1. Colon Cancer Stage I-III
Palak Desai, MD

3. Trends in Cancer incidence rates among men 1975-2010

4. Trends in Cancer incidence rates among women 1975-2010

6. The risk of an American woman developing cancer over her lifetime is a little more than one in three.

7. Colon Cancer Etiology Sporadic (65%–85%) Familial (10%–30%)
Rare CRC syndromes (<0.1%)
Hereditary nonpolyposis colorectal cancer (HNPCC) (5%)
Familial adenomatous polyposis (FAP) (1%)
Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996

8. Risk Factors Physical Inactivity/obesity Smoking NSAIDS
Adenomatous polyps
Age >50
Inflammatory Bowel Disease
History of Cancer
Family History of Colorectal Cancer
Physical Inactivity/obesity
Smoking
NSAIDS
Diets/Supplements
Race

9. Diet dietary fiber vegetables fruits antioxidant vitamins calcium
folate (B Vitamin)
decreased risk

10. Diet consumption of red meat animal and saturated fat
refined carbohydrates
alcohol
increased risk

11. Familial Risk Approximate Familial setting Life time risk of Colon Ca
Gen population risk in US 6%
1 first degree relative with colon ca Two-Three fold increase
2 first degree relatives with colon ca Three-Four fold increase
1st° relative Δ with colon ca ≤ 50 yrs Three-Four fold increase
One 2nd or 3rd ° relative with colon ca 1.5 fold increase
Two 2nd ° relatives with colon ca Two-Three fold increase
One 1st ° relative with polyp Two fold increased

12. Adenoma- Cancer Sequence
Loss of
APC
Activation
of K-ras
Deletion of 18q
Loss of
TP53
Other
alterations
Normal
epithelium
Hyper-
proliferative
epithelium
Early
adenoma
Inter-
mediate
adenoma
Late
adenoma
Carcinoma
Metastasis
Adapted from Fearon ER. Cell 61:759, 1990

13. Risk of Colorectal Cancer
General population 5%
Personal history of colorectal neoplasia
15%–20%
Inflammatory bowel disease
15%–40%
70%–80%
HNPCC mutation
>95%
FAP 20 40 60 80
100
Lifetime risk (%) 3

14. Clinical Presentation

15. Colorectal Cancer by Site

16. Stage at Diagnosis
Adapted from NCI Cancer Facts and Figures 2010

17. Stages of Colon Cancer

19. Prognosis and 5 yr survival rates for Colon Cancer
Stage I (T1-2N0) - 93%
Stage IIA (T3N0) - 85%
Stage IIB (T4N0) - 72%
Stage IIIA (T1-2 N1) - 83%
Stage IIIB (T3-4 N1) - 64%
Stage IIIC (N2) - 44%
Stage IV - 8%

20. Dukes Classification

21. Initial Treatment

23. Evidence Blocks

25. High Risk Features T4 tumors (stage IIB/IIC)
poorly differentiated histology
Lymphovascular invasion
Perineural invasion
Bowel obstruction
Less than 12 lymph nodes sampled
+ margins

26. Adjuvant Therapy Consideration
IMPACT Meta-analysis 1995
The three studies were pooled for combined analysis.
Each trial was multicenter and used the same treatment regimen (fluorouracil mg/m2 plus folinic acid 200 mg/m2 daily for 5 days, every 28 days for 6 cycles).
1526 patients with resected B (56%) and C (44%) carcinoma of the colon were enrolled 736 were assigned to the treatment group and 757 to the control group.
Fluorouracil/folinic acid significantly reduced mortality by 22% (95% Cl 3- 38; p=0·029) and events by 35% (22-46; p<0·0001), increasing 3-year event-free survival from 62% to 71% and overall survival from 78% to 83%.
Compliance with treatment was good; more than 80% of patients completed the planned treatment.
Side-effects were clinically acceptable with only 1 treatment-related death. The commonest side-effects were gastrointestinal, but severe toxic effects (WHO grade 4) occurred in fewer than 3% of cases.
Study showed that fluorouracil plus high-dose folinic acid is a well- tolerated and effective 6-month adjuvant regimen for colon cancer.
IIa to IIIc
IMPACT group, Lancet 1995

27. Adjuvant Therapy for Stage II Disease?
Gill et al, Meta-analysis
pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone
Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS.
Age was significant only for OS.
Adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade.
A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients.
Gill et al, JCO 2004

28. These results suggest that the benefit of adjuvant therapy is greater in patients at higher risk because of nodal status.

29. Adjuvant Therapy for Stage II Disease?
Quasar Trial
After apparently curative resections of colon or rectal cancer, 3239 patients were randomly assigned to receive chemotherapy with fluorouracil and folinic acid (n=1622) or to observation (with chemotherapy considered on recurrence; n=1617).
Chemotherapy was delivered as six 5-day courses every 4 weeks or as 30 once-weekly courses of intravenous fluorouracil (370 mg/m2) with high-dose (175 mg) L-folinic acid or low-dose (25 mg) L-folinic acid.
Quasar Collaborative Group, Lancet 2007

30. Quasar Trial
There were 293 recurrences in the chemotherapy group and 359 in the observation group; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 ( ; p=0.001).
Treatment efficacy did not differ significantly by tumor site, stage, sex, age, or chemotherapy schedule.
Authors proposed that Chemotherapy with fluorouracil and folinic acid could improve survival of patients with stage II colorectal cancer, although the absolute improvements are small: assuming 5-year mortality without chemotherapy is 20%, the relative risk of death translated into an absolute improvement in survival of 3.6% (95% CI ).
However, 64% of patients had less than 12 LNs sampled, therefore those patients may actually have been patients with higher risk disease who were more likely to benefit from adjuvant therapy

31. Adjuvant Therapy for Stage II Disease
Wu et al, 2012
Meta-analysis of 12 randomized controlled trials from to 2010 in which surgery alone was the control arm, found a significant benefit to adjuvant therapy in patients with stage II colon cancer
5 year OS HR was 0.81
5 year DFS HR was 0.86.
The trials used various chemotherapy regimens.
Wu et al, J Gastrointest Surg, 2012

32. Adjuvant Therapy for Stage II Disease
O’Connor et al, 2011
Analysis of 24,847 patients with stage II colon cancer from the SEER database
Of the patients with stage II cancer, 75% had one or more poor prognostic features.
Adjuvant chemotherapy was received by 20% of patients with stage II disease and 57% of patients with stage III disease.
O’Connor et al, JCO 2011

33. After adjustment, 5-year survival benefit from chemotherapy was observed only for patients with stage III disease (hazard ratio[HR], 0.64; 95% CI, 0.60 to 0.67).
No survival benefit was observed for patients with stage II cancer with no poor prognostic features (HR, 1.02; 95% CI, 0.84 to 1.25) or stage II cancer with any poor prognostic features (HR, 1.03; 95% CI, 0.94 to 1.13).

34. Addition of Oxaliplatin?
MOSAIC Trial (more later)
Post-hoc exploratory analysis of the MOSAIC trial did not show a significant DFS benefit of FOLFOX over 5-FU/LV for patients with stage II disease at a follow up of 10 years (HR= 0.64, P= 0.258).
After a longer follow up, no difference in 10 year OS was observed in the stage II subpopulation (79.5% vs 78.4%, HR= 1.00, P= 0.98)
In addition, patients with high risk disease receiving FOLFOX did not have improved DFS compared with those receiving infusional 5-FU/LV (HR = 0.72 ,P = 0.063).
No OS benefit was seen in the stage II population overall or in the stage II population with high-risk features.
André et al, JCO 2015

35. Microsatellite Instability
MSI is an important piece of information to consider when deciding whether to use adjuvant chemotherapy in patients with stage II disease
Evidence shows that MSI is a marker of a more favorable outcome and a predictor of decreased benefit from adjuvant therapy with a fluoropyrimidine alone in patients with stage II disease.
Date from PETACC-3 trial showed that tumor specimens characterized by MSI-H are more common in stage II than in stage III disease (22% vs 12%, P<0.0001)
Another study showed that only 3.5% of stage IV tumor were characterized as MSI-H, suggesting that these tumors have a decreased likelihood to metastasize.
Because patients with stage II msi h tumors may have a good prognosis and do not benefit from 5-FU adjuvant therapy, the panel recommends that MMR or MSI testing be performed for al patinets with stage II disease and adjuvant therapy should not be given to patients with low risk stage II msi H tumors.
Roth et al, JCO 2010, Koopman et al, Br J Cancer 2009

36. MOSAIC Trial
Compared the efficacy of FOLFOX and 5-FU/LV in the adjuvant setting in 2246 patients with completely resected stage II and III colon cancer.
Updated 10 year data was published last year in JCO
André et al, JCO 2015

37. MOSAIC Trial
After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX) arms were
67.1% versus 71.7% (hazard ratio [HR], 0.85; P = .043) in the whole population
79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease.
Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation.
BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014).
HRs for DFS and OS benefit in the FOLFOX4 arm were:
0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR
0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation.

39. Patients below age of 75
A low stage 2, b high stage 2, 3 n1 stage 3, 4 n2 stage 3

40. FOLFOX For Stage III Disease
Sanoff et al
Analysis of 5 observational data sources, including the SEER-medicare and NCCN Outcomes Databases
Showed that the addition of oxaliplatin to 5-FU/LV gave a survival advantage to the general stage III colon cancer population treated in the community.
The survival advantage associated with the addition of oxaliplatin to adjuvant 5-FU was evident across diverse practice settings (3-year OS: RCTs, 86% [n = 1273]; SEER-Medicare, 80% [n = 1152]; CanCORS, 88% [n = 129]; NYSCR-Medicaid, 82% [n = 54]; NYSCR-Medicare, 79% [n = 180]; and NCCN, 86% [n = 438]).
A statistically significant improvement in 3-year overall survival was seen in the largest cohort, SEER-Medicare, and in the NYSCR-Medicare cohort (non-oxaliplatin-containing vs oxaliplatin-containing adjuvant therapy, adjusted HR of death:
pooled RCTs: HR = 0.80, 95% CI = 0.70 to 0.92, P = .002;
SEER-Medicare: HR = 0.70, 95% CI = 0.60 to 0.82, P < .001;
NYSCR-Medicare patients aged ≥65 years: HR = 0.58, 95% CI = 0.38 to 0.90, P = .02).
The association between oxaliplatin treatment and better survival was maintained in older and minority group patients, as well as those with higher comorbidity.
Sanoff et al, J Natl Cancer Inst, 2012

41. Solid line = oxaliplatin; Dotted line = non-oxaliplatin
Solid line = oxaliplatin; Dotted line = non-oxaliplatin. ACCENT shown in black; SEER–Medicare, green; CanCORS, red; NYSCR– Medicare, yellow; NYSCR–Medicaid, purple; NCCN, blue. B) ACCENT. C) SEER–Medicare (HR of death = 0.74, 95% CI = 0.63 to 0.86, P < .001). D) CanCORS (HR of death = 0.68, 95% CI = 0.44 to 1.04, P = .07). E) NYSCR–Medicaid (HR of death = 0.76, 95% CI = 0.34 to 1.72, P = .51). F) NYSCR–Medicare

42. FLOX
NSABP- C 07
Randomized, phase III trial comparing the efficacy of FLOX vs Bolus 5FU/LV in patients with stage II or III colon cancer
2407 Patients who had undergone a potentially curative resection were randomly assigned to either:
FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus leucovorin 500 mg/m2 IV weekly for 6 weeks during each 8- week cycle for three cycles (FULV),
or the same FULV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX).
Kuebler et al, JCO 2007

43. NSABP C-07
Rates of 4 year DFS were 73.2% for FLOX and 67% for FULV with a HR of 0.81 (P=0.005)
Recent update on this study showed benefit of FLOX in DFS was maintained at 7 year median follow up.

44. NSABP C Safety
Cross study comparisons between FLOX and FOLFOX showed that grade 3/4 diarrhea seemed to be considerably higher with FLOX than FOLFOX.
Rates of grade 3/4 diarrhea were 6.6% and 10.8% for patients receiving FOLFOX and infusional 5-FU/LV, respectively in the MOSAIC trial. Whereas 38% (FLOX) and 32% (bolus 5-FU/LV) reported grade 3/4 diarrhea in the NSABP C-07 trial

45. Capecitabine
Single-agent oral capecitabine as adjuvant therapy for patients with stage III colon cancer was shown to be at least equivalent to bolus 5-FU/LV with respect to DFS and OS

46. X-ACT Trial
Multicenter randomized, open-label, trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer.
Patients were assigned to 24 weeks of capecitabine mg/m(2) twice daily on days 1-14 every 3 weeks or 5- FU/FA. The primary end point was disease-free survival (DFS).
A total of 1987 patients were randomized to capecitabine (n = 1004) or 5-FU/FA (n = 983) between November 1998 and November 2001
Twelves et al, Annals of Oncology 2011

47. With a median follow-up of 6
With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of
DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) ] P<0.0001
overall survival (OS) (HR = 0.86; 95% CI ). P<0.001
This pattern was maintained in all subgroups, including patients aged ≥ 70 years.

48. XELOX
NO16968 trial
After curative resection, patients were randomly assigned to receive XELOX, as
oxaliplatin 130 mg/m(2) on day 1 + capecitabine 1,000 mg/m(2) twice daily on days 1 to 14 every 3 weeks
bolus FU/FA, for 6 months.
The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS).
1,886 patients (XELOX, n = 944; FU/FA, n = 942).

49. XELOX- NO16968 Seven-year DFS rates were Seven-year OS rates were
63% in XELOX group
56% in FU/FA group
HR=0.80; 95% CI, 0.69 to 0.93; P = .004.
Seven-year OS rates were
73% in XELOX group
67% FU/FA in group
HR, 0.83; 95% CI, 0.70 to 0.99; P = .04.
A total of 68% and 77% of patients who experienced relapse or a new colorectal cancer in the XELOX and FU/FA groups, respectively, received drug treatment for metastatic disease.
XELOX improved OS compared with bolus FU/FA in patients with resected stage III colon cancer after a median follow-up of almost 7 years.
Schmoll et al, JCO, 2015

50. XELOX vs. FOLFOX
Patients with resected stage III colon cancer from four randomized controlled trials (NSABP C-08, XELOXA, X- ACT, and AVANT; 8734 patients in total) were pooled and analyzed.
The treatment regimens included in the analyses were:
XELOX
leucovorin and fluorouracil
capecitabine
FOLFOX-4 (leucovorin, fluorouracil, and oxaliplatin)
modified FOLFOX-6 (mFOLFOX-6). 
Schmoll et al, Lancet Oncol 2014

52. 3, 4, and 5 year DFS, RFS, and OS by Treatment Group

53. Post-Relapse Survival

54. Safety

55. Adjuvant XELOX and FOLFOX
Schmoll and colleagues showed that combination therapy with oxaliplatin for stage III colon cancer provides consistently improved outcomes, irrespective of the fluoropyrimidine backbone (capecitabine or leucovorin and fluorouracil), and that the benefit of combining oxaliplatin with a fluoropyrimidine is not compromised by decreased survival following relapse.
Based on these data XELOX and FOLFOX are listed in the NCCN guidelines as a category 1 designation as preferred adjuvant therapy for patients with stage III colon cancer

56. Other Adjuvant Regimens
Other adjuvant regimens studied for the treatment of early- stage colon cancer include 5-FU based therapies incorporating Irinotecan
CALGB 89803
1,264 patients were randomly assigned to receive either standard weekly bolus FU plus LV regimen or weekly bolus Irinotecan plus FU plus LV.
The primary end points of the study were overall survival (OS) and disease-free survival (DFS).
The addition of Irinotecan to weekly bolus FU plus LV did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity (neutropenia, neutropenic fever, and death)
This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment
Similar resutls were observed in a trial looking at IFL vs bolus 5 fu in stage II/III patients. Folfiri has not been shown to be superior to 5-fu/lv in the adjuvant setting.
Saltz et al, JCO 2007

57. Adding Bevacizumab? NSABP C-08 2,673 patients Patients received;
modified FOLFOX6 once every 2 weeks for a 6-month period (control group)
modified FOLFOX6 for 6 months plus bevacizumab (5 mg/kg) once every 2 weeks for a 12-month period (experimental group).
The primary end point of the study was disease-free survival (DFS) and overall survival (OS) was a secondary end point.
Allegra et al, JCO 2013

58. Adding Bevacizumab?- NSABP C-08
With a median follow-up of 5 years, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.93; 95% CI, 0.81 to 1.08; P = .35).
The secondary end point of OS was no different between the two study arms for all patients (HR, 0.95; 95% CI, to 1.13; P = .56) and for those with stage 3 disease (HR, 1.0; 95% CI, 0.83 to 1.21; P = .99).

59. Adding Bevacizumab?- NSABP C-08
Cancer recurred in 286 and 283 patients in the control and bevacizumab- containing arms, respectively.
Of these patients, 191 and 190 died in each arm, respectively.
Although not statistically significant (P = .10), patients in the bevacizumab arm appeared to have a more rapid rate of death relative to those whose disease recurred in the control arm (HR, 1.15; 95% CI, 0.94 to 1.41).

60. Cetuximab? NCCTG Intergroup, N0147 Trial PETACC-8 Trial
Assessed the addition of Cetuximab to FOLFOX in adjuvant treatment of stage III colon cancer
In patients with wild-type or mutant KRAS, cetuximab provided no added benefit and was associated with increases in grade 3/4 adverse events
PETACC-8 Trial
Open-label randomized, phase III trial
Compared FOLFOX with or without Cetuximab as adjuvant therapy in stage III colon cancer patients
Analysis of the wild-type KRAS exon 2 subset found that DFS was similar in both arms (HR= 0.99)
Adverse events (rash, diarrhea, mucositis, infusion-related reactions) were more common in the cetuximab group.
Cetuximab has no role in the adjuvant treatment of colon cancer
Alberts et al, JAMA 2012, Taeib et al, Lancet Oncology 2014

62. Treatment Summary
Patients with stage I disease and patients with MSI-High, low risk stage II disease do not require adjuvant therapy
Patients with low risk stage II disease can be enrolled in a clinical trial, observed without adjuvant therapy, or considered for capecitabine or 5-FU/LV.
Based on the results of the MOSAIC trial, and possible long term sequelae of oxaliplatin based chemo, the NCCN does not consider FOLFOX to be an appropriate adjuvant therapy option for patients with stage II disease without high risk features

63. Treatment Summary
Patients are deemed high-risk stage II disease, if they have any of these poor prognostic features:
T4 tumors (stage IIB/IIC)
poorly differentiated histology
Lymphovascular invasion
Perineural invasion
Bowel obstruction
+ margins
These patients can be considered for adjuvant chemotherapy with 5-FU/LV, capecitabine, FOLFOX, XELOX, or FLOX
Observation without chemo is also an option for this population

64. Treatment Summary
For patients with stage III disease, the NCCN recommends 6 months of adjuvant chemotherapy after primary surgical treatment.
Treatment options include FOLFOX, XELOX, FLOX, single agent capecitabine, or 5-FU/LV in patients whom oxaliplatin therapy is believed to be inappropriate.

70. Thank You