gy/32# v 74Gy/37#• Significant improvement in biochemical

progression-free survival• Significantly greater late bowel toxicity

HR=1·47 (95%CI: 1·12–1·92) (RTOG ≥2.0 ie >4-6 bowel opening,

moderate cramping) • No significant increase in bladder toxicity.

Conformal CT planned Conformal CT planned radiotherapyradiotherapy

Intensity-modulated radiotherapyIntensity-modulated radiotherapy

Radiation Dose Escalation Radiation Dose Escalation improves biochemical controlimproves biochemical control

64% vs. 80% bPFS at 5 years

55Gy/20 vs. 35.75Gy/13 + HDR 8.5Gy x 2220Hoskin

(Mt Vernon)

2007

60% vs. 71% bPFS at 5 years

64Gy/32 vs. 74Gy/37843Dearnaley

(RTO1)

2007

54% vs. 64% FFF at 5 years

68Gy/34 vs. 78Gy/39664Peeters

(Dutch)

2006

61% vs. 80% bPFS at 5 years

70.2Gy vs. 79.2Gy (proton boost)393Zietman

2005

59% vs. 78% bPFS at 5 years

70Gy/35 vs. 78Gy/39301Pollack

(MDA)

2007 update

ResultComparisonNRCT

bPFS=biochemical progression free survival FFF= freedom from failure

Mount Vernon trialMount Vernon trial

• Phase III RCT – 220 patients

55Gy/20# v 35.75Gy/13# + 17Gy/2# HDR

• Significantly improved biochemical progression-free survival (p=0.03) with HDR

• No increase in toxicity

HDR brachytherapyHDR brachytherapy

• 12-15 metal catheters inserted peripherally to about 1 cm beyond gland

• Template sutured and needles fixed in position

Treatment deliveryTreatment delivery

• A single stepping source system moves the source (Ir-192) to pre-determined positions using a motor+cable.

• Treatment (8.5 Gy per fraction) delivered in approx 10 min.

Equivalent dosesEquivalent doses

αβ ratio

77.0122.0214.535.75Gy/13# +17Gy/2#

External beam + HDR boost

70.198.2155.855Gy/20#

87.7113.1165.274Gy/37#

External beam

103.51.5

Hoskin et al, 2007

CHHiP TrialCHHiP Trial

• Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer

• Hypothesis: hypofractionated radiotherapy schedules for localised prostate cancer will improve the therapeutic ratio by either:

a) Improving tumour control

b) Reducing normal tissue side effects

Eligibility criteriaEligibility criteria

• Histologically proven carcinoma of the prostate • Clinical disease stage T1b – T3a, N0, M0 (1997

TNM System) • PSA ≤ 30ng/ml • Estimated risk of seminal vesicle involvement

under ≤30% • WHO performance status 0 or 1 • No previous androgen deprivation • Life expectancy likely to be in excess of 10 years

(5 years for poorly differentiated cancers)

Trial SchemaTrial Schema

T1B - T3A N0 M0 Estimated Risk of SV involvement ≤ 30% PSA ≤ 30ng/ml

Randomise

Group 1

74Gy / 37F 7.5 weeks (Standard)

Group 2

60Gy / 20F 4.0 weeks (Hypofractionation)

Group 3

57Gy / 19F 3.8 weeks (Hypofractionation)

Normal tissue constraints (CHHiP)Normal tissue constraints (CHHiP)

• Rectum:

30% ≤ 65Gy

• Bladder:

50% ≤ 50Gy

• Femoral heads:

50% ≤ 50Gy

The FutureThe Future

• Proton therapy

• Radiosensitisers- chemotherapy: weekly docetaxel- novel agents

• Predictive factors for radiotherapy response