Colon Cancer Overview
Jason A. Zell, DO, MPH
Division of Hematology/Oncology
Dept. of Medicine, & Dept. of Epidemiology, University of California Irvine
UC Irvine Internal Medicine Residency
Core Lecture Series
UCIMC (10/13/14) and LBVAMC (10/16/14)
Disclosures

No relevant financial disclosures
*Off-label use of drugs will be discussed only in the context of clinical trials.
Overview



Epidemiology, Screening
Staging
Current Management Strategies for CRC
– Multidisciplinary Treatment by Stage
Surgery
 Chemotherapeutic & Biologic Agents

– Multidisciplinary management of metastases

Tertiary Prevention / Survivorship
Case Presentation #1


74 year male with stage II (T3N0M0) sigmoid
colon cancer status post laparoscopic sigmoid
colectomy 30 days ago, MSS tumor, no high
risk features. He is in excellent performance
status without significant comorbidity.
Do you recommend adjuvant chemotherapy?
Case Presentation #2


44 year male with Stage IIIc (T3N2bM0)
sigmoid colon cancer (11 of 33 lymph nodes
involved with cancer). He is now 21 days
status post laparoscopic sigmoid colectomy, in
excellent performance status.
What treatment and/or prevention strategies
can be offered to this patient?
Case Presentation #3


36 year female with Stage IVa (TxNxM1)
sigmoid adenocarcinoma (M1 due to multiple
liver metastases). RAS status (KRAS, NRAS) is
wild type. Pt is in excellent performance
status.
What is your recommended 1st line treatment
regimen for her?
CRC Risk Factors

Intrinsic
– Age
– Personal history of colorectal
polyps or cancer
– Inflammatory bowel disease
– Race/ethnicity
– CRC family history
– Inherited syndromes


FAP
HNPCC

Extrinsic
– Diet


–
–
–
–
–
Red meat, processed meat
Cooking methods
Physical inactivity
Obesity
Smoking
Alcohol
Type II diabetes
American Cancer Society
http://www.cancer.org/docroot/CRI/content/CRI_2_4_2X_What_are_the_risk_factors_for_colon_and_rectum
_cancer.asp
U.S. Cancer statistics, 2014:
Estimated New Cases & Deaths
CA: A Cancer Journal for Clinicians
Volume 64, Issue 1, pages 9-29, 7 JAN 2014 DOI: 10.3322/caac.21208
http://onlinelibrary.wiley.com/doi/10.3322/caac.21208/full#caac21208-fig-0001
U.S. Cancer statistics, 2014:
Incidence Rates
CA: A Cancer Journal for Clinicians
Volume 64, Issue 1, pages 9-29, 7 JAN 2014 DOI: 10.3322/caac.21208
http://onlinelibrary.wiley.com/doi/10.3322/caac.21208/full#caac21208
Cancer
Statistics, 2014:
Mortality Rates
CA: A Cancer Journal for Clinicians
Volume 64, Issue 1, pages 9-29, 7 JAN 2014 DOI: 10.3322/caac.21208
http://onlinelibrary.wiley.com/doi/10.3322/caac.21208/full#caac21208
Colorectal carcinogenesis.
Shiff S J , Rigas B J Exp Med 1999;190:445-450
© 1999 The Rockefeller University Press
2012 CRC Avg Risk Screening Guidelines
Beginning
at age 50, both men and women at average risk for
developing colorectal cancer should use one of the screening tests
Cancer PREVENTION (Tests that detect polyps as well as CA)
High Quality Colonoscopy every 10 years, or
Flexible sigmoidoscopy (FSIG) every 5 years*, or
Double contrast barium enema (DCBE) every 5 years*, or
CT colonography (CTC) every 5 years*
Tests That Primarily Detect Cancer
Annual guaiac-based fecal occult blood test (gFOBT) with high test sensitivity
for cancer *, ** or
Annual fecal immunochemical test (FIT) with high test sensitivity for cancer*,**
or
Stool DNA test (sDNA), with high sensitivity for cancer*, interval uncertain
* Colonoscopy should be done if test results are positive.
** For gFOBT or FIT used as a screening test, the take-home multiple sample method should be used.
gFOBT or FIT done during a digital rectal exam in the doctor's office is not adequate for screening.
Adherence to CRC Screening
• 1 in 3 US adults age 50-75 have not
been screened (Am Soc GI Endoscopy)
Alternatives to Colonoscopy
• CT Colonography, “Virtual Colonoscopy”
– Similar to standard colonoscopy in its ability
to detect CRC and precancerous polyps in
people 65 years and older (D. Johnson et al,
J. Radiology, Feb. 24, 2012)
– However: requires prep, high cost, does not
eliminate discomfort, and is inconvenient
Alternatives to Colonoscopy
• Fecal Immunochemical Testing (FIT)
– Stool test for human blood epitopes
– Detects similar number of CRCs compared with
colonoscopy (NEJM 366 (8):697ff, Feb 23, 2012
– “COLONPREV” trial, preliminary results)
•
•
•
•
•
Final results in 2021.
Compliance higher in FIT group (34% vs. 25%)
CRC detection rates = NS
Stage at diagnosis = NS
Detection of adenomas: Colonoscopy>FIT testing
Alternatives to Colonoscopy
• Multitarget Stool DNA testing (“Cologuard”)
• Stool test for KRAS mutations, aberrant NDRG4 and
BMP3 methylation, and β-actin, plus a hemoglobin
immunoassay
– Trial of Multitarget DNA vs. FIT testing for CRC screening
(comparing to colonoscopy results)
• NEJM April 3, 2014, Vol 370(14), pp 1287-1297
–
–
–
–
–
DNA test vs. FIT:
Sensitivity: 92% vs. 74% for CRC
Sensitivity: 69% vs. 46% for polyps with HGD
Specificity: 90% vs. 96% (complete negative colo)
“Cologuard”: FDA approved August 2014
Colorectal Cancer
Rank
136,830 cases in US in 2014
71,830 (men)
#3
65,000 (women)
#3
50,310 deaths in US in 2014
26,270 (men)
#3
24,040 (women)
#3
Lifetime probability: 1 in 20 (men)
1 in 22 (women)
5-year Survival (%)
Survival
CA: A Cancer Journal for Clinicians
Volume 64, Issue 1, pages 9-29, 7 JAN 2014 DOI: 10.3322/caac.21208
http://onlinelibrary.wiley.com/doi/10.3322/caac.21208/full#caac21208
TNM Staging (AJCC-7)
Surgery: considerations

High Risk Features
–
–
–
–
–
–
–


Grade 3 or 4
Lymphovascular invasion
Bowel obstruction
<12 lymph nodes examined
T4 lesion
Tumor perforation
Inadequate or close surgical margins
Tumor Subsite Location*
For Rectal Cancer- Total Mesorectal Excision
*Wray, C, Hinojosa, MW, Ziogas, A, Le, H, Stamos, MJ, and Zell, JA. Tumor subsite location within the colon
is prognostic for survival after colon cancer diagnosis. Dis Colon Rectum, 2009 Aug;52(8):1359-66.
Colorectal Cancer:
Chemotherapeutic & Biologic Agents

Chemotherapy
– 5-Fluorouracil (5FU)
+ leucovorin
– Capecitabine
– Oxaliplatin
– Irinotecan (CPT-11)

Biologic Agents
– Bevacizumab

US FDA approved 2/26/04
– Cetuximab

US FDA approved 2/12/04
– Panitumumab

US FDA approved 9/27/06
– Ziv-aflibercept

US FDA approved 8/3/12
– Regorafenib

US FDA approved 9/27/12
“Personalized Medicine”
(Molecular Diagnostics)

Patient-Specific Tests
– UGT-1A1
polymorphism
– Dihydropyrimidine
dehydrogenase (DPD)
deficiency

Tumor-Specific Tests
– Microsatellite Instability (MSI)
– KRAS mutation analysis

Codons 12, 13, 61
– Extended RAS testing

KRAS, NRAS
– BRAF V600E mutation
– Gene Signature Profiling
– Circulating Tumor Cells

FDA approved in 2007
Management of Colon
Cancer by Stage

Non-metastatic Colon Cancer
NCCN Guidelines for Treatment of Colon Cancer
Clinical
Workup
Presentation
Findings
Resectable:
nonobstructing
Resectable
colon
cancer
(M0)
www.nccn.org
•Pathology
review
•Colonoscopy
•CBC,
chemistry
profile, CEA
•CT-C/A/P
•PET-CT not
routinely
indicated
v.2.2015, 10/4/14
Resectable:
obstructing
(unprepped)
Locally
unresectable
or medically
inoperable
Surgery
Colectomy + en bloc removal
of regional lymph nodes
Colectomy + en bloc
removal of regional
lymph nodes
or
Resection + diversion
or
Stent
or
Diversion
Systemic Chemotherapy
NCCN Guidelines for Treatment of Colon Cancer
Pathologic Stage
Tis, T1N0M0,
T2N0M0
None
T3N0M0, no highrisk features
T3N0M0 w/ highrisk features: grade
3-4, lymphovascular
invasion, bowel
obstruction, <12
lymph nodes
examined, perforation,
close/indet./+margins
TanyN1-3M0
www.nccn.org
Adjuvant Therapy
Capecitabine or
5FU/LV or Clinical
Trial or Observation
FOLFOX or
Capecitabine or
5FU/LV or CAPOX
or Clinical Trial or
Observation
FOLFOX, CAPOX,
Capecitabine or
5FU/LV or Clinical Trial
v.2.2015, 10/4/14
SURVEILLANCE
Stage 0 or Stage I
Colon Cancer


Surgery
Colonoscopy Surveillance
Stage II Colon Cancer
MSI Status is Prognostic
MSI-H
MSS/MSI-L
Ribic, CM et al, New England J Medicine 349 (3):247-257, 2003
MSI and Adjuvant 5FU-based Chemotherapy
MSS/MSI-L
MSI-H
Ribic, CM et al, New England J
Medicine 349 (3):247-257, 2003
Stage II Colon Cancer
“Adjuvant Chemotherapy for Stage II Colon Cancer: Are We Closer to Finding the Patients Who
Benefit?” Vergo, M, et al., ASCO 2010 Education Book, pp 123-9.
Surgical Resection,
Stage II Colon Cancer
MSI-H
MSI-Low/MSS
No chemotherapy
after discussion
with patient
High-Risk Clinical
& Pathological
Features
Consider chemotherapy
after discussion with
patient
Molecular Risk
Profile*
Moderate (>=5%) or
small (3-4%) absolute
benefit from
chemotherapy
Very small (<3%)
absolute benefit
from chemotherapy
Consider chemotherapy
after d/w patient
No chemotherapy
after d/w patient
*Kerr, D, et al. J Clin Oncol, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition); 27(15S) (May 20 Suppl), 2009: 4000
Stage III Colon Cancer:

Adjuvant chemotherapy:
– 5FU, leucovorin, oxaliplatin (FOLFOX)
Mosaic Trial1
2
 NSABP C-07

– Capecitabine, oxaliplatin3 (CAPOX)
– Biological Agents?     NO!
1
Andre, T., et al, N Engl J Med 2004; 350:2343-2351
2
Kuebler, JP et al, J Clin Oncol 2007 25, 2198-2204.
3Haller,
DG, et al, J Clin Oncol. 2011 Apr 10;29(11):1465-71.
Stage III Colon Cancer (cont’d):

Adjuvant chemotherapy:
– Duration of treatment? 6 months

CALGB 80702 (6 months vs. 3 months FOLFOX)
– Calcium/Magnesium Salts  No benefit1
1Loprinzi,
C, et al, J Clin Oncol 31, 2013 (suppl; abstr 3501)
NCCN Guidelines* for Treatment of Colon Cancer
Surveillance
• H&P Q3m for 2y, then Q6m for 5 years
• CEA Q3-6m for 2y, then Q6m for a total of 5y
for T3 or greater
• CT-C/A/P in Yr 1-5 for High Risk Pts
• Colonoscopy @ 1yr, except if no preoperative
colonoscopy 3-6mo
• If Advanced Adenoma repeat at 1yr
• If no AArepeat @ 3yrs then Q-5yrs
• PET-CT not routinely recommended
* www.nccn.org v.2.2015, 10/4/14
Tertiary Prevention of CRC:
Diet, Lifestyle, & Chemoprevention*
• Dietary patterns and survival after CRC diagnosis
• Physical activity after colon cancer diagnosis
• Therapeutic Prevention
*Journal of Clinical Oncology, VOL 28, ISSUE 26 - SEPTEMBER 10, 2010
Therapeutic Prevention of CRC: NonSteroidal Anti-inflammatory Drugs (NSAIDs)
• Aspirin improves survival in PIK3CA-mutant CRC
patients
Reference: Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor
PIK3CA mutation, and colorectal-cancer survival. N Engl J Med.
2012;367:1596-606.
• Conflicting data have emerged
Beyond Adjuvant Therapy:
US Colon Cancer Tertiary Prevention Trials testing NSAIDs
SWOG 0820
CALGB 80702
PI: Zell, Brown
PI: Meyerhardt
Polyamine Inhibitors:
Eflornithine, Sulindac,
Placebo
NSAIDs:
Celecoxib vs. Placebo
Treatment Duration
3-years
3-years
Number of Patients
1488
2500
Stage
0-III
III
No
FOLFOX: 3 vs 6m
1-yr post-operative
Perioperative
Yes
Yes
2019
2016
Post-Adjuvant
Treatment
Adjuvant Chemo
Assigned?
On-Study Timeline
Exclusion of High-CV
Risk Patients?
Results Anticipated
www.clinicaltrials.gov
Stage IV Colorectal Cancer
Historical Progress: Management of
Advanced Colorectal Cancer
Supportive Care
~4-6 mo
1 Active Drug (5-FU/LV,
Capecitabine)
~10-12 mo
2 Active Drugs (5-FU/LV +
Oxaliplatin/Irinotecan;
Capecitabine +
Oxaliplatin/Irinotecan)
~15 mo
~20 mo
2 Active Drugs + bevacizumab
20.3 mo
24-31 mo
2/3 Active Drugs +
Targeted/Biologic Agents
0
6
12
18
24
Median Survival (months)
Stage IV Colorectal Cancer

First-line:
Chemotherapy + biologic
- FOLFOX + bevacizumab,
- FOLFIRI + bevacizumab
- FOLFIRI + cetuximab or panitumumab if tumor is
KRAS wild type
- Which regimen first – bevacizumab or
cetuximab?
- Doesn’t matter: CALGB 80405
-J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3)
*Van Cutsem E et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal
cancer (mCRC) treated with or without cetuximab: the CRYSTAL experience. 2008 ASCO annual meeting. Abst# 2
Vascular Endothelial Growth
Factor (VEGF)

Bevacizumab
– Humanized monoclonal
antibody targeting VEGF
– Overall Response=none
– Complications:




Bleeding, Thrombosis,
Hypertension, Proteinuria
Wound dehiscence
Bowel perforation
Ziv-aflibercept (VEGF-trap)
– Recombinant fusion protein
– Complications: as above

Regorafenib (multikinase
inhibitor) VEGFR/Raf/Kit/PDGFR
Agents bind or trap VEGF, reducing
tumor angiogenesis
EGFR Monoclonal
Antibodies

Cetuximab

– Overall Response = 10%
– Complications:





Diarrhea
Skin toxicity
Infusion reactions
Hypomagnesemia
Interstitial lung disease
Panitumumab
– Overall Response = 10%
– Complications:



Diarrhea
Skin toxicity
Hypomagnesemia
KRAS-wild type patients only!
Epidermal Growth Factor Receptor
Siddiqui and Piperdi. Ann Surg Oncol. 17:1168 2010
Multidisciplinary Management of
Colorectal Liver Metastasis




Complete resection of CLM yields 30-50% 5-year survival
Incomplete resection: comparable to no resection
Preoperative chemo may convert unresectable CLM 
resectable disease
Postoperative chemotherapy  improved outcomes
Gallagher, D, and Kemeny, N. Oncology 2010; 78:237-248.
Chua, TC et al. Ann Surg Oncol, 2010; 17:492-501
Cytoreductive Surgical
Resection

Diaphragmatic peritonectomy
HIPEC
Cytoreductive Surgery & Heated
Intraperitoneal Chemotherapy (HIPEC)


Indication: (limited) peritoneal metastases
RCT: CRS+HIPEC (5FU infusion, IP MMC) (n=105)
Verwall et al, J Clin Oncol 21:3737-3743, 2003
Stage IV Colorectal Cancer

Second-line:
– Bev beyond progression (ASCO 2012)

–
–
–
–

FOLFOX-bev FOLFIRI-bev
FOLFIRI-ziv-aflibercept
FOLFIRI + cetuximab or panitumumab (KRAS-wt)
Regorafenib
Clinical Trial*
Third-line and beyond
– Single agent cetuximab, or panitumumab
– Regorafenib
– Clinical Trial *
Patient-Centered Approach to Clinical Research at UC
Irvine’s Chao Family Comprehensive Cancer Center:
Colon Cancer Disease-Oriented Team, aka “Colon DOT”
Clinical Trials
Translational Research
Basic Science, Epidemiology
Colorectal Cancer Trials at UC
Irvine
Adenoma ACF
Prev/Obese/Metformin
Recently Completed
Active Enrollment
High-Risk
CRC Stage Stage
Adenoma Stage 0
I
II
Stage
III
Stage IV
Accrual: UCI=13 (all sites=44)
Prevention: Erlotinib/ACF
Colon & Rectum
Tertiary Prevention: Dietary Arginine Restriction + Aspirin
S0820 Eflornithine/Sulindac, Phase III
UCI=13 (all=39)*
Colon & Rectum
Colon, Rectosigmoid
n=25 (of 25)
n=6 (all=27)
N1048 – PROSPECT Trial (neoadj FOLFOX vs. 5FU-XRT)
Rectal T3N1-2
n=4
ROLARR, Phase III Operative Trial: Robotic vs. Laparoscopic
Rectal T3N1-2
n=32
C80702: Adjuvant FOLFOX 3vs 6moCelecoxib vs Placebo
Colon
1st Line
1st Line Metastatic – None
E7208: CPT-11/Cetuximab/Ramucirumab, Phase II
FOLFIRI-Ziv-aflibercept, Phase IV
n=1
Approved by Colon DOT 9/23/14
2nd Line, KRAS-wt
n=6
2nd/3rd/4th Line
Case Presentation #1


74 year male with stage II (T3N0M0) sigmoid
colon cancer status post laparoscopic sigmoid
colectomy 30 days ago, MSS tumor, no high
risk features. He is in excellent performance
status without significant comorbidity.
Do you recommend adjuvant chemotherapy?
Case Presentation #2


44 year male with Stage IIIc (T3N2bM0)
sigmoid colon cancer (11 of 33 lymph nodes
involved with cancer). He is now 21 days
status post laparoscopic sigmoid colectomy, in
excellent performance status.
What treatment and/or prevention strategies
can be offered to this patient?
Case Presentation #3


36 year female with Stage IVa (TxNxM1)
sigmoid adenocarcinoma (M1 due to multiple
liver metastases). RAS status (KRAS, NRAS) is
wild type. Pt is in excellent performance
status.
What is your recommended 1st line treatment
regimen for her?
Summary





Personalized medicine for CRC is here (patient &
tumor-specific factors)
Stage I: surgery
Stage II: surgery, then markers define treatment
course; no role for biologic therapy
Stage III: surgery + adjuvant chemotherapy; no
role for biologic therapy
Stage IV: markers define treatment course;
biologic agents are standard; multimodal
treatment often indicated.