Presentations of Localized Rectal Cancer

1
IORT Rationale in Times of Chemoradiation
ISIORT 2008 Madrid, Spain
Brian Czito, MD Associate Professor Department of
Radiation Oncology Duke University Medical
Center Durham, NC USA
2
Rectal Cancer Radiation Therapy

• The Traditional U.S. Approach
• Postop Pelvic RT with Concurrent Maintenance
  5-FU Based ChT For Pts With Resected Stage II and
  III Dz

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Rationale Of Adjuvant Tx

• Criteria For Tx Based On Operative And
  Pathological Findings
• Minimize Over-Treatment (Stage I, IV, ?? Select
  T3 N0T1-2 N1)

4
Rationale Of Adjuvant Tx

• LF after surgery gtT3 dz-common (historically
  30)
• The U.S. Trials of the 1980s and 1990s Have
  Validated This Approach For Stage II III Rectal
  Cancer

5

Postoperative Randomized Trials
Local Failure
Distant Failure Overall Survival GITSG
(1986) Surgery 24
34
28 Surgery Chemo 27
27 43 Surgery
Radiation 20
30 43 Surgery
Chemoradiation 11 26
57 NSABP R-01 (1988) Surgery
25
26 48 Surgery
Chemo 21
24 58 Surgery Radiation
16 31
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6
Postoperative Randomized Trials
Local
Failure Distant Failure Overall
Survival NCCCG/Mayo (1991) Surgery Radiation
25 46
38 Surgery Chemoradiation 14
29 53
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Justification of ChemoradiationPostoperative
Randomized Trials
Local Failure
Distant Failure Overall Survival Intergroup
(1992) Surgery ChemoRT -
40 60 (Bolus
5FU) Surgery Chemo RT -
31 70 (PVI
5FU)
8
Rectal Cancer Important Clinical Trials
(2001-2004)

• TME Is RT Necessary?
• Preop RT(? ChT) vs. Postop RT(?ChT)?

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Total Mesorectal Excision
10
Total Mesorectal Excision
Moderate, irregularity
Optimal TME
Poor TME
of mesorectal surface
11
TOTAL MESORECTAL EXCISION
lower edge of mesorectum
upper anal canal
Distal resection margin after TME is about 2cm
above dentate line.
12
Dutch CKVO 95-04 Study
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Dutch CKVO 95-04

• TME training workshops, symposia, video
  instruction, direct supervision of first 5
  procedures

14
Dutch CKVO 95-04 Results- 5 Yr
LF OS
LF-M LF-M- 25 Gy/TME 5.8 64
15.5 3.7 TME
11.4 64 23.3
9.1 Caveat 56 Stage I/II

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MRC CR07 Preop RT vs Selective Postop RT/ChT
25 Gy TME TME 45 Gy/5-FU (
Radial Margin)
Operable Rectal Cancer
Stage III ChT
n1350
Sebag-Montefiore ASCO 2006
16
MRC CR07 Trial 3 Yr Results
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MRC CR07 Importance of Surgical Dissection and
RT
Quirke ASCO 2006
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Advantages Of Preop EBRT

• Improved Tolerance (Less Normal Tumor Irradiated)
• Sphincter Preservation
• Improves Resectability for T4 tumors
• ? Better oxygenated tumor/ ?drug delivery
• Disadvantage Potential for overtreating T1 and
  T2 cancers

19
Advantages Of Preop EBRT

• Tumor Can Be Clearly Defined Digital, Endoscopy,
  Imaging Findings
• New Era Of Novel Agent - Irradiation Combinations

20
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
  Vs. TME Surgery and Postop 5-FU and Leucovorin /
  EBRT (Stage II/III)

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CAO/ARO/AIO-94 Trial Results
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Preop vs. Postop RT/ChT The German Rectal Cancer
Study Group
Increase in sphincter preservation in preop group
NEJM 20043511731-40
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CAO/ARO/AIO-94 Trial 5 Yr Results
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CAO/ARO/AIO-94 Trial Conclusions

• Preop ChT EBRT vs Postop ChTEBRT
• Improved LC
• Distal Lesions Enhanced Sphincter Preservation
• Less Acute Toxicity
• Less Chronic Toxicity (14 vs 24)

25
Selected Ph III Trials of Preoperative RT/ChT for
T3/4 Rectal Ca Pts
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Neoadjuvant vs Adjuvant Tx Rectal Cancer

• Hard Data Phase III German Trial
• Strong Evidence For Enhanced Sphincter Sphincter
  Preservation
• Incorporation of New Cytotoxic as well as Novel
  Agents Into Current Protocols

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Radiation Sensitization New Agents

• Capecitabine (Oral 5-FU)
• Thymidylate synthetase inhibition
• Irinotecan
• Topoisomerase I inhibition
• Oxaliplatin
• Inter/intra-strand DNA crosslinks
• Anti-EGFR Cetuximab, Gefitinib, Erlotinib
• Anti-VEGF Bevacizumab

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Neoadjuvant Capecitabine/RT
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Phase I / II Oxaliplatin/EBRT Studies
30
NSABP R-04Phase III of Preoperative
Capecitabine Chemoradiation in Rectal Trial
Resectable Stage II and III Rectal Cancer
Stratification Gender Tumor Stage (II vs III)
Intended Surgery (Sphincter Saving vs Other)
XRT (45Gy in 25 Fractions) Capecitabine 825
mg/m2 BID Continuously During XRT
XRT (45Gy in 25 Fractions) CI 5-FU 225 mg/m2/Day
During RT
Oxaliplatin
Placebo
Placebo
Oxaliplatin
Surgery
5.4Gy boost for non-fixed tumors, 10.8Gy for
fixed tumors
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Europe PETACC-6
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Phase I / II Cetuximab/EBRT Studies
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Bevacizumab
Bevacizumab, oxaliplatin, and capecitabine with
radiation therapy in rectal cancer Phase I trial
results. Czito BG, Bendell JC, Willett CG, Morse
MA, Blobe GC, Tyler DS, Thomas J, Ludwig KA,
Mantyh CR, Ashton J, Yu D, Hurwitz HI.
IJROBP 2007
Complete pathological response to bevacizumab and
chemoradiation in advanced rectal cancer. Willett
CG, Duda DG, di Tomaso E, Boucher Y, Czito BG,
Vujaskovic Z, Vlahovic G, Bendell J, Cohen KS,
Hurwitz HI, Bentley R, Lauwers GY, Poleski M,
Wong TZ, Paulson E, Ludwig KA, Jain RK.
Nat Clin Pract Oncol 2007
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Local Control

• Using preop CMT? modern surgical techniques
  approx 92-97 at 5 yrs!
• Should we declare victory, holster the IORT gun
  and leave the battlefield?

35
Dutch CKVO 95-04 update

• Multivariate (LC) RT, tumor location, TNM stage,
  radial margins
• Stage III LR 21 S alone, 11 RT?S
• R 20-24
• Local recurrences may recur late (curve still
  rising at 8 yrs)
• Conc Even with optimal surgery, LR rates remain
  high in pts with locally advanced disease,
  potentially compromised margins

Ann Surg 2007
36
Locally Advanced Dz

• Variable definitions tethered to deeply invasive
  of other organs
• Practical definition R0 resection unlikely
• Problem pts preop RT?R0 resection-historically gt
  1/3 LF

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MDAH

• 45 pts T4 disease
• CMT? radical resection (only 3 IORT)
• LF4- 20
• LF5 (R0 pts only) 30
• Almost all LF in RT field
• Conc T4 dz pts high risk of LF despite CMT with
  aggressive resection

IJROBP 2001
39
Locally Advanced Rectal

• U Heidelberg
• 243 pts T3/4, gt 5mm perirectal spread or N
• Pre/postop CMT, IOERT 10-15 Gy
• LF all 7 preop 3
• LC5 presacral space (IORT field) 97
• LC RFs N (89 v 97), R (72 v 94)
• T4 LC5 93

IJROBP 2007
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Locally Advanced Rectal

• Conc IORT significantly ? LF
• RF for LC N, R
• Encouraging LC rates T4 dz

42
Netherlands

• 123 pts with locally advanced (narrow/no margin
  on mesorectal envelope by imaging) or
  unresectable (T4) disease
• 50 Gy EBRT?S
• 27 pts IORT margins lt 2mm
• LC 58 IORT vs 0 S alone R pts
• Conc IORT improves LC/OS in pts with close/
  margins

Dis Colon Rectum 2006
43
University Hospital Gregorio Maranon, Madrid

• 281 pts (95 gt T3, 58 N)
• CMT?S /- IORT
• Crude pelvic recurrence rate 8.5, most
  presacral
• Presacral recurrence /- IORT 3 vs 11 (sig)
  Presacral recurrence 10yrs 95 vs 84
• Conc IORT improves presacral control in LA
  rectal cancer close margins, N dz, no adjuvant
  chemo may impact LC rates

ISIORT 2008
44
European Pooled Analysis

• Netherlands, Rome, Heidelberg, Madrid
• 651 pts locally advanced rectal cancer treated
  with multimodal therapy including IORT
• OS5/LC5 67/88
• Conc IORT based CMT in marginally resectable pts
  results in excellent long-term outcomes

ISIORT 2008
45
Local Recurrence

• What we are trying to avoid
• Poor prognosis-historically 5 yr S 0-5
• Significant morbitity/mortality
• Limited EBRT options if previously tx
• Therapeutic nihilism

46
Mass General

• 69 pts LR rectosigmoid cancer
• 60/69 previously unirradiated
• EBRT/- ChT?S with possible IORT
• OS5/LC5 27, 35
• R0 vs R1 OS5 40 vs 14
• LC5 56 vs 17
• Most pts distant dz
• Conc IORT important in multimodal salvage
  curative resection important

Radiother Oncol 2001
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Mayo Clinic

• 607 pts resected, recurrent rectal cancer
• 65 prior EBRT 60 chemotherapy
• 96 RT b/f or after S with IORT
• OS5 30 LF 38, DM 62
• R0 OS5 46 R1 27 R2 16
• Conc Long-term S possible, esp with R0 resection

ISIORT 2008
48
Netherlands

• 147 M0, locally recurrent pts
• Preop RT /- chemo (50.4 Gy, 30.6 Gy if prior
  RT)?S IORT
• Med OS 28 mo OS5 32 LC 54
• Conc Multimodal therapy with radical resection
  is indicated, including reirradiation

ISIORT 2008 Ann Surg Oncol 2008
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Rectal Cancer Summary

• Adjuvant CMT tried and true, but.
• Preoperative 5-FU Radiation is a new standard
  in Stage II-IV Dz
• RT ?TME improves LC vs TME alone
• Current studies evaluating integration of new
  agents into treatment
• Locally advanced pts High rates of LF despite
  neoadjuvant CMT with TME

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Rectal Cancer Summary

• IORT improves LC rates and ultimate outcomes
• Appropriate candidates include adjacent organ
  adherence, potentially close/compromised margins
• Locally recurrent pts treat aggressively when
  appropriate OS5 20-35
• Even with IORT, distant failure remains a major
  obstacle

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Thank You