1. Colorectal Cancer An oncologists perspective
SpR Teaching Dec 2012
Erica Beaumont

2. Summary Neoadjuvant Radiotherapy for rectal cancer
Neoadjuvant Chemotherapy for colon cancer
Adjuvant chemotherapy
Liver metastases
Palliative treatments

3. The MDT
Old roles should now be superseeded by using each team members expertise to ensure optimum Mx

4. Neoadjuvant Radiotherapy
Operable rectal cancer (SCPRT)
Inoperable / threatened CRM (CRT)
Modern Context
MRI staging
TME

5. Gina Brown et al. Radiol 1999;211:215-222
More recently the MERCURY study group have published results from international multicentre study which confirms accuracy of MRI measurements of extramural spread when compared to path specimens.
Gina Brown et al. Radiol 1999;211:
MERCURY study gp. Diagnostic accuracy of preop MRI in prediciting curative resection of rectal cancer: prospective observational study. BMJ 2006; 333: 779

6. MERCURY Study
428 pts
MRI mesorectal fascia involvement by tumour significantly predicted for local recurrence
DFS and OS showed that avoidance of preop RT safe in patients with MRI defined good prognosis disease (3% local recurrence)
Allows stratification of patients and better targeting of preoperative radiotherapy for reduced patient toxicity and morbidity
Phase II/III trials to identification of key imaging predictors of patients at risk of developing metastatic disease on initial staging
MERCURY staging study in rectal cancer Bmj, 2006; Salerno,Daniels et al. Dis Colon Rectum, 2009). 6

7. TME Surgery Total mesorectal excision reduces local recurrence rates
30-40% without TME, 3.7% with TME  
TME varies between surgeons (experience, training technique )
How can oncologists assess quality of surgery? Surgeons objectively assess Sx?
Heald Lancet 1986;  1(8496):
Heald Lancet 1993;  341(8843):457-60 
Original paper - not much interest
prospective FU data – renewed & increased interest in technique & now op of choice (with nerve preservation)
Pathologist able to provide independent second unbiased opinion – to guide oncologists & feedback for surgeons
Phillip Quirke – Leeds pathologist
APR - Where distal clearance <1cm, sphincter involvement, poor anal tone
TME Hartmann’s (resection with end stoma)- Frail or elderly patients, unsuitable for restorative surgery, staged interventions or perineal dissection

8. Quality of Surgery Quirke
Raised awareness of importance the circumferential resection margin and quality of TME specimen
Developed graded assessment of TME
Used in Dutch study & CR07

9. Quality of TME in Dutch Study
Nagetaal path paper 2002 from Dutch study looked at 180 pts. Local & distant recurrence rates for those with gd 1 TME was 36% compared with 20% in those with gd 3 TME

10. Influence of quality of TME surgery

11. Quality of TME and outcome CR07
3 yr LR
3 yr DFS
Plane of Sx N
Pre
Post HR
Musc prop
141 9%
29%
2.76
79%
65%
1.75
Intra meso
382 6%
12%
2.02
78%
75%
1.13
Mesorectal
596 1%
4.47
87%
80%
1.53

12. Potential benefits of neoadjuvant RT
Improving survival
Reducing risk of local recurrence
Improving the chance of sphincter saving surgery
Increasing the chance of complete resection in advanced disease

13. Post Op RT Decrease rel risk LR by 30-40%
Absolute decrease 25.8% vs 16.7% (p< )
Rectal cancer † decreases by 8.6%
*Lancet Meta-analysis CRC collaborative gp. >2000 pts 8 post op RCTs

14. Pre op RT >6000 pts 14 RCTs Decrease relative risk LR of 50-60%
Absolute decrease 22.2% vs 12.5% (p< )
Rectal cancer † decrease by 22%
Lancet meta-analysis 2001
Early trials such as MRC CR2 study 1984 using BED < 30Gy no benefit
4 trials used BED > 30Gy 3 of which were 25/5
Young pts stage III seemed to have greatest risk & therefore benefit from RT

15. Short Course Preoperative RT SCPRT

16. SCPRT – Swedish studies
>1100 pts with resectable rectal Ca Sx vs RT 25/5 + Sx ( )
Not TME
25/5#/1W
5 yr LR 27% vs 12%
5 yr OS 48% vs 58%
Only pre op study showing survival benefit
Benefits maintained - most recent update JCO 2005
Swedish Rectal Cancer Trial. N Engl J Med 1997; 336: 980-7
Included some pts from Stokholm II study
Update JCO 2005
Median follow-up time was 13 years. OS 38% v 30% (P .008). The cancer-specific survival 72% v 62% (P .03), and local recurrence rate was 9% v 26% (P .001), respectively. The reduction of local recurrence rates was observed at all tumor heights, although it was not statistically significant for tumors greater than 10 cm from the anal verge.

17. SCPRT – Dutch study Sx vs preop RT 25/5 + Sx in operable Rectal cancer
1748 pts underwent complete resection
2yr LR 8.2% vs 2.4% *
Longer FU relative benefit maintained
Also assessed importance of CRM and quality of surgery* *
* Kapiteijn et al. Preop RT combined with TME for resectable rectal cancer. NEJM 2001; 345: 638
* * Nagtegaal et al. Dutch CCG co-operative. Macroscopic evaluation of rectal cancer specimen. 2002; 20: 1729
Some surgeons argued that pre-op RT in Swedish studies was simply making up for poor surgery. So Dutch study important in showing additional benefit of RT to TME surgery.
The Dutch Colorectal Cancer Group trial does show that, even with low local failure rates associated with modern surgical techniques, short course preop RT still of benefit: an absolute reduction in rate of local failure of 5.8% (3.8 to 7.9), NNT=17

18. Risk factors for LR
Greatest risk for LR – Sx alone, low/ mid vs high tumours & stage II/III

19. Influence of CRM on LR & OS
A – LR with AR
B – LR with APR
C – OS with AR
D – OS with APR
Grey = CRM -
Black = CRM +
Data from Dutch study Sx alone arm. CRM + rates were 29% for APRs vs 13% for AR
Definition of CRM + is tumour = or < 1mm from resection margin consistently assoc with high rates of LR

20. Low rectal cancers have worse outcomes
APR v AR in Dutch study OS
38.5% v 57.6% (p=0.008)
CRM+
30.4% v 10.7% (p=0.002)
Perforation rate
13.7% v 2.5% (p<0.001)

21. SCPRT – CR07 SCPRT vs selective post op CRT with TME Sx 1350 pts
676 Sx alone of whom 11% CRM +
3 yr LR 4.7% v 11.1% (HR 2.47, 95% CI )
3 yr DFS 79.5% v 74.9% (HR 1.31, 95% CI )
Benefit consistent for all levels & stages
JCO 2006 ASCO Proceedings Part I. Vol 24; No. 18S: 3511

22. Side effects of SCPRT Minimal acute toxicity
Poor wound healing (esp perineal)
Bowel dysfunction – faecal incontinence
Less of a problem for patients post APR

23. Who should have SCPRT? To reduce local recurrence in:
Low rectal cancers (APR)
Bulky T3
Node positive disease

24. Long Course Chemoradiotherapy

25. Polish study 312 pts with rectal cancer palpable by DRE
Primary end point – sphincter preservation
Secondary endpoints –LR, toxicity
Operation specified by surgeon pre RT
Randomised to 25/5 vs 45/25 + 5FU wk 1&5
Reassessed to decide on final operation post RT
Bujko et al. Radioth Oncol 2004; 72: 15
Polish study: Sphincter preservation following preop RT for rectal cancer: report of a RCT comparing SCPRT with conventionally fractionated CRT

26. Polish study No difference in sphincter-preservation rates
More acute Gd 3 & 4 toxicity with CRT
18% v 3% (p=0.001)
More pCR, less N+ & CRM+ with CRT
16.1% v 0.7%, 31.6% v 47.6%, 4.4%v 12.9%
Thought to be due primarily to surgical bias.
These results would be expected due to the timing of the surgery following RT

27. Polish study No difference late toxicity No difference in 4 yr LR
28.3% v 27%
No difference in 4 yr LR
15.6% v 10.6% (p=0.21)
More interesting to note result of late toxicity & LR – however this was not the primary endpoint so trial not properly powered to answer this question

28. Why give CRT?
Downstage inoperable tumours (but is there a role for SCPRT?)
Downstage tumours where there is a threatened CRM (by primary or node)

29. Practicalities of RT Tattoos Empty rectum, full bladder CT scan
SCPRT: 5 daily treatments the week before surgery
CRT: daily treatments with bd capecitabine chemotherapy

30. Toxicities of RT
Acute: sore skin, tiredness, nausea, diarrhoea, PR bleeding, urinary
Late: bowel dysfunction, urinary, small bowel stricture, infertility, menopause, poor wound healing, vaginal stricture, impotence, pelvic bone fragility, risk of second malignancy

31. Planning RT CT scan Fields vs volumes Aristotle trial
Include – mesorectum
Extension of tumour beyond mesorectum (+margin)
Sup: sacral promontory
Inf: obturator foramen, or 2-3cm below tumour

32. Adjuvant Radiotherapy
Post-op if positive margin (R1 resection)
Only if no pre-op RT given
Not as effective as pre-op RT
Better than nothing

33. Neoadjuvant chemotherapy for colon cancer

34. FOXTROT trial Ongoing Initial data: 150 patients
Locally advanced (T3/4) colon tumours on CT
3 cycles (6 weeks) FOLFOX chemo and Surgery vs Surgery alone

35. FOXTROT No diff post-op morbidity (p=0.8)
Decreased T and N stage with neoadjuvant chemo (p=0.04)
Decreased margin involvement (p=0.002)
Lancet Oncol 2012; 13:

36. Adjuvant Chemotherapy

37. Rectal Cancer All data extrapolated from colon cancer
SCPRT – does not downstage cancer
CRT – downstages cancer
Treat on initial clinical staging
Chronicle trial failed to recruit
Good prognostic group: ypT0 ypN0 M0
Distant metastases 8.9%, 5yr DFS 85%

38. Colon cancer Initial studies done with 5FU
Intergroup 035 (5FU vs no chemo)
5yr OS benefit for Dukes C 13%
5yr OS benefit for Dukes B 3-5%
X-ACT (capecitabine vs 5FU)
4% benefit for cap
MOSAIC (5FU /oxaliplatin vs 5FU)
3yr DFS benefit of 5%

39. Current Practice Node positive tumours High risk node negative tumours
5FU / Oxaliplatin
If less fit / elderly, Cap alone
High risk node negative tumours
EMVI, T4, R1, Emergency presentation, <12 nodes
Cap / 5FU alone
5FU / Oxalipatin if lots of risk factors

40. What does this mean for patients?
6 months treatment (SCOT trial ongoing)
Tiredness, nausea, diarrhoea, stomatitis
Palmar plantar syndrome
Neuropathy, orolaryngeal spasm
Haematological toxicity
Cardiac toxicity
Thromboembolic disease
DPD deficiency

41. Follow Up Often CNS led Risk stratified Regular CT scans
Timing controversial
To assess for resectable liver mets

42. Treatment of liver metastases

43. Liver only disease Assessment Resectable Unresectable
CT, MRI Liver, PET
Resectable
Refer for surgery, ?chemo upfront
EPOC B
Unresectable
K-Ras status
Chemotherapy for 3 months and reassess
SIRT (FOXFIRE trial)

44. Chemotherapy FOLFOX Every 2 weeks for 6 cycles, PICC line
If k-ras wild-type and unresectable for Cetuximab
mAb EGFR
Celim study: ph 2 (Lancet Oncol 2010)
RR: 68% with FOLFOX and Cetuximab
Resectability increased from 32% to 60%

45. Why liver resection?
Historically 50% colorectal cancer patients develop liver mets
30% present with liver mets
Resection can give 5yr OS rates of 21-43%

46. After liver resection 3 months adjuvant chemotherapy
6 monthly CT scans
Further liver resections may be possible

47. Presentation with liver mets
2 problems: liver and primary
Which will kill patient first?
Risk of obstruction – surgery vs stent?
Will delaying chemo harm patient?
Risk of micrometastatic disease elsewhere
Synchronous resections?
Controversial area

48. Lung metastases Extrapolate from liver data
Resection of <5 lung mets
No adjuvant chemo
PULMIC study

49. Palliative Treatments

50. Primary in situ Does resecting the primary give an advantage?
Assess for obstruction
Stents
May prevent use of bevacizumab (anti-angiogenesis Ab)

51. Chemotherapy
In fit patients (PS 0-1), multiple lines of chemotherapy can give months survival
Chemo drugs: 5FU / Capecitabine, Oxaliplatin, Irinotecan
Biological therapies: Cetuximab, Bevacizumab, Panitumumab
New agents: Aflibercept, Regorafenib

52. Liver therapies
RFA
Chemoembolisation
SIRT

53. Radiotherapy Rectal cancer Bone mets
25Gy/5# can downstage
8Gy/1# can stop bleeding
Hard to give if has had RT pre-op
Bone mets
Back pain from para-aortic disease
Lung met with haemoptysis