rectal cancer: advanced technologies chris willett, m.d. department of radiation oncology duke...

Rectal Cancer: Advanced Technologies

Chris Willett, M.D.

Department of Radiation Oncology

Duke University Medical Center

Durham, NC

Gastric Intergroup 0116: RT Considerations

• 35% of initially submitted RT plans: Major deviations (2/3 undertreatment)

• 2 D Therapy: AP/PA

www.rtog.org 3

Median Survival By Rx Arm AndMedian Survival By Rx Arm And RT Compliance—All Patients RT Compliance—All Patients

Treatment ArmTreatment Arm Per protocolPer protocol Variation Variation AcceptableAcceptable

VariationVariation

UnacceptableUnacceptable

p-value p-value for trend for trend

(1 sided)(1 sided)

5FU Arm5FU Arm 1.50 yrs1.50 yrs 1.52 yrs1.52 yrs 1.18 yrs1.18 yrs

0.080.08

n / (95% CI)n / (95% CI) 117 /(1.28, 1.90)117 /(1.28, 1.90) 82 /(1.21,1.91)82 /(1.21,1.91) 12 /(1.06,1.84)12 /(1.06,1.84)

Gem ArmGem Arm 1.89 yrs1.89 yrs 1.41 yrs1.41 yrs 1.37 yrs1.37 yrs

0.030.03

(n / 95% CI)(n / 95% CI) 99 /(1.54, 2.48)99 /(1.54, 2.48) 94 /(1.24,1.73)94 /(1.24,1.73) 12 / (1.18, 2.37)12 / (1.18, 2.37)

Stage II/III Rectal Ca: 2006 Management

• Preoperative EBRT + 5-FU Based ChT

• Surgery

• Adjuvant ChT

Preoperative EBRT: Rectal Ca

• CTV: 45 Gy / 1.8 Gy Fx

• GTV: 50.4 (T3) – 54 Gy (T4) / 1.8 Gy Fx

• 3 Fields (PA and Laterals) or 4 Fields (AP/PA and Laterals)

• Minimize SB Tx: Prone / False Table Top / Bladder Distention

T4 Rectal Cancer: 4 Fields

M. Mohiuddin 2006

Ph III German Trial (CAO/ARO/AIO-94)

823 Pts. with cT3/T4 or N+ randomized to:

• Preop 5-FU and Leucovorin / EBRT and TME Surgery

• TME Surgery and Postop 5-FU and Leucovorin / EBRT (Stage II/III)

NEJM 2004

CAO/ARO/AIO-94 Trial: 5 Yr Results

Pelvic

Failure

(%)

DM

(%)

DFS

(%)

OS

(%)

Preop Tx

(405 Pts)

7* 30 59 78

Postop Tx

(392 Pts)

11 34 55 73

CAO/ARO/AIO-94 Trial: Results

pCR

(%)

Acute GI

G 3/4

Toxicity

(%)

Late G 3/4 GI Toxicity

(%)

Sph

Preserv

Rate

(%)

Preop Tx

(405 Pts)

8* 12 * 13* 39*

Postop Tx

(392 Pts)

0 18 27 19

CAO/ARO/AIO-94 Trial: Conclusions

Preop ChT + EBRT vs Postop ChT+EBRT:

• Improved LC (93%)• Distal Lesions: Enhanced Sphincter

Preservation• Less G3/4 Acute (12%) / Chronic GI

Toxicity (18%)

PMH Phase 2 Trials: Results

Dose (Gy)

pCR (%) 2 Yr LC (%)

2 Yr DFS (%)

Acute G3/4 Toxicity (%)

40(n=46) 15 72 62 13

46(n=52) 23 90 84 4

50(n=36) 33 89 80 14

Fox Chase Phase I Rectal Ca

Dose (Gy): 45 Gy + 1.2 BID

Downstaging

54.6 (n=10) 50%

57 (n=7) 57%

61.8 (n=6) 67%

23 Pts: 4 pCR (17%)

Rectal Ca: New Agents with EBRT

• Oral 5-FU: Capecitabine (TS inhibition)• Irinotecan (topo I inhibitor)• Oxaliplatin (inter & intra-strand DNA cross-links)• Anti EGFR: Cetuximab, Gefitinib, Erlotinib• Anti-VEGF: Bevacizumab

RTOG 0012: CPT-11, 5-FU & RT Preop

Phase II, Pts with cT3-T4 Disease Randomized to:

CPT-11 + 5-FU & RT 50.4-54 Gy/1.8 Gy qd

5-FU & RT 55.2-60 Gy/1.2 Gy bid

Opened: February 2002 Accrual: 100 Closed: January 2003

R

JCO 2006

RTOG 0012: Results pCR

(%)

Acute

G ¾ GI

Toxicity

(%)

Late G 3/4

GI Toxicity

(%)

EBRT / 5-FU + CPT-11 (54 Pts)

28 19 2.0

EBRT / 5-FU

(52 Pts)

28 13 2.0

CALGB 89901 Phase I/II: Oxali, 5-FU & RT Preop

M T W Th F Sa SuOxal

X

5FU X X X X X X XXRT X X X X X

5FU 200mg/m2/d; RT 50.4Gy; Oxali 30–60mg/m2/d

MTD = 60 mg/m2, Gr 3 diarrhea21/32 (66%) completed 6 cycles26/32 (81%) completed 4 cycles

JCO 2006

CALGB 89901: Results

pCR

(%)

Acute

G3/4

Diarrhea

(%)

Late G 3/4

GI Toxicity

(%)

EBRT / 5-FU + Oxaliplatin (Phase II– 32 Pts)

25 37 No Comment

RTOG 0247: Cape, RT + Oxali or CPT-11 Preop

Phase II, Pts with cT3-T4 Disease Randomized to:

Oxali (50 d 1, 8, 15, 22 & 29), Cape (825 BID, 5 d per w) & RT 50.4 Gy/1.8 Gy qd

CPT-11 (50 d1, 8, 22 & 29), Cape (600 BID, 5 d per w) & RT 50.4 Gy/1.8 Gy qd

Opened: February 2004 Amended: March 2005 Planned Accrual: 141

R

E5201 Preop INT Trial

Preop CMT*

FOLFOX

SURG

Bevacizumab±

* = bolus 5FU ± LV, CI, or capecitabine

NSABP R-04 Preop

Capecitabine (825 mg BID) 50.4 Gy

CI 5-FU (225 mg/m2/d) 50.4 Gy

+ Oxaliplatin (60 mg/m2 qw)

+ Oxaliplatin (60 mg/m2 qw)

Stratify

• T2 vs. T3• M vs. F• SP vs. APR

n=1460

Rectal Ca: Preoperative Tx

New Cytotoxic Agents + 5-FU during EBRT : Higher Rates of Acute GI Toxicity

• ? Rates of Late GI and other Toxicity

Dose-Volume Relationship of Acute SB Toxicity

• 40 Rectal Ca Pts: EBRT (50.4 Gy) + 5-FU

• 3 D Tx Planning with SB excluding techniques – bladder distention, prone position, false table top.

• Correlate Acute SB Toxicity (Diarrhea/Pain) to Volume of SB Irradiated

Baglan et al: Int J Rad Onc Biol Phy 2002


40 Patients – Overall Toxicity Rates

• Grade 0: 7/40 (17.5%)

• Grade 1: 15/40 (37.5%)

• Grade 2: 8/40 (20%)

• Grade 3: 10/40 (25%)

• No Grade 4/5

Dose (Gy) Threshold V G3 SB Toxicity

5 500 45% (10/22)

10 300 53% (10/19)

15 150 50% (10/20)

20 145 53% (10/19)

25 140 59% (10/17)

30 140 59% (10/17)

35 135 59% (10/17)

40 125 59% (10/17)


Volume Effect: Acute SB Toxicity

V15 (cm3) # Pts G0-2 SB Toxicity

G3 SB Toxicity

<150 20 100% 0%

150-299 20 70% 30%

≥ 300 20 30% 70%


• 41 Rectal Ca Pts: EBRT (45 Gy) + 5-FU/Leucovorin

• All 3 D Tx Planning

• Correlate Acute SB Toxicity (Diarrhea) to Volume of SB Irradiated

Tho et al: Int J Rad Onc Biol Phy 2006

Diarrhea<G2

Median SB V

Diarrhea ≥G2

Median SB V

V5 24 276

V10 16 274

V15 4 194

V20 0 94

V30 0 70

V35 0 64

V40 0 54

>V42.75 0 23


Rectal Ca: 3-D

Rectal Ca: IMRT

IMRT in Rectal Ca: Reduction in Bowel Dose

• Royal Marsden: 5 Patients with Locally Advanced Rectal Ca

• Dosimetric Comparison of 3-D Conformal Radiation Therapy to IMRT

• No Clinical Data

Int J Rad Onc Biol Phy 2006

IMRT: Reduction in V of Bowel Irradiated to High Dose

Mean

Dose (Gy)

V50

(%)

V45(%) V40 (%)

3 D

CRT

27.1 6.4 26.4 31.4

IMRT

9 Field

28.3 2.6 9.0 21.6

IMRT

5 Field

28.2 2.2 8.2 21.0

IMAT in Rectal Ca: Reduction in Bowel Dose

• Ghent Hospital: 7 Patients with Locally Advanced Rectal Ca (4 Pre and 3 Post)

• Dosimetric Comparison of 3 D Conformal Radiation Therapy to IMAT


IMAT: Reduction in V of Bowel Irradiated to High Dose

Mean

Dose (Gy)

V90

(%)

> V15

(%)

3 D

CRT

17.0 19.1 45.6

IMAT 12.4 6.6 33.0


• 8 Patients (Glasgow) with Locally Advanced Rectal Ca

• Dosimetric Comparison of 3-D Conformal Radiation Therapy to IMRT




• With the use of IMRT vs. 3 D CRT: Statistically significant reduction in Median dose (5.08 Gy) and Mean dose (3.15 Gy) to Small Bowel


Conclusions

• GI Toxicity (Acute and Late): Important Consideration

• Toxicity will increase with new agents with template of EBRT (50 Gy) + 5-FU

• Dosimetric plans show reduction in Bowel irradiation with IMRT vs. 3 D CRT

• No Clinical Data• Clear Need for Phase II Trials with IMRT

rectal cancer: advanced technologies chris willett, m.d. department of radiation oncology duke...

Documents