COLON CANCER What every doctor should know: A general medical update

Vail Colorado February 3-7 2008 Scott D. Goldstein M.D.

Incidence, Prevalence
Fourth most common internal malignancy Second only to lung cancer as a cause of cancer death 2004 Data:
146,940 new cases in the US (11% of all cancers) 56,600 deaths from colorectal cancer Slight increase annually in incidence, but mortality continues to decline Women: 5.5%; men: 5.9% Women: 2.3%; men: 2.4% Following breast cancer in women and prostate cancer in men

Incidence stabilized since mid-1990s

At birth, probability of eventually developing CRC in US: Probability of dying of CRC in US:

Epidemiology
Age:
Predominantly a disease of older patients Peak incidence in 7th decade Can occur at any age, 20s and 30s ~5% CRC in patients <40 years

Sex:
2005 incidence: 73,470 women and 71,820 men 2005 mortality: 27,750 women and 28,540 men

Epidemiology
Family History:
Numerous reports indicating an increased incidence in first-order relatives Fuchs Study (119,116 patients):
1.72 RR: 1 first degree relative 2.75 RR: 2+ first degree relatives 5.37 RR: <45 years and 1+ first degree relative +FDR: average onset about 10 years earlier than sporadic

St. John Study:

1.8 OR: 1 first degree relative 5.7 OR: 2 first degree relatives
Fuchs et al. N Engl J Med 1994;331:1669-1674. St. John et al. Ann Int Med 1993;118:785-790.

Epidemiology
Family History No family history 1 First-Degree Relative 2+ First-Degree Relatives 1 First-Degree Relative, Diagnosed <45yo 1 First-Degree Relative with Adenoma Relative Risk 1 2.3 4.3 3.9 2.0 Absolute Risk by Age 79 4% 9% 16% 15% 8%

www.cancer.gov/cancerinfo/pdq/genetics/colorectal. 11/19/2003

Epidemiology
Site:
Numerous studies over last 50 years Each shows gradual shift from rectum and left colon to right colon Result of screening distal 25cm?

Geographic Distribution:

Wide variation in different countries Western countries have the highest incidence

United States and Canada are intermediate Lowest: India, El Salvador, Kuwait, Martinique, Poland, and Mexico Increased risk in urban areas as compared to rural areas

Scotland, Luxembourg, Czechslovakia, New Zealand, Denmark, and Hungary

Environmental Exposure and Food Habits:

Japanese Americans have higher incidence than same in Japan European or North American born Israelis 2.5x >risk than those born in Asia or North Africa
The incidence becomes similar after arrival in Israel Their children have same risk as other Americans

Etiology and Pathogenesis

Adenoma-Carcinoma Sequence Inflammatory Bowel Disease Genetics Dietary Factors Irradiation Ureteric Implantation Post-Cholecystectomy Activity and Exercise

Adenoma-Carcinoma Sequence
Well-defined phases of progression Clonal disease
5-10 year process Cellular mutation allows better survival and proliferative expansion

Aberrant crypt foci to microadenomas to adenomatous polyps Dysplastic cells develop within polyps

Breakthrough subepithelial barrier Invade through layers of bowel wall Muscularis mucosa to pericolic tissues to nodes to distant sites

Adenoma-Carcinoma Sequence

Carcinogenesis Genes
Proto-Oncogenes:
K-ras src c-myc sporadic adenomas, cancer, UC

Tumor Suppressor:
APC 5q DCC 18q p53 17p MCC DPC4

FAP advanced adenomas, cancer poor prognostic indicator

DNA Mismatch Repair:

HMSH2 MLH1 PMS1 PMS2 GTBP

HNPCC HNPCC HNPCC HNPCC

Dietary Factors
Western diets:
Naturally occurring chemicals: mycotoxins, plant alkaloids Synthetic compounds: food additives and pesticides Compounds produced by cooking: polycyclic aromatic hydrocarbons and heterocyclic amines (genotoxic)

Fat: both total fat intake and non-dairy animal fats Meat: Fiber:
High intake of red and processed meat Inverse relationship with poultry and fish

Calcium:

Inverse relationship with CRC: ?temporal relationship Can bind intraluminally with bile acids and fatty acids, reducing their mitogenic effect Inverse relationship with calcium intake Increased risk with OR 2.6 reported Most studies related to beer intake and increases in rectal cancer Odds ratio for >40 pack years: 3.31 for adenomas ACS CPSII Study, 1997: 12% of CRC death in general US population attributable to smoking
1,184,657 patients, multivariate analysis: smoking, h/o smoking, never smoked

Alcohol Ingestion: Smoking:

Irradiation
Sporadic reports of colon and rectal cancers developing after XRT for pelvic malignancies Average interval from irradiation to diagnosis is 15.2 years Different pathology:
Higher incidence of mucin-producing tumors

Adjusted hazard ratio: 1.7 (SEER Data)

Ureteric Implantation
Development of neoplasia at or near site of ureterosigmoidostomy Risk: 8.5-10.5 to 80-550 times increased Trending away from this operation, but must be remembered in patients having undergone it Treat endoscopically or by resection

Post-Cholecystectomy
Considerable epidemiologic evidence to suggest that bile acids play an important role in the development of CRC Suggested etiology:
Precise action remains to be determined Normally bile acid pool circulates 2-3x per meal Circulates even during fasting after cholecystectomy Enhanced circulation results in increased exposure of bile acids to degrading action of intestinal bacteria A step in formation of known carcinogens RR: 1.21, greatest for right colon and rectum Increased risk: right colon RR: 1.59 to 4.5

Schernhamer et al: (85,184:877 pts) Lagergren et al: (278,460 pts) Other studies:

Activity and Exercise

Persky et al Study:
Relative increase of 1.3 to 2.0 in those with sedentary jobs

Thune et al Study:
Reduced risk in those engaged in >4hrs /week

Numerous hypotheses presented likely very multifactorial

Persky et al. Problems in Current Surgery: Controversies in Colon Cancer. 1987:11-23. Thune et al. Br J Cancer 1996; 73:1134-1140.

Macroscopic Pathology
Ulcerative Polypoid Annular Diffusely Infiltrating

Ulcerated Pathology

Most common type Roughly circular mass with raised, irregular, everted edge and a sloughing base Confined to one aspect of the bowel wall, but may occupy a larger portion of the bowel circumference

Polypoid Pathology

aka cauliflower type Large fungating mass projecting into the bowel lumen Often a low-grade malignancy ~10% mucin producing: colloid carcinoma

Annular Pathology

aka stenosing Occupies the entire circumference of the bowel wall Lumen usually considerably compromised, with proximal dilation Most frequent in transverse and descending colon

Diffusely Infiltrating Pathology

Diffuse thickening of the intestinal wall For most part, covered in intact mucosa Preserves layers of intestinal wall Most common in the rectosigmoid, but can occur anywhere Similar to linitis plastica of stomach Only 85 documented cases in literature (1995)

Pathology
Microscopic Appearance Considerable variation in histologic appearance Well-differentiated: 20% Mod-differentiated: 60%

Lymph node mets 25%, 5-yr survival 77% Lymph node mets 50%, 5-yr survival 61% Lymph node mets 80%, 5-yr survival 29%

Poorly-differentiated: 20%

Histo-/Pathology

AdenoCA

Poorly-diff adenoCA

Mod-diff adenoCA

Mucinous adenoCA

Mucinous adenoCA

Modes of Spread: Direct Continuity

Estimated to proceed roughly at the rate of one quarter of bowel circumference every 6 months Occurs more rapidly in transverse than longitudinal direction Unusual for microscopic spread to extend >1cm beyond the grossly visible disease Radial extension into adjacent organs and structures Mechanisms: 1) mechanical pressure produced by a rapidly proliferating neoplasm may force malignant cells along tissue planes of least resistance 2) increased cell motility can contribute to malignant invasion 3) malignant cells may secrete enzymes capable of degrading the basement membrane, breaking down cellular barriers

Modes of Spread
Transperitoneal Spread Lymphatic Spread
Transmural extension, peritoneal penetration Peritoneal implants, omental implants Stepwise spread: sentinel lymph node mapping Cascade Hypothesis: liver to lungs to other sites Circulating malignant cells: (no adverse effect)

Hematogenous Spread

Implantation

28% pts during induction; 50% pts during laparotomy

Concerning reports of implantation of exfoliated malignant cells On raw surfaces: hemorrhoidectomy, fistula, fissure surfaces; suture lines; abdominal scars; mucocutaneous junction of ostomies

Site of Spread
100 patients with intestinal carcinoma
50 cured by operation 5 die from lymphatic spread 10 die from local recurrence 35 die from blood-borne metastases Liver: Lungs: Bones: Brain: 77% 15% 5% 5%

Organs most frequently involved:

T Categories

Tx: no description of the tumor's extent is possible because of incomplete information Tis: involves only the mucosa, it has not grown beyond the muscularis mucosa (inner muscle layer) of the colon or rectum T1: T2: T3: T4:
this stage is also known as carcinoma in situ or intramucosal carcinoma

through the muscularis mucosa and extends into the submucosa through the the submucosa, and extends into the muscularis propria completely through the muscularis propria into the subserosa spread completely through the wall into nearby tissues or organs

N&M Categories for Colorectal Cancer

Nx: no description of lymph node involvement is possible because of incomplete information N0: no lymph node involvement is found N1: cancer cells found in 1 to 3 nearby lymph nodes N2: cancer cells found in 4 or more nearby lymph nodes Mx: no description of distant spread is possible because of incomplete information M0: no distant spread is seen M1: distant spread is present

Submucosal Invasion Classification

sm 1 = invasion limited to the upper 1/3 of the mucosa sm 1 a = horizontal invasion limited to less than of the width of the carcinoma component in the mucosa sm 1 b = invasion limited to to of the width of the carcinoma component in the mucosa sm 1 c = invasion extending more than of the width of the carcinoma component in the mucosa sm 2 = invasion limited to the middle 1/3 of the submucosa sm 3 = invasion of the lower 1/3 of the submucosa

Kudo S et al. Endoscopy 1995; 27:54-57

Residual Tumor (R)

R0: R1:
Complete resection, margins histologically negative No residual tumor left after resection Incomplete resection, margins histologically involved Microscopic tumor remains after resection of gross disease Incomplete resection, margins involved Gross disease remains after resection

R2:

Colon Cancer Staging

STAGE Stage I TNM T1 N0 M0 DUKES Dukes A PROGNOSIS 5 year survival >90%

T2 Stage II T3

N0 N0

M0 M0 Dukes B 5 year survival 70-85%

T4

N0

M0

5 year survival 55-65%

Stage III

any T

N1

M0

Dukes C

5 year survival 45-55%

any T

N2, N3

M0

5 year survival 20-30%

Stage IV

any T

any N

M1 (distant)

Dukes D

5 year survival <5%

Stage Grouping
Stage 0: Tis, N0, M0:

Stage I: T1, N0, M0, or T2, N0, M0: Stage IIA: T3, N0, M0: Stage IIB: T4, N0, M0:

It has not grown beyond the inner layer (mucosa) of the colon or rectum, aka carcinoma in situ or intramucosal carcinoma Through the muscularis mucosa into the submucosa or it may also have grown into the muscularis propria Through the wall of the colon or rectum into the outermost layers Through the wall of the colon or rectum into other nearby tissues or organs

Stage IIIA: T1-2, N1, M0: Stage IIIB: T3-4, N1, M0:

Through the mucosa into the submucosa or it may also have grown into the muscularis propria And it has spread to 1-3 nearby lymph nodes Through the wall of the colon or rectum or into other nearby tissues or organs And has spread to 1-3 nearby lymph nodes but not distant sites Any T but has spread to 4 or more nearby lymph nodes but not distant sites Any T, any N, but has spread to distant sites such as the liver, lung, peritoneum, or ovary

Stage IIIC: Any T, N2, M0:

Stage IV: Any T, Any N, M1:

Colorectal Cancer Staging

Colon Cancer Staging

T1: T2: T3: T4: submucosa into muscularis through muscularis adjacent invasion TNM STAGING
I II III IV T1,2 N0 M0 >90% T3,4 N0 M0 40-85% any T N1 M0 30-65% any T any N M1 <5%

5 yr

N1: 1-3 nodes N2: 4+ nodes N3: nodes along named vascular trunk M0: no evidence M1: metastatic spread

DUKES STAGING

A: mucosa/submucosa 90% B1: into muscularis 70-85% B2: thru muscularis 55-65% C1: B1 + nodes 45-55% C2: B2 + nodes 20-30% D: metastasis 0%

5 yr.

Clinical Features
May present in one of three characteristic ways:
Insidious onset of chronic symptoms Acute intestinal obstruction Perforation with peritonitis 77-92% 6-16% 2-7%

Most common symptom is bleeding Next most common presenting symptom is a change in bowel habits Pain occurs as commonly as a change in habits Iron-deficiency anemia
Constipation or diarrhea

Synchronous Carcinoma
Incidence ranges from 2-8% Preoperative total colon evaluation
Colonoscopy is optimal method

Diagnosis
History may not be helpful Early diagnosis may depend on screening

Endoscopy
Anoscopy
Can make anorectal diagnoses

Rigid Sigmoidoscopy
Indispensible in evaluation of rectum Can more effectively judge distances

Flexible Fiberoptic Sigmoidoscopy Colonoscopy

Major role in screening, diagnosis

Colonoscopy

Radiology
Barium Enema Ultrasound CT Scan MRI
Intra-op liver ultrasound, 93.3% sensitivity Evaluation of primary malignancy and liver Extent of disease, adjacent organ relationships

PET Scan

Generally not as sensitive as CT Increased sensitivity with endoanal coil More accurate than CT in identifying malignancy Especially useful in follow-up, hepatic evaluation

Air Contrast Barium Enema

CT Scan Reconstruction

Virtual Colonoscopy

Carcinoembryonic Antigen
Field Effect Normal levels depend on specific assay, but in general <5
Elevated in smokers More likely to be elevated in men and older patients CEA expressed by normal mucosa adjacent to carcinomas Gradient effect, falling off by 5cm

80+% of patients with advanced colonic adenocarcinoma have elevated circulating CEA Pre-op CEA correlations: Correlation with pathology: Recurrence signal:
Inversely with grade of carcinoma, survival Directly with pathologic stage, post-op recurrence Well-differentiated lesions: 95% elevated Poorly-differentiated lesions: 30% elevated

Elevation after resection with normalization of values is concerning Usual decrease by 1 month, but may take up to 4 months Slow or no decrease may indicate incomplete resection or metastasis

Surgical Principles
Resection based on lymphatic drainage, blood supply Suture ligate named or large vessels Go to root of mesentery to get lymphatic drainage En bloc resection of involved structures Remember intra-op US for liver lesions

Segmental Resection

Anastomosis or Not?

Complicated Carcinomas
Obstruction
Stenting

Perforation Bleeding Invasion of Adjacent Viscera

Obstruction
Right-sided lesions: Left-sided lesions:
TOC is resection with primary anastomosis Removal of right and proximal transverse colon Three-stage procedure Hartmanns procedure Two-stage procedure Subtotal colectomy On-table lavage Primary resection

Stenting

Colonic Stenting
Dohmoto, 1991:
Used for palliation Used prior to surgery

Tejero et al, 1994:

Can be used to relieve acute obstruction Permits elective oral preparation, +/- colonoscopy May allow subsequent resection with primary anastomosis Multiple randomized, non-randomized, noncontrolled trials show it is safe and allows single stage surgery

Colonic Stenting

Perforation
Reported in 3-9% of patients with CRC Free perforations present with peritonitis Generalized peritonitis:
Hartmanns procedure, or with mucus fistula Possible to anastomose and divert

Right-sided perforation with left-sided cancer

Subtotal colectomy including perforation and cancer

Invasion of Adjacent Viscera

Resection en bloc all or part of the attached viscus Exceptions:
Duodenum or base of bladder Remove primary lesion and mark structures at risk with metal clips M&M related to anterior exenteration or Whipple probably greater than possible benefit

Palliative Resection
Resection performed to eliminate symptoms of local disease
Avoids obstruction, massive bleeding, effects of local invasion Can relieve symptoms, and sometimes prolong life-expectancy

Added M&M related to procedure may outweigh any temporary symptomatic relief

Synchronous, Metachronous Carcinomas

Incidence of synchronous lesions: 1.5-7.6% Conventional resection for close lesions Subtotal colectomy for widely separated lesions
Consider two segmental resections

Occurrence of second primary: 2.4%

Liver Metastasis
Diagnosis, sensitivity:
CT angiography 74%, US 57%, CT 57% Rec against biopsy for risk of local dissemination

Only 10% develop mets amenable to resection Indications for resection continue to broaden Contraindications to resection:
Total hepatic involvement, advanced cirrhosis, jaundice, IVC or main PV invasion, extrahepatic involvement (except lung)

Anatomic, nonanatomic, enucleation resections

Liver Metastasis

Pulmonary Metastasis
Resectability: 1) Ideally solitary, possibly solitary in each lung 2) Primary should be controlled locally 3) No other evidence of metastasis 4) Medical condition should allow for thoracotomy and pulmonary resection
Except concomitant hepatic metastatectomy

Adjuvant Therapy
Five general underlying principles: 1) there may be occult, viable malignant cells in circulation and/or established, microscopic foci of malignant cells locally or at distant sites 2) therapy is most effective when the burden of malignancy is minimal 3) agents with reported effectiveness against the carcinoma are effective 4) Cytotoxic therapy shows a dose-response relationship and therefore must be administered in maximally tolerated doses, and the duration of therapy must be sufficient to eradicate all malignant cells 5) The risk-to-benefit ratio for therapy must be favorable to individuals who may remain asymptomatic for their natural life expectancy after resection of their malignancy
Intravascular, intralymphatic, or intraperitoneal

Radiotherapy
Used extensively for rectal cancer Little use in colon cancer Indications considered appropriate for use:
1) involvement of lymph nodes 2) known inadequate margins of resection 3) adherence to the retroperitoneum, sacrum, or pelvic sidewalls 4) transmural penetration to a macroscopic degree 5) extensive microscopic penetration with the presence of positive lymph nodes

5-Year Relative Survival for Colon Cancer by AJCC Stage

Percent alive 5 years or more after being diagnosed with colon cancer Derived from people who have had colorectal cancer in the past
depending on their stage of disease at diagnosis. Improvements in treatment may result in a better outlook for more recently diagnosed patients.

5-year survival rate refers to the percentage who live at least 5 years after their cancer is diagnosed Relative survival rates dont include patients dying of other diseases Five-year relative survival rates are considered to be a more accurate way to describe the prognosis for patients with a particular type and stage of cancer These 5-year rates are based on patients diagnosed and initially treated more than 5 years ago May no longer be accurate because improvements in treatment may result in a better outlook for recently diagnosed patients JNCI 2004;96:1420
Used to produce a standard way of discussing prognosis

5-Year Relative Survival for Colon Cancer by AJCC Stage

Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IIIC Stage IV 93% 85% 72% 83% 64% 44% 8%

Colorectal Cancer Survival

4 YEAR SURVIVAL
25% c colon and liver resection 70% c colon and liver resection, after ruling out extrahepatic spread

5 YEAR SURVIVAL, ALL COMERS

50% c colon cancer 40% c near obstructing colon cancer, but NO perforation (WORSE) 47% c near obstructing colon cancer, but WITH perforation pH is most important for cancer cell survival, so if abscess is acidic get fewer mets cannot compete with bacteria no perforation has higher chance for carcinomatosis