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
Dose-Volume Relationship of Acute SB Toxicity
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)
Dose-Volume Relationship of Acute SB Toxicity
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%
Dose-Volume Relationship of Acute SB Toxicity
• 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
Dose-Volume Relationship of Acute SB Toxicity
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
• No Clinical Data
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
IMRT in Rectal Ca: Reduction in Bowel Dose
• 8 Patients (Glasgow) 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 in Rectal Ca: Reduction in Bowel Dose
• 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
Int J Rad Onc Biol Phy 2006
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