non Metastatic colonic cancer management

1. Case presentation on non
Metastatic Colonic Cancer
By:Gebrekirstos,COR-II,AAU
Moderator: Dr Munir
March19,2019

2. Investigations modality of Colonic ca
• CBC-IDA
• OFT
• Electrolytes
• CEA-for prognosis & follow up
• Colonoscopy –to see extent of tumor & R/O synchronous
primaries (occur in 1-3%)
• Base line CT scan of abdomen, pelvis & chest with contrast.
• Abdomino pelvic MRI- if :
-pt is allergy for contrast material
-CKD pt (GFR <30ml/min)
-CT-scan is inadequate
-Low laying sigmoid mass

3. Investigations modality of Colonic ca …
• PET/CT scan –indications
-Equivocal finding on contrast CT/MRI
-Pt contraindicated for IV contrast
-Curable M1 (skull base to mid thigh)
• MSI-H status, especially stage II(High risk)
• K-RAS/BRAF testing-in met colonic ca

5. Pathologic staging
• Parameters that should be reported are:
1) Grade of the cancer
2) Depth of penetration(T)
3) Number of LN evaluated and number of +ve LN(N)
4) Margin status(proximal, distal, radial, mesenteric)
5) LVI
6) PNI
7) Tumor deposits
8) Assessment of distant met(peritoneum, abdominal
organs & non regional LNs)-M

6. Staging

7. Management of respectable colonic ca
• Management modalities:
-Surgery(colonoscopic, laparoscopic, open)
-Adjuvant CT
-Neoadjuvant CT
-Chemoradiation
-Investigational adjuvant approaches

8. Management of polyp
• It is by surgical resection.
• pedunculated lesion polypectomy is
appropriate if no unfavorable histology.
• Polyps where colectomy is indicated:
-Sessile polyps
-Fragmented specimen
-Margin can’t be assessed
-Unfavorable histology(G3/4,LVI,+ve margin)

9. Management of polyp & stage I ….
• Early stage I cancers found after polypectomy
not require further resection if :
-Negative margin >2 mm
-Well differentiated tumor
-No LVI
-5 yrs survival with surgery only is 95%
• Those that recur are most likely improperly
classified stage II or III lesions.

10. Management of polyp & stage I ….

11. Anatomic resection
• For invasive stages I to III colon ca surgical
approach depends on size and location of lesions,
and the extent resection is dictated by its vascular
and lymphatic supply & at least 12 LN should be
harvested.
-Rt Hemicolectomy
-Transverse hemicolectomy
-Lt hemicolectomy
-Sigmoidoctomy
-Total colectomy

12. surgical resection….

13. Surgical management …..
• 5 yrs survival post resection:
-97% - T1 N0
-85-90% for T2 N0
Adjuvant -65-75% for T3-4 N0/T0-2 N+
CT -50%-T3 N+
indicated -35% -T4 N+

14. Adjuvant chemotherapy
• Indication of adjuvant CT in resected non metastatic colonic
ca:
-Stage III pts
-High risk stage II pts
-T4 - High grade
-<12 LN sampled - LVI
-bowel obstruction/perforation -PNI
-+ve/close/unknown margin
• Choice of CT depends on the stage , pt age, comorbidity, pt
performance.

15. Timing of adjuvant CT
• Adjuvant colon ca trials suggest initiation of
CT within 6-8 wks of resection.
• Meta analysis of 10 studies (involving 15,000
pts) shows each 4wks CT delay results in 14%
decrease in OS, indicating adjuvant CT should
be started as soon as the pt is medically fit.

16. Adjuvant CT for stage II colonic ca
• Schrag et al
• Objective-to determine extent of adjuvant CT
use in stage II colon ca pts
• Method -Using the SEERs-linked database, 3151
pts aged 65 to 75 stage II colon ca with no high
risk was identified.
• The primary outcome-CT use within 3 months of
surgery.
• Survival for treated and untreated patients was
compared.

17. Adjuvant CT for stage II colonic ca….
• Result-27% of pts received CT with in 3 months
of surgery (Younger age,white race, unfavorable
tumor grade, and low comorbidity).
• 5 yrs survival - 75% untreated pts
-78% for treated
• Conclusion- substantial percent of Medicare
beneficiaries with resected stage II colon ca
receive adjuvant CT despite its uncertain benefit.

18. Adjuvant CT for stage II colonic ca….
• ASCO recommendation CT use for stage II
colonic ca :routine use of adjuvant CT for
medically fit patients with stage II colon
cancer is not recommended unless they have
high risk features.

19. MMR defect
• Incidence of MSI-H,(PETACC-3 trial)
-Stage II-22%
-Stage III-12%
-Stage IV-3.5%
This shows MSI-H tumors are rare to metastasis.

20. MMR defect…
• Sargent et al- examine MMR status as a predictor
of adjuvant therapy benefit in pts with stages II &
III colon ca
• Number of pts examined 457,70(15%) were
dMMR.
• End point-primary =DFS
-Secondary =OS
• No benefit in DFS from 5FU-based treatment was
observed for stage II pts with dMMR but
advantageous in pts with pMMR tumors & stage
III ca.

21. MMR defect …
• In the pooled data set of 1,027 patients (n=
165 with dMMR), these findings were
maintained; in pts with stage II dMMR tumors,
treatment was associated with reduced OS.

22. MMR defect…

23. Stage II adjuvant ….NCCN conclusion.
• Decision making regarding use of adjuvant CT
for pts should incorporate pt-physician
discussion individualized for the pt & should
include explanation of:
-disease specific characterstics
-prognosis
-efficacy & toxicity of treatement
Centered pt’s choice

24. Stage III colonic ca
●Low risk stage III(T1-3,N1)
-3 months CapeOx is non inferior than 6 months
-non inferiority of 3 vs 6 months FOLFOX not
proved
● High risk stage III(T4,N1-2 or any T,N2)
-3 month FOLFOX is inferior than 6months
-non inferiority of 3 months CapeOX to 6
months not proved

25. Oral fluoropyrimidine
• 2 types (Capacitabine & uracil/tegafur (UFT)
• Twelves et al
• Purpose –to assed non inferiority of oral 5-FU to Myo
clinic 5-FU/LV in adjuvant stage III colon ca.
• Method- 1,987 stage III colon ca pts randomly
assigned to receive either oral capecitabine (1,004
patients) or Mayo Clinic bolus 5-FU/LV (983 pts). Each
treatment was planned for 24 weeks.
• Result-DFS in the capecitabine group was at least
equivalent with significantly fewer adverse events than
5-FU/LV group

26. Oral fluoropyrimidine…
• This trial demonstrates that capecitabine is a
reasonable alternative to IV 5-FU/LV in
reliable, motivated pts who are able to comply
with a complex schedule of oral medication.

27. Semimonthly vs monthly 5FU/LV
• Andre et al;
• Purpose- to compare every 2vs4 wks & 24vs
36 wks adjuvant 5FU/LV in stage II& III colonic
• Method-total of 905 pts randomly assigned to
LVFU2 vs LVFU & 24 vs 36 wks with median
follow-up of 41 months.
• Conclusion: LVFU2 is less toxic than FULV. With
no statistically significant d/ce in DFS/OS b/n
the treatment groups or treatment durations.

28. MOSAIC trial
• Purpose-to evaluate efficacy of Oxaloplatin contain CT.
• Method-2,246 stage II& III pts (aged 18-75 yrs)were randomly
assigned to receive 5FU/LV (1123 pts)or FOLFOX for 6 months.
• End points - primary =DFS
-Secondary= OS & safety
• 5 yrs DFS -FOLFOX=73.3%
- 5FU/LV 67.4%
• 6yrs OS -stage II- 78.5%(FOLFOX),76% (5FU/LV)
-stage III -72.9%(FOLFOX) 68.7%(5FU/LV)
• Frequency of grade 3 peripheral sensory neuropathy in pts
receiving oxaliplatin,
-1.3% -12 months after treatment
-0.7% at 48 months.

30. MOSAIC trial….

32. MOSAIC trial…
• Long-term data from MOSAIC trial support
benefit of oxaliplatin in adjuvant stage III
colon ca pts.
• Specifically, 10- year OS(stage III)
-67.1% -with oxaloplatin
- 59%, -with out oxalplatin ,P = .016
• This benefit was seen regardless of MMR
status or BRAF mutation.

33. CapeOx vs FOLFOX
• Pectasides et al-RCT, phase III comparing adjuvant CapeOx &
FOLFOX in stage III & high risk stage II CRC
• Methods –pts assigned to group A(12 round FOLFOX) or group B (8c
CapeOx)
• End point-DFS
• Results-441 pts were enrolled,408 pts being eligible.
- After a median follow up of 74.7 months:
3-yr DFS-79.8 % = FOLFOX
-79.5 % =CAPOX
3-year OS -87.2 % =FOLFOX
-86.9 % = CAPOX group
• Conclusions: No significant d/ces observed in the efficacy of
FOLFOX Vs CAPOX , but definitive conclusions cannot be drawn b/c
of the small sample size

34. FOLFOX vs CapeOx
• FOLFOX and Cape/Ox appear more similar
than d/t at this time & interchangeable use in
the adjuvant setting is justifiable.

35. 3 month vs 6 month therapy
• IDEA(International Duration Evaluation of
Adjuvant Chemotherapy) trial
• Ask weather 3 month oxaloplatin containing
adjuvant is non inferior to 6 months
• 6 parallel trails reported together
• 12,834 pts involved
• Prespecified end point –DFS
• Pts permitted to selected either FOLFOX or
CapeOx and randomly assigned to 3 vs 6 month
therapy.

36. 3 month vs 6 month therapy…
• The two arms appeared to perform quite similarly(not
show non inferiority of 3 vs 6 months with non
inferiority margin of 1.12)
3-year DFS -74.6% -3months
-75.5% -6months
• The d/ces were most notable in subset of pts treated
with FOLFOX:
3-year DFS -76% - 6months
-73.6%- 3months
• Cape/Ox, 3 months of treatment did appear to be
noninferior to 6 months.

37. Adjuvant in elderly
• Adjuvant CT usage decrease with age.
• Population studies indicates adjuvant CT is beneficial in
older pts.
• MOSAIC trial subgroup analysis-
• Purpose-to determine effect of of oxaloplatin addition
to 5FU/LV in stage II & elderly pts.
• Method-of the 2246 pts, 899 was stage II(330 –H,569-
L) 319 pts aged b/n 70-75.
• Result-no statistically significant benefit (OS and DFS)
with addition of oxaliplatin to 5FU/LV as adjuvant
treatment for either stage II and elderly patients

38. Investigational adjuvant therapy
• Investigational adjuvant therapy in stage III :
- Portal Vein Infusion
- Intraperitoneal Chemotherapy
- Vaccines
- Active Specific Immunotherapy
- Preoperative Chemotherapy

39. Neoadjuvant CT for resectable...
• NCCN panel 2016 added option of neoadjuvant
CT(FOLFOX & CapeOx) for pts with resectable clinically
T4b.
• Randomized phase 3 (FOxTROL)trial Neoadjuvant
FOLFOX/capeOx was asses if neoadjuvant CT improve
DFS.
• 150 pts with T3(>=5mm invasion beyond muscularis
propria) & T4 assigned to 3 round preoperative then 9
round adjuvant FOLFOX or upfront surgery & 6 cycle
FOLFOX, preoperative result in significant dawn staging
with acceptable toxicity.

40. chemoradiation in colonic ca
• Neo/adjuvant RT with 5-FU based CT can be
considered for selected cases(T4 tumors&
recurrent diseases, locally
unrespectable/medically unfit)
• RT field is the tumor bed defined by preoperative
imaging or surgical clips.
• Dose 40-45 Gy,25-28≠
• Boost -IORT if available if not EBRT/BT (10-20 GY)
to limited volume.
• Critical structures large bowel, stomach & liver.

41. Irinotecan, Bevacizumab, Cetuximab &
Panitumumab
• NCCN recommend not to use adjuvant
bivacizumab,
cetuximab,penitumumab,irinotecan in
respectable non metastatic colonic ca
• Although it has substantial activity in the
metastatic setting, irinotecan has no
meaningful activity in the adjuvant
setting(PETACC-3, ACCORD 02 & CALGB trials)

42. Conclusion of adjuvant CT…NCCN
• Stage I, low risk stage II& stage II pt with MSI-H
no adjuvant CT
• High risk stage II with no MSI-H adjuvant
CT(capecitabine or 5FU/LV) is indicated
• Low risk stage III oxaloplatin containing adjuvant
is indicated(CapeOx category 1 for 3 month,
FOLFOX category 1 for 6 month)
• High risk stage III CapeOx or FOLFOX(both
category 1 for 6 months)
• In stage III pts if oxaloplatin is inappropriate use
capcitabine or 5FU/LV.

44. Prognostic factors
• CAP prognostic and predictive factors in CRC.
-Category I- proven to be prognostic import.
-Category IIA- repeatedly shown to have prognostic
-Category IIB - promising but lacking sufficient data
for inclusion in category I or IIA.
-Category III -not yet sufficiently studied to
determine their prognostic value.
-category IV -adequately studied to have
convincingly shown no prognostic significance.

45. Prognostic factors…

46. Follow up…

47. Case critics
Good
• Documentation
• Surgical procedure choice
• Chemotherapy choice
• Surgery & pathology -LN
• Pre surgery Colonoscopy
Improve
• Investigations(base line
CEA, mid cycle CT, )
• Chemotherapy initiation
delay
• Chemo schedule
• Follow up(Abdpelvic & chest
CT, colonoscopy)
• Health education

48. References:
• Devita 11e
• NCCN
• PEREZ 7e
• Uptodate 2018

49. Thank You!

50. Questions?