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colorectal cancer incidence in the US

-Annual US incidence (2012) ~143,460
-Annual US mortality (2012) ~51,690
2nd Leading Cause of Cancer Death

Commonly used screening techniques for the diagnosis of CRC

Fecal occult blood test (FOBT)
Flexible sigmoidoscopy
Colonoscopy
Double contrast barium enema
Digital rectal exam (for rectal cancer only)

Stage II CRC is

-disease demonstrates muscular invasion without nodal involvement, and the role of adjuvant therapy remains controversial.

Stage III CRC

Patients have both muscular invasion and nodal involvement and are treated using adjuvant chemotherapy.

Stage IV CRC

-metastatic involvement of distant lymph nodes and/or distant organs.

metastasis commonly associated with CRC

hepatic

Stage at which most CRC patients present

Most patients present with stage II (22%) or III (29%) disease.
Unresectable stage IV disease is generally fatal.

risk factors for CRC

-Aging >50.
-Family history: first or second degree relative with colon cancer.
-History of colonic polyps: large or many
-IBD: ulcerative colitis or Crohn's disease.
-Hereditary conditions: account for 15% of CRC.
Familial adenomatous polyposis (FAP)
Hereditary nonpolyposis colorectal cancer (HNPCC)
-Diabetes: 40% increased risk of colon cancer.
-Diet: a diet high in fats (especially animal fats).
-Cigarette smoking/ alcohol: may increase risk.
-Sedentary lifestyle
-Race: African Americans have the highest numbers of colorectal cancer in the United States - reason is still unknown

Dietary fat and colon cancer

-Modest positive correlation between fat intake and incidence of colorectal cancer.
-Also seen in Chinese migrant studies

Obesity and CRC risk

-Increasing body size related to risk of postmenopausal breast cancer
-Weight gain in adult life correlated with risk of colorectal cancer
-Low levels of physical activity in adult life indirectly associated with both colon and breast cancer

Dietary factors with positive correlation to CRC

-Fat consumption
-obesity

Dietary factors with no correlation to CRC

-Fiber consumption

Dietary factors with unclear relationship to CRC

Fruits and vegetables
-possibly weakly protective

CRC risk and weight

-Risk increases with increasing weight and sedentary individuals
-increasing weight in very active individuals appears to be protective against colon cancer

CRC and folate acid/antioxidant vitamins (A, C, E)

-Fully tested and multivitamins have been shown to be strongly inversely related to colon cancer risk in a dose-dependent fashion

Aspirin and CRC

-10 of 11 observational and/or cohort studies show an inverse correlation between use and both incidence and mortality
-Relative risk reductions were in the range of 0.5 for both incidence and mortality
-only prospective randomized controlled study could NOT confirm these findings after 12 years of follow-up

Primary prevention of colorectal cancer

1. Reduce dietary animal fats.
2. Maintain ideal body weight.
3. Multi-vitamins and/or folic acid may be helpful and are not harmful.
4. Fruits and vegetables may be helpful.

Reasons to screen for CRC

-Lifetime incidence 5 %
-90% of cases occur after age 50
-One-third of patients with colorectal cancer die from the disease
*Colorectal cancer is a preventable disease
*

Adenoma carcinoma sequence

Normal mucosa→ adenoma→ severe dysplasia→ cancer

reasons why normal mucosa→ adenoma

Hyperproliferation
DNA hypo-methylation

Reasons for adenoma→ severe dysplasia

Oncogene mutation

Reasons for severe dysplasia→ cancer

Allelic deletions
aneuploidy

Requirements for effective CRC screening

-Modalities need to be able to accurately identify early disease at a point where intervention makes a difference in survival

Reason why primary screening is effective for CRC

-Majority of CRC arises from polyps called adenomas which may progress to cancer
-the development of CRC is a multiple step process that takes many years to occur
-screening can detect early cancers leading to better prognosis and also can lead to colonoscopic removal of precancerous adenomas and reduce the actual development of colon cancer

Genetic variations accumulated by polyps prior to becoming cancerous

-APC (adenomatous polyposis coli) gene/mismatch repair gene that leads to adenoma transformation
-K-ras, DCC (deleted in colon cancer) gene and the tumor suppressor p-53 are affected which leads to the growth of larger, more advanced adenomas and possibly cancer

Time it takes for an adenoma to develop into cancer

10 years

2 categories of colorectal screening

1. Tests that detect cancer (cancer detection only)
2. Tests that detect polyps and cancer (cancer detection and prevention)

Tests that detect cancer

1. Guaiac based fecal occult blood test-yearly
2. Immunochemical-based fecal occult blood test-yearly
3. Stool DNA-interval uncertain

Task that detect polyps and cancer

1. Flexible sigmoidoscopy-every 5 years
2. Colonoscopy-every 10 years
3. Barium enema-every 5 years
4. CT colongraphy-every 5 years

Weakness of FOBT screening tests

-Lack of sensitivity and specificity
-at best 25% of large advanced polyps and cancers are detected
-lack of specificity leads to false positive testing and unnecessary colonoscopy

adherence rates for cancer screening

-adherence rates for colorectal cancer screening are below those of breast, cervical and prostate cancer
-evidence base to support colorectal cancer screening is stronger than for any of the other cancers
-colorectal cancer screening is more cost-effective than these cancers.
-Only 45-63% adhere to screening recommendations

Percent by which sigmoidoscopy has reduced CRC mortality

45-60%

Reason why total colonoscopy is replacing sigmoidoscopy as the screening test of choice

Increasing prevalence of right-sided lesions that sigmoidoscopy cannot detect

Endoscopic colonoscopy

Screening test of choice in the United States
-53% reduction in colorectal cancer mortality in patients who had a screening colonoscopy with polypectomy
-provides the most sensitive test for detection of adenomatous polyps
-sensitivity approaches 98 to 99% for adenomas >6 mm
-Combines complete examination of colon with direct therapy of removing dysplastic polyps
-role of polyps as precursor to cancer provides rationale for endoscopic screening illustrated by the benefit of adenoma removal by polypectomy at the time of colonoscopy

US adults >50 who have had sigmoidoscopy or colonoscopy

colonoscopy screening recommendation for patients with history of adenomatous polyps

-1-2 adenomas < 10 mm → every 5 years
-advanced adenoma >10 mm → every 3 years
-large sessile adenomas removed at colonoscopy → repeat in 3-6 months

CT colonography/Virtual colonoscopy

Computed tomography procedure that uses helical, multiple thin section images along with specialized computer programming to provide three-dimensional and two-dimensional images of the colon

Family history and CRC risk

-Risk of colorectal cancer increases by number of family members affected, age family member affected, and if 1st degree relative
-Colorectal Ca in 1st degree relative before 60 or two 1st degree any age
Colonoscopy at age 40 or 10 years before youngest, THEN every 5 years
-Family history significantly increases a person's risk of colon cancer by up to 30%

Lifetime Colon Cancer Risk by Family History

2 most common colorectal cancer syndromes

-Familial adenomatous polyposis (FAP)
-hereditary non-polyposis colorectal cancer syndrome (HNPCC)

CRC Predisposing factors

Familial adenomatous polyposis

-Rare autosomal dominant syndrome
-inherited mutation in the adenomatous polyposis coli (APC) gene

Clinical features of FAP

-Multiple colorectal adenomatous

Epidemiology of FAP

Prevalence = 1/10,000
-male = female
-average age of polyp formation = 16 years
-approximately 25,000 cases in the US
-accounts for <1% of all CRC

Screening recommendations for family history of FAP

Sigmoidoscopy/colonoscopy recommended yearly beginning at age 10-12 with treatment being total colectomy when patient develops colon polyps

Prognosis in untreated FAP patients

-Cancer risk = 100%
-average age of onset = 39 years
-average life expectancy after prognosis: 42 years

Quick facts about HNPCC

-Early age of onset
-multiple primary cancers
-right colon predominance
-few or no adenomas
-autosomal dominant
-endometrial cancer possible

Hereditary non-polyposis colorectal cancer syndrome

-Autosomal dominant disorder that carries an 80% lifetime risk of colorectal cancer
-accounts for 2-10% of all CRC's
-mutations in theML H1 and MLH2 mismatch repair genes most common
-mutation allows for accelerated adenoma-carcinoma sequence of about 2 to 3 years
-cancers are often right-sided
-frequent extra colonic cancers are found particularly in the uterine and ovaries

Went to suspect HNPCC

In people who have multiple family members with cancers of the colon, endometrium, ovaries, small bowel, GU, pancreas

Amsterdam criteria 321 rule for the diagnosis of HNPCC

-3 family members with HNPCC associated cancer
-2 generations affected
-1 person diagnosed before age 50
-FAP excluded

HNPCC Screening

-Genetic testing for MLH1 and MLH2 mutations
-colonoscopy screening performed every 1-2 years beginning at age 20 to 25

HNPCC Treatment

-Total/subtotal colectomy if colorectal cancer or advanced adenoma
-prophylactic colectomy

Cecal (right colon) carcinoma

colorectal cancer signs/symptoms

-Mostly silent
-don't produce symptoms until late in the disease process
-majority of CRC is diagnosed through screening while the patient is asymptomatic

Signs and symptoms of CRC in the colon

*-Abdominal pain (>40%)
-change in bowel habits
-hematochezia*
-other signs that may be present and indicate more advanced stage include weight loss, weakness, nausea and vomiting, perforation

Signs and symptoms of Cecal (right colon) CRC

Occult bleeding
anemia
stool positive for occult blood

Signs and symptoms of sigmoid (left colon) CRC

-Colonic obstruction
-change in bowel habits due to smaller lumen
-decreased compliance of this portion of bowel

Signs and symptoms of rectal CRC

-Change in bowel habits
-change in stool caliber
-bleeding
-tenesmus
-less commonly patients complained of lower back or sacral pain radiating to the legs

Types of benign polyps

hyperplastic
juvenile (retention)
Peutz-Jeghers polyps

Peutz-Jeghers syndrome

autosomal dominant
multiple hamartomatous polyps throughout the GI tract
melanocytic mucosal and cutaneous pigmentation

Neoplastic polyps

-Adenomas: tubular/villous →Danger proportional to size
-Severe dysplasia in epithelium develops before invasion

Colorectal cancer histopathology

-55,000 deaths per year in the US
-CRC constitutes 10-15% of all cancer deaths
-only 20% of CRC occurs in people younger than 50

3 major pathways leading to the development of colorectal carcinoma

1. APC/Beta Catenin WNTsignaling pathway-accounts for 80% of sporadic CRC through classic adenocarcinoma pathway
2. Microsatellite instability pathway associated with defects in DNA mismatch repair genes-accounts for the development of CRC in HNPCC or Lynch syndrome
3. Increase CpG island methylation in the absence of microsatellite instability

Histopathology of colon and rectal adenomas (benign neoplasms)

-Common with advancing age
-can arise de novo through the APC/Beta catenin WNT signaling pathway
-generally appear 1st as polyps and can be found on screening tests

inflammatory polyps

-Seen in adults
-lesions are histologically identical to juvenile polyps
-characterize as hamartomas, tumors made of benign cells native to that region but put together in an abnormal way
-show positional anaplasia

Juvenile polyp

Seen in children and adolescents
-small tumors have dilated benign glands, stromal fibrosis and variable amount of inflammatory cells

Hyperplastic polyps

-benign polyps usually in the sigmoid
-thought to arise secondary to decreased shedding of cells and so pile up in the mucosal layer

Adenomatous polyps

Have sustained genetic damage and are known to be precursors of adenocarcinoma
-divided into 3 categories by their histologic appearance:
1. Tubular (>75% tubular structure)
2. Villous (>50% villous structure)
3. Tubulo-villous (25-50% villous structure)

factors that influence the malignant potential of Adenomatous polyps

-Size >4 cm
-histology (villous is worse)
-appearance (sessile flat is worse than pedunculated)
-grade

Normal colon versus adenomatous polyp

villous adenoma

CRC red flag symptoms

Abdominal pain > 40 %, non-specific
Change in stool habits > 40 %, left sided
Hematochezia 40 %, rectal cancer
Weight loss - rare
Iron deficiency anemia
-Approx 10 %, right sided
Weakness, fatigue -Rare, nonspecific

CRC impact of symptoms

Worse outcome if diagnosed with symptoms
-Symptomatic (48 % 5 years survival) vs.
-Asymptomatic (71 % 5 year survival)
-# of symptoms inversely related to survival
-Perforation or obstruction very poor predictor of outcome

Diagnosis/Staging colon elavuation

Colonoscopy
-Gold standard - allows for tissue diagnosis
-Can rule out synchronous cancers or polyps

Diagnosis/staging with CT scan abdomen/pelvis and CXR

Allows pre-operative assessment for metastatic disease

Diagnosing/staging of rectal cancer

-colonoscopy
-CT scan
-CXR
-Trans-Rectal Ultrasound (TRUS)
Allows assessment for adenopathy as well as tumor depth which are important for determining stage and appropriate treatment approach
-not useful for cancers that are so large they completely obstruct the rectum

CRC stages

Tx: primary tumor cannot be assessed
T0: no evidence of primary tumor
Tis: carcinoma in situ-intraepithelial or invasion of lamina propria
T1: tumor invades sub mucosa
T2: tumor invades muscularis propria
T3: tumor invades through muscularis propria into pericolorectal tissue
T4a: tumor penetrates to the surface of the visceral peritoneum
T4b: tumor directly invades or is adherent to other organs or structures

proximal colon adenocarcinomas

Tend to be polyploid exophytic masses
-more commonly present with bleeding and anemia

Distal colon adenocarcinomas

-More often annular circumferential lesions prone to causing obstruction as the presenting symptom

Carcinoid tumors

Of neuroendocrine original
-can occur in the appendix and rectum as well as the small bowel
-usually do not develop distant metastases

Basaloid or cloacogenic carcinoma

-Rare tumor derived from the basal layer of the regional epithelium
-significant metastatic potential

Squamous cell carcinoma of the rectum

Associated with HPV infection

Diagnosis/staging history

Focus on symptoms, weight loss, and other comorbidities that may play a role in considering the proper treatment approach

Diagnosis/staging physical exam

-Focus on abdominal exam by attempting to palpate a tumor mass as well as assessment for hepatomegaly or ascites
-digital rectal exam is important when assessing a palpable rectal cancer to allow for accurate description of size, location, morphology, and tumor mobility

Colonoscopy for staging/diagnosis of CRC

-More sensitive than barium enema
-considered the gold standard for evaluation and tissue diagnosis
-useful in ruling out the possibility of synchronous colon cancers which can be found in 2 to 8% of cases

CRC staging by routine laboratory evaluation including CEA

-Important in patients presenting with bleeding/anemia
-Carcinoembryonic antigen (CEA) is produced by some tumors and may serve as a baseline for postoperative follow-up
-CEA is elevated in smokers

True colon cancers versus rectal cancers

True colon cancers are large bowel cancers arising above the peritoneal reflection
rectal cancers are found below the peritoneal reflection

Colon cancer spread

-intra-mucosal extension
-direct invasion
-lymphatics
-hematogenously
-via the portal system
-intraperitoneally
liver is most common site of metastasis

Rectal cancer spread

-Intra-mucosal extension
-direct invasion
-lymphatics
-hematogenously

Rectal cancer treatment/Total mesorectal excision

-Removes en bloc rectum and mesorectum
-Allows for removal of radial tumor spread as well as nodal drainage basin
-Proven benefit to this approach with regard to local recurrence
-prevents rectal cancers from invading the fat and connective tissue of the mesorectum when it penetrates the thickness of the bowel wall
-includes removal of all the tissue of the rectum along with its encompassing envelope

Reason why radiation therapy is used for the treatment of rectal cancer but not for colon cancer

Lateral/radial spread of rectal cancer into the pelvic soft tissue makes recurrence in this area particularly dangerous
-surgery alone is not enough to prevent this risk of local recurrence
-recurrence in the para-rectal tissue has high morbidity
-patient experience great pain and suffering prior to death

Drainage from the upper rectum

Follows the portal system (inferior mesenteric vein) making liver metastases the most common site
-middle and lower rectum drain into the hypogastric/internal iliac system and into systemic circulation
-allows for potential metastases outside the liver; most likely the lungs

Adjuvant chemotherapy

-Chemotherapy given postoperatively to decrease risk of recurrence
-Typical course is 6 months
-Chemotherapy regimens all include 5-FU in some capacity
-adjuvent therapy in Stage III patient's with 5-FU and leucovorin improve survival and is the standard of care

5-FU Mechanism of action

Inhibits Thymidylate Synthase (TS)
Bolus: Inhibits RNA synthesis
Infusion: Inhibits DNA synthesis

5-FU side effects

-Loading Schedule: Neutropenia and stomatitis
-Weekly Bolus: Diarrhea
-Continuous Infusion: "Hand-foot syndrome"How

Capecitabine

-Oral pro-drug of 5-FU
-Activated by Thymidine Phosphorylase
-Potential concentration in the tumor

Capecitabine side effects

"Hand-Foot syndrome"
Diarrhea
Nausea
Rash

5-FU preferred therapy

5-FU bolus with leucovorin plus a 46 hour infusion of 5-FU

Oxaliplatin

Third generation platin compound
-Favorable toxicity profile
-Reversible neurotoxicity
-Mild hematologic toxicity
-No renal or ototoxicity
*Synergy with other chemotherapy agents
5FU, irinotecan, paclitaxel*

Postoperative Follow-up

Every 3-6 months for first 5 years
-History and physical
-CBC, chemistries, CEA
Surveillance CT scan annually for 5 years
-More frequently in high risk patients
*Colonoscopy at 1 year and then at 3 years
*

Rectal cancer treatment options

1. Surgery followed by radiation therapy and chemotherapy - adjuvant approach
2. Radiation therapy and chemotherapy followed by surgery - neoadjuvant approach

reason why radiation therapy is not used for colon cancer

-no soft tissue space adjacent to most of the colon
-peritoneal cavity lies on the other side of the bowel wall
-Recurrence pattern differs from that of rectal cancer
*Rectal: local recurrences common
Colon: distant recurrences (e.g. liver)*

Roles of radiation therapy

1. To sterilize microscopic disease in the mesorectal tissues, hopefully preventing a local recurrence
2. To downsize the primary tumor to allow for a sphincter-sparing surgery (LAR rather than APR)

Advantages of Neoadjuvant Approach

-Usually less morbid & better tolerated
-Radiation fields are smaller (less tissue needs to be treated)
-Blood supply intact
-Less delay in treatment

anus anatomy

Performance Status

Grade -ECOG
0 - Fully active, able to carry on all pre-disease performance without restriction
1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2 - Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours
3 - Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4 - Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5 - Dead

Regional Therapy

-Surgical Resection
-Tumor Ablation
Cryotherapy
RFA
-HAI Chemotherapy
-Selective Internal Radiotherapy
SIR-Spheres

Regional Therapy - Surgery

Only potential curative option with metastases limited to the liver or lung.

Resection of isolated hepatic metastases produces a 5-year survival rate of 24%-58%.

Benefit to peri- post-operative chemotherapy.

FOLFOX

-Oxaliplatin, Day 1
-Leucovorin, Day 1
-5-FU Bolus, Day 1
-5-FU infusion over 48 hours

Toxicities w 5-FU similar, oxaliplatin with different toxicity profile

FOLFIRI

-Irinotecan, Day 1
-Leucovorin, Day 1
-5-FU Bolus, Day 1
-5-FU infusion over 48 hours

Diarrhea, neutropenia as adverse events
Acute versus delayed
Dose adjustment required in hepatic insufficiency

Irinotecan, Day 1
Leucovorin, Day 1
5-FU Bolus, Day 1
5-FU infusion over 48 hours

-Inhibitor of topoisomerase 1
-First agent with benefit beyond 5-FU alone
-IFL superior to 5-FU/LV alone
-Tough treatment
Diarrhea, grade 3-4 23 vs 12%

UGT 1a1

-involved with congjugation of bilirubin into a water soluble excretable product
-Also glucuronidates other things, steroids, drugs
-Impaired glucuronidation causes buildup of toxic metabolite SN-38, causing severe toxicity
-Neutropenia, diarrhea

Oxaliplatin Toxicity

Myelosuppression
Neuropathy
-Can be severe, most resolve to grade 1 or less by one year
-Often the dose-limiting/duration-limiting side effect of chemotherapy
Ca+Mg infusion-prophylactically vs. reactively

Antiangiogenic Strategies

-Inhibit new blood vessel formation
-Inhibit tumor growth
-Target angiogenic components of tumor, stroma, and endothelial cells

One approach involves targeting vascular endothelial growth factor (VEGF), a key pro-angiogenic factor expressed in many human tumors. Monoclonal antibodies such as bevacizumab bind to VEGF, preventing ligand binding to the VEGF receptor and thus blocking receptor activation.

Bevacizumab side effects

-Hypertension
-Arterial embolic phenomena
-Bleeding
-Proteinuria
-Wound dehiscence
-Consider waiting postop at least 4 weeks
-Perforated viscus

Inhibition of the EGFR Pathway

Cetuximab

-Human/murine chimeric antibody directed at blocking EGFR
Requires the absence of a K-Ras mutation

Panitumumab

-"Fully humanized" monoclonal antibody, no murine component
less immunogenic, less incidence of infusion reaction (<1%)

Palliative care

-Important to engage palliative care early
-Explain to patients at diagnosis about expected survival
-Better management of pain, nausea, emotional trauma, bereavement counseling

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