It describes the current as well as state of the art data of neoadjuvant therapy of cancer rectum and the proposed future challenges.

1. Neoadjuvant Therapy in Rectal Cancer:
Complete Clinical versus Pathological
Response.
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University

2. Member of Advisory Board, Consultant, and Speaker for:
● Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen
Cilag, Merck Serono, Novartis, Pfizer
● The content of this presentation does not relate to any product
of a commercial interest
Speaker Disclosures:

3. Principles:
Surgery is the cornerstone in
management
However,

4. Local Recurrence Following Surgery Alone:
Clinical Colorectal Cancer, Vol. 4, No. 4, 233-240, 2004

5. Adjuvant Radiation Therapy:
Clinical Colorectal Cancer, Vol. 4, No. 4, 233-240, 2004

6. Local Recurrence: Better Insight:
Circumferential
Margins
Number Local
Recurrence
Rate
P
> 2 mm 987 3.3% < 0.0001
1 – 2 mm 100 8.5% 0.02
< 1 mm 227 13.1 0.08
Int. J. Radiation Oncology Biol. Phys., Vol. 55, No. 5, pp. 1311–1320,
2003

7. Total Mesorectal Excision (TME):
● Removal of peri-rectal
tissues involving lateral &
circumferential margins of
mesorectal envelop.
Dis Colon Rectum. 2013 May;56(5):535-50.

8. Total Mesorectal Excision (TME):
Clinical Colorectal Cancer, Vol. 4, No. 4, 233-240, 2004
N Engl J Med. 2001;345:638 – 646.
Adjuvant
Radiation
Therapy
 LR =
2.4%

9. Adjuvant Chemoradiation in Stages II & III
Rectal Cancer:
● GITSG.
● NCCTG.
● NSABP R-01.
N Engl J Med 1986; 315:1294.
FJ Natl Cancer Inst 1988; 80:21.
N Engl J Med 1991; 324:709.
Adjuvant
Fluoroupyremidine
X 2 months
CRT – 6 Weeks
Adjuvant
Fluoroupyremidine
X 2 months
Adjuvant Therapy = 6 months

10. Neoadjuvant Therapy:
The German Study: A Shifting Concept
N Engl J Med 2004;351:1731-40.

11. German CAO/ARO/AIO-94: 11 Years
Update:
Sauer R et al. JCO 2012;30:1926-33

12. Neoadjuvant Therapy:
TME Trial “Short Course”: 10 Years F.U.
10 - Year RTh + S S P
LR 5% 11% < 0.0001
OAS 48% 49% 0.86
CCSD 17% 22% 0.04
Lancet Oncol 2011; 12: 575–82
CCSD: Cumulative Incidence of Cancer Specific
Death.

13. Neoadjuvant Therapy:
TME Trial: 10-Year Subset Analysis.
Lancet Oncol 2011; 12: 575–82
OAS Benefit

14. Neoadjuvant Therapy:
Short versus Long Radiation Therapy
Course:
Polish Trial Trans-Tasman
Radiation
Oncology Group
• Local Recurrence.
• DFS
• Distant Recurrence
• OAS
• Severe Late
Toxicity
EQUIVALENT
J Clin Oncol 2012; 30:3827.
Br J Surg 2006; 93:1215
Distal Tumors:
LC > SC
LR = 0 : 12

15. Radiation + Chemotherapy are
MANDATORY in Neoadjuvant Therapy:
Gastrointest Cancer Res 1:49-56. ©2007 by International Society of Gastrointestinal
Oncology

16. Neoadjuvant Therapy:
The Use of Capecitabine:
The Cancer Journal • Volume 13, Number 3, May/June 2007
EQUIVALEN
T

17. Neoadjuvant Therapy:
Adding Oxaliplatin:
Curr Opin Oncol 2012, 24:441–447
• ++ Toxicity & -- Compliance.
• Did not improve:
1. R0 RR.
2. pCR.
3. Sphincter Preservation

18. The PETACC-6 RCT<br />
Neoadjuvant Therapy:
Adding Oxaliplatin:

19. <br />PETACC-6: <br />Early analysis at 31 months shows no major differences between arms<br />
Neoadjuvant Therapy:
Adding Oxaliplatin:

20. Neoadjuvant Therapy:
Adding EGFR Inhibition:
Curr Opin Oncol 2012, 24:441–447

21. Neoadjuvant Therapy:
Adding VEGF Inhibition:
Curr Opin Oncol 2012, 24:441–447

22. Neoadjuvant Therapy:
Indications:
1. T3 – T4 Lesions: The only definitive indication.
2. cT3N0: Should be treated (understaging).
3. Depth of Extramural Invasion:
– T3 lesions (>5 mm)  ++ LNs involvement 
Higher Cancer Specific Mortality (54% Versus 85%).
– Selection of high risk T3 for treatment.
– Approved outside US.
4. T1 – 2 lesions with Positive Nodes.
5. Low situated lesions.
6. Invasion of mesorectal fascia.
Br J Cancer 2000; 82:1131
www.uptodate.com (September 2015)

23. Neoadjuvant Therapy:
Treatment Outcome:
Complete
Response
cCRpCR
• 15 – 30%.
• Small & Less
Advanced
Lesions
• 10 – 12 Weeks.
• Involution to flat
scar.
• DRE & Endoscopy.
• Imaging:
• Endorectal US
• PET-CT
• MRI.
• ypT0N0
Martin R. et al. Surg Oncol Clin N Am 23 (2014) 113–125

24. Neoadjuvant Therapy:
Treatment Outcome in Relation to
Pathological Outcome: German Study:

25. Grade Regression Fibrosis
0 No All cells are viable
1 Minor < 25% fibrosis
2 Moderate 26 – 50%nFibrosis
3 Good >50%
4 Total No Viable Cells
Neoadjuvant Therapy:
Tumor Regression Grade:
Grade 10 – year
DM
P 10 – Year
DFS
P
0 - 1 39.6%
0.005
63%
0.0082 - 3 29.3% 73.6%
4 10.5 % 89.5%
J Clin Oncol 32:1554-1562. © 2014

26. Neoadjuvant Therapy:
Impact of Pathological CR:
British Journal of Surgery 2012; 99: 918–928
Can we Avoid Surgery?

27. Can we Avoid Surgery?

28. Can we Avoid Surgery?
JCO. VOLUME 29 􏰉 NUMBER 35 􏰉 DECEMBER 10 2011
21 Patients
pCR
Neoadjuvant CRT
For Stages II & III
Wait & See
MRI, Endoscopy &
Biopsy
Median Follow up
=25 months
1 Patient  LR
 Surgery
20 Pts, Stages II &
III  NAT  pCR
Median Follow up
=35 months
2 – Year DFS: 91%
2 – Year OAS: 93%

29. Neoadjuvant Therapy:
Problems with Current Practice:
CRT
5.5 Weeks 6 wks
TME
1 – 2 weeks
4-6
wks
Adjuvant Cth
18 weeks
• Delayed.
• Reduced.
• Omitted
CRT TME
Neodjuvant
Chemoth.
Neodjuvant
Chemoth.
CRT TME
Adopted from Deborah Schrag’s Presentation at 2015 ASCO Annual Meeting

30. Total Neoadjuvant Paradigm:
Brown University Study (CONTRE)
FOLFOX
X 8 Courses
CRT + Cape TME
Pathologic
Grade
Total Number Stage II Stage III
38 7 31
0 (Complete) 13 1 12
1 14 4 10
2 8 1 7
3 3 1 2
• 35 Pts Completed Treatment.
• pCR = 33%.
Perez et al. ASCO 2014, Abstract 3050

31. The Cochrane Review Metanalysis Demonstrates DFS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on DFS:

32. The Cochrane Review Metanalysis Demonstrates OS Adjuvant Treatment Benefit
Impact of Adjuvant Therapy on OAS:

33. Slide 12

34. Near total neoadjuvant therapy

35. Postop Adjuvant 5FU or FOLFOX for Rectal Cancer: The ADORE Trial: Randomized Phase II <br />

36. <br />German CAO/ARO/AIO-04 Study:<br />Adjuvant FOLFOX has better DFS, not OS than 5FU after pre-op ChemoRT

37. Questions: Total Neoadjuvant: Yes/No?
Adjuvant Cth: Yes/No?
Long versus Short Course?

38. PROSPECT: N1048 is ongoing<br />Selective Use of Pelvic XRT<br />
Can we Omit Radiation From NAT?

39. MSKCC 07-021: Phase II Trial of Selective Radiation for Rectal Cancer
Can we Omit Radiation From NAT?

40. What to do today?
● Clinical Trial whenever possible.
● Careful assessment.
● Chemosensitization by 5-FU or Capecitabine is enough.
● Upfront chemotherapy is appealing  Total & Near Total
NAT should be encourgaed  pCR.
● TME IS THE STANDARD SURGICAL APPROACH
(STAGES II & III).
● Postoperative chemotherapy should be discussed and
considered for high risk patients  DFS.