Presentation given by Ian Geh, Queen Elizabeth Hospital & Heartlands Hospital, at the Dukes' Club AGM.

1. Dukes' Club Annual Meeting, Kenilworth. 24-26 February 2012
What's New in Rectal
Cancer? The Apparent
Complete Response
Ian Geh
Consultant Clinical Oncologist
Queen Elizabeth Hospital & Heartlands Hospital
Birmingham, UK
Ian.Geh@uhb.nhs.uk

2. Preoperative Radiotherapy Schedules for
Rectal Cancer
Long Course Pre-operative Radiotherapy
6-12 weeks Surgery
phase I 45Gy in 25F; (phase II 5.4Gy 3F)
Short Course Pre-operative Radiotherapy (SCPRT)
Max 10 days Surgery
25Gy in 5F

3. Preoperative Radiotherapy Schedules for
Rectal Cancer
Long Course Pre-operative Radiotherapy
6-12 weeks Surgery
phase I 45Gy in 25F; (phase II 5.4Gy 3F)
Long Course Pre-operative Chemoradiotherapy (CRT)
capecitabine 825 mg/m2
6-12 weeks Surgery
phase I 45Gy in 25F; (phase II 5.4Gy 3F)

4. Addition of Radiotherapy to Surgery
Non-TME Surgery TME Surgery
EORTC
RT (5 wks)
FFCD
EORTC German
CRT (5 wks) FFCD Polish
NSABP R-03 Australasian
Dutch
MRC CR07
SCPRT (1 wk) Swedish
Polish
Australasian
Dutch
Surgery Swedish
MRC CR07
Post op CRT NSABP R-03 German

5. Local Recurrence
Non-TME Surgery TME Surgery
17%
RT (5 wks) -
17%
9% 6%
CRT (5 wks) 8% 16%
11% 4%
6%
5%
SCPRT (1 wk) 11%
11%
7%
11%
Surgery 27%
11%
Post op CRT 11% 13%

6. pCR in Resected Patients
Non-TME Surgery TME Surgery
5%
RT (5 wks) -
4%
14% 8%
CRT (5 wks) 11% 16%
15% ns
1%
0%
SCPRT (1 wk) 0%
1%
ns
2%
Surgery -
-
Post op CRT - -

7. Radical Resection for Rectal Cancer:
One Size Fits All?
• How do we achieve best results at the minimum price?
Locally advanced cancers
Early rectal cancer
• Postoperative morbidity & mortality
Most units 2-5%
High risk groups
• Permanent stoma 10-30%
Variation between surgeons, units & networks
Higher rates in socially deprived regions
• Long-term sequelae
Sphincter and sexual function
Second cancers

8. What happens if there is no tumour?
• Pathological complete response (pCR)
What does this mean?
Was surgery necessary?
• Microscopic foci of residual disease
What does this mean?
Would pCR occur if I waited longer?

9. Significance of pCR Following
Preoperative RT
• Measure of efficacy of preoperative RT
3-4% from RT alone
10-30% from CRT

10. Significance of pCR Following
Preoperative RT
• Measure of efficacy of preoperative RT
3-4% from RT alone
10-30% from CRT
• Associated with improved outcomes

12. Significance of pCR Following
Preoperative RT
• Measure of efficacy of preoperative RT
3-4% from RT alone
10-30% from CRT
• Associated with improved outcomes
• Can we abandon surgery if pCR achieved?

13. Nigro et al. Dis Colon Rectum 1974; 17: 354-6

14. Preoperative CRT in Anal Cancer
CRT: 30 Gy in 15 fractions over 3 weeks
mitomycin C (d1) & 5FU (d1-4, 29-32)
Surgery: 4-6 weeks later
no. pCR %
APR 12 7 58
Local excision 14 14 100
No biopsy 2 - total 81%
Nigro et al 1983

15. Mitomycin/5FU CRT in Anal Cancer
No. CvM T3-4 Gy Boost LRC CFS OS
UKCCCR 295 65% 51% 45 15-20 61% - 65%
EORTC 51 100% 77% 45 15-20 68% 72% 70%
RTOG 87-04 146 100% 47% 45 ±9 - 80% 80%
RTOG 98-11 322 100% 26% 36-45 ±10-14 75% 90% 84%
Birmingham 133 68% 54% 30 20-25 84% 60% 81%

16. Radiotherapy Instead of Surgery
Habr-Gama et al. Reassess 8 wks
Ann Surg 2004
No residual
Long disease:
course Follow up
265
CRT
Resectable 50.4 Gy
rectal ca in 28 F
0-7 cm
Clinical
5FU/FA
Residual
d1-3
Disease:
d36-38
Resection

17. Radiotherapy Instead of Surgery
Habr-Gama et al. Reassess 8 wks Follow up schedule:
Ann Surg 2004
No residual
Long disease: DRE, proctoscopy, CEA
course Follow up Y1 monthly
265
CRT Y2 2 monthly
Resectable 50.4 Gy
rectal ca in 28 F Y3 6 monthly
0-7 cm
Clinical
5FU/FA CT abdo / pelvis
Residual
d1-3
Disease: 6 monthly
d36-38
Resection

18. Radiotherapy Instead of Surgery
Habr-Gama et al. Reassess 8 wks
Ann Surg 2004
No residual
Remains clear at 12 m
Long disease: Stage 0
course Follow up
265
CRT
Resectable 50.4 Gy
rectal ca in 28 F 194 (73%)
0-7 cm yp st 0 (pCR)
Clinical
5FU/FA
Residual
d1-3
Disease:
d36-38 yp stage I – III
Resection

19. Radiotherapy Instead of Surgery
Habr-Gama et al. Reassess 8 wks 71 (27%)
Ann Surg 2004
No residual
Stage 0 71 (27%)
Long disease: If clear at 12 m
course Follow up
265
CRT
Resectable 50.4 Gy Total stage 0 93 (35%)
rectal ca in 28 F 194 (73%)
0-7 cm pCR (stage 0) 22 (8%)
Clinical
5FU/FA
Residual
d1-3
Disease: yp stage I – III
d36-38
Resection 172 (65%)
Stage 0 group: 10y OS 98%, DFS 84%, 2 LRs

20. Recent Series of Non-Operative
Management
No. cCR LR (%)
Brazil (Habr-Gama 2004) 265 71 (27%) 2 (3%)
Mt Vernon (Hughes 2010) - 10 6 (60%)
MSK (Smith 2012) 311 32 (10%) 6 (19%)
Exeter (Dalton 2011) 49 12 (24%) 0 (0%)
Holland (Maas 2011) 192 21 (11%) 1 (5%)
Marsden (Yu 2011) - 19 9 (47%)

21. Factors Influencing pCR Following
Preoperative RT
• Size and stage of tumour
Locally advanced (T3-4) tumours
Early (T1-2) tumours
• Timing of surgery following completion of
preoperative RT
• Thoroughness of pathologist
Will he find the needle in the haystack?
• Radiotherapy & chemotherapy

22. Factors Influencing pCR Following
Preoperative RT
• Size and stage of tumour
Locally advanced (T3-4) tumours vs early (T1-2) tumours
No. Selection for CRT pCR
Birmingham 267 CRM threatened 7%
German 2004 421 uT3/4 or N1 8%
FFCD 2006 375 non selective 11%
EORTC 2006 506 non selective 14%
ACOSOG 2010 94 T2 44%
Bujko 2009 44 mainly T1/T2 54%

23. Factors Influencing pCR Following
Preoperative RT
• Timing of surgery following completion of
preoperative RT
Longer duration results in better tumour response and
pathological downstaging
Does this translate to better outcomes?
Could outcomes be worse?
NCRI 6 vs 12 Week Trial

24. Factors Influencing pCR Following
Preoperative RT
• Thoroughness of pathological examination
Will he find the needle in the haystack?
Lack of standardisation of definition of pCR

25. Obliterated
vein
Fibrosis and previous site of vascular invasion

28. Standardisation of Definition of pCR
Consensus from CORE II Trial;
• Take 5 blocks from site of tumour, if no residual tumour;
• Embed whole of suspicious area, if no residual tumour;
• Take 3 levels through each block, if no residual tumour;
• Defined as pCR

29. Factors Influencing pCR Following
Preoperative RT
• Radiotherapy & chemotherapy
Optimal RT dose & fractionation
Interaction between RT and chemotherapy;
• choice of chemotherapy drug(s)
• optimal scheduling of chemotherapy

30. Systematic Review of Preoperative
CRT Trials
64 Phase II-III Trials (4372 pts)
No. Adjusted 95% CI p=
pCR mean
Use of second drug 1280 0.17 0.13-0.23 0.001
Delivery of 5FU / equiv. 929 0.20 0.16-0.24 0.03
Radiation dose <45 Gy 481 0.09 0.05-0.14 0.02
Sanghera et al. Clin Oncol 2008

31. Addition of Oxaliplatin to
Fluoropyrimidines: Trials
5FU Capecitabine
NSABP R-04 NSABP R-04
CAO/ARO/AIO-04 PETACC-6
No Oxaliplatin
STAR-01 ACCORD 12
German MARGIT German MARGIT
NSABP R-04 NSABP R-04
Oxaliplatin CAO/ARO/AIO-04 PETACC-6
STAR-01 ACCORD 12

32. Addition of Oxaliplatin to
Fluoropyrimidines: pCR Rates
5FU Capecitabine
19%
22%
13%
No Oxaliplatin 14%
16%
14%
5%
19%
21%
Oxaliplatin 17%
19%
16%

33. NCRI Aristotle Trial
R 460 CRT 45 Gy 25F TME
A Capecitabine Surgery
MRI Defined N
Locally D
Advanced O
Rectal M
AdenoCa I CRT 45 Gy 25F
460 TME
S Irinotecan
Surgery
E Capecitabine
Tumour at / beyond fascia
Very low tumour (levator / sphincter / anal canal involved)

34. UK Perspective
• Standard of care is different from USA and most of
Europe
• pCR rates depend on MDT 'threshold' to give CRT;
any T3?
any N1?
CRM threatened only?
• CRT reserved for locally VERY advanced rectal cancers
• Very few patients with clinical CR

35. Clinical Complete Response Not
Achieved
• Proceed with planned surgery;
% with pCR
% with residual tumour?

37. Clinical Complete Response Achieved
• Proceed with planned surgery;
% with pCR
% with residual tumour?
• Wait and watch;
Optimum follow up strategy and for how long?
How salvageable are recurrences?
% cured?
– NCRI Wait and Watch Trial

38. Future Developments
• Early rectal cancers
Higher pCR rates
Balancing number of patients at risk of 'overtreatment'
• Better predictive tools of pCR
• Better CRT regimens

39. Summary
• pCR is the key to progress for non-surgical
treatment
• Outcomes of 'true pCRs' are excellent
irrespective of surgical management
• Challenges of non-surgical management
– management of early stage cancers
– achieving a suitable compromise for patient
– successful salvage of failures

40. Mark Davies
"I have never lived my
life on what ifs and
maybes and I wasn't
going to sacrifice my
bum on an off chance."