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Colon Cancer
Stage I-III
Palak Desai, MD
Trends in Cancer incidence rates
among men 1975-2010
Trends in Cancer incidence rates
among women 1975-2010
Colon Cancer Etiology
Sporadic
(65%–85%)
Familial
(10%–30%)
Rare CRC
syndromes
(<0.1%)
Familial adenomatous
polyposis (FAP) (1%)
Hereditary
nonpolyposis
colorectal cancer
(HNPCC) (5%)
Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996
Risk Factors
 Adenomatous polyps
 Physical Inactivity/obesity
 Age >50
 Smoking
 Inflammatory Bowel Disease
 NSAIDS
 History of Cancer
 Diets/Supplements
 Family History of Colorectal
Cancer
 Race
Diet
dietary fiber
vegetables
fruits
decreased risk
antioxidant vitamins
calcium
folate (B Vitamin)
Diet
consumption of red meat
animal and saturated fat
increased risk
refined carbohydrates
alcohol
Familial Risk
Approximate
Familial setting
Colon Ca
Life time risk of
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
Adenoma- Cancer Sequence
Loss of
APC
Normal
epithelium
Hyperproliferative
epithelium
Activation
of K-ras
Early
adenoma
Deletion
of 18q
Intermediate
adenoma
Adapted from Fearon ER. Cell 61:759, 1990
Loss of
TP53
Late
adenoma
Other
alterations
Carcinoma
Metastasis
Risk of Colorectal Cancer
5%
General population
Personal history of
colorectal neoplasia
15%–20%
Inflammatory
bowel disease
15%–40%
70%–80%
HNPCC mutation
>95%
FAP
0
20
40
60
Lifetime risk (%)
80
100
Clinical Presentation
Colorectal Cancer by Site
Stage at Diagnosis
Distant (cancer has
metastasized)
19%
Regional (spread to
regional
lymphnodes)
37%
Adapted from NCI Cancer Facts and
Figures 2010
Unknown
(unstaged)
5%
Localized (confined
to primary site)
39%
Stages of Colon Cancer
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%
Dukes Classification
Initial Treatment
Evidence Blocks
High Risk Features







T4 tumors (stage IIB/IIC)
poorly differentiated histology
Lymphovascular invasion
Perineural invasion
Bowel obstruction
Less than 12 lymph nodes sampled
+ margins
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 370-400 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 338; 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 welltolerated and effective 6-month adjuvant regimen for colon cancer.
IMPACT group, Lancet 1995
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
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
 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 (0.67-0.91;
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
1.0-6.0).
 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
Adjuvant Therapy for Stage II Disease
 Wu et al, 2012
 Meta-analysis of 12 randomized controlled trials from 1988
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
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
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).
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
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.
Roth et al, JCO 2010,
Koopman et al, Br J Cancer 2009
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
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.
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
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 8week 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
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)
NSABP C-07 -- 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 C07 trial
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
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 1250
mg/m(2) twice daily on days 1-14 every 3 weeks or 5FU/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
 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)
0.77-1.01] P<0.0001
 overall survival (OS) (HR = 0.86;
95% CI 0.74-1.01). P<0.001
 This pattern was maintained in
all subgroups, including
patients aged ≥ 70 years.
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).
XELOX- NO16968
 Seven-year DFS 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.
Schmoll et al, JCO, 2015
XELOX vs. FOLFOX
 Patients with resected stage III colon cancer from four
randomized controlled trials (NSABP C-08, XELOXA, XACT, 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
3, 4, and 5 year DFS, RFS, and OS
by Treatment Group
Post-Relapse Survival
Safety
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
Other Adjuvant Regimens
 Other adjuvant regimens studied for the treatment of earlystage 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
Saltz et al, JCO 2007
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
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,
0.79 to 1.13; P = .56) and for
those with stage 3 disease
(HR, 1.0; 95% CI, 0.83 to
1.21; P = .99).
Adding Bevacizumab?- NSABP C-08
 Cancer recurred in 286 and
283 patients in the control
and bevacizumabcontaining 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).
Cetuximab?
 NCCTG Intergroup, N0147 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.
Alberts et al, JAMA 2012, Taeib et al, Lancet Oncology 2014
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
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
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.
 Thank You