colon cancer vail 2008

8/6/2019 Colon Cancer Vail 2008

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COLON CANCERWhat every doctor should know:

A general medical update

Vail Colorado

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


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Incidence, Prevalence

Fourth most common internal malignancy Second only to lung cancer as a cause of cancer death

Following breast cancer in women and prostate cancer in men

2004 Data:

146,940 new cases in the US (11% of all cancers) 56,600 deaths from colorectal cancer

Incidence stabilized since mid-1990s Slight increase annually in incidence, but mortality continues to

decline

At birth, probability of eventually developing CRC inUS: Women: 5.5%; men: 5.9%

Probability of dying of CRC in US: Women: 2.3%; men: 2.4%


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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


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Epidemiology

Family History:

Numerous reports indicating an increased incidencein 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:


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Epidemiology

Family History Relative Risk Absolute Risk by Age 79

No family history 1 4%

1 First-Degree Relative 2.3 9%

2+ First-Degree Relatives 4.3 16%

1 First-Degree Relative,Diagnosed


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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

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

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

Environmental Exposure and Food Habits: Japanese Americans have higher incidence than same in Japan

Their children have same risk as other Americans

European or North American born Israelis 2.5x >risk than those born in Asia orNorth Africa The incidence becomes similar after arrival in Israel


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Etiology and Pathogenesis

Adenoma-Carcinoma Sequence

Inflammatory Bowel Disease

Genetics

Dietary Factors

Irradiation

Ureteric Implantation

Post-Cholecystectomy

Activity and Exercise


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Well-defined phases of progression 5-10 year process

Clonal disease Cellular mutation allows better survival and proliferative

expansion

Aberrant crypt foci to microadenomas to adenomatouspolyps

Dysplastic cells develop within polyps Breakthrough subepithelial barrier Invade through layers of bowel wall

Muscularis mucosa to pericolic tissues to nodes to distant sites


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Carcinogenesis Genes

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

Tumor Suppressor:

APC 5q FAP DCC 18q advanced adenomas, cancer p53 17p poor prognostic indicator MCC DPC4

DNA Mismatch Repair:

HMSH2 HNPCC MLH1 HNPCC PMS1 HNPCC PMS2 HNPCC GTBP


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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:

High intake of red and processed meat Inverse relationship with poultry and fish

Fiber: Inverse relationship with CRC: ?temporal relationship

Calcium: Can bind intraluminally with bile acids and fatty acids, reducing their mitogenic effect Inverse relationship with calcium intake

Alcohol Ingestion: Increased risk with OR 2.6 reported Most studies related to beer intake and increases in rectal cancer

Smoking: 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


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Irradiation

Sporadic reports of colon and rectalcancers developing after XRT for pelvicmalignancies

Average interval from irradiation todiagnosis is 15.2 years

Different pathology:

Higher incidence of mucin-producing tumors

Adjusted hazard ratio: 1.7 (SEER Data)


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Ureteric Implantation

Development of neoplasia at or near siteof ureterosigmoidostomy

Risk: 8.5-10.5 to 80-550 times increased

Trending away from this operation, butmust be remembered in patients havingundergone it

Treat endoscopically or by resection


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Post-Cholecystectomy

Considerable epidemiologic evidence to suggest that bile acids playan important role in the development of CRC

Precise action remains to be determined

Suggested etiology: Normally bile acid pool circulates 2-3x per meal

Circulates even during fasting after cholecystectomy Enhanced circulation results in increased exposure of bile acids todegrading action of intestinal bacteria

A step in formation of known carcinogens

Schernhamer et al: (85,184:877 pts) RR: 1.21, greatest for right colon and rectum

Lagergren et al: (278,460 pts) Increased risk: right colon Other studies:

RR: 1.59 to 4.5


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Activity and Exercise

Persky et al Study:

Relative increase of 1.3 to 2.0 in those withsedentary jobs

Thune et al Study:

Reduced risk in those engaged in >4hrs /week

Numerous hypotheses presented likelyvery 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.


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Macroscopic Pathology

Ulcerative

Polypoid

Annular

Diffusely Infiltrating


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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


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Polypoid Pathology

aka cauliflower type

Large fungating mass projecting into the bowel lumen

Often a low-grade malignancy

~10% mucin producing: colloid carcinoma


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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


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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 occuranywhere

Similar to linitis plastica of stomach

Only 85 documented cases in literature (1995)


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Pathology

Microscopic Appearance

Considerable variation in histologicappearance

Well-differentiated: 20% Lymph node mets 25%, 5-yr survival 77%

Mod-differentiated: 60%

Lymph node mets 50%, 5-yr survival 61% Poorly-differentiated: 20%

Lymph node mets 80%, 5-yr survival 29%


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Histo-/Pathology

AdenoCA Poorly-diff adenoCA Mod-diff adenoCA

Mucinous adenoCA Mucinous adenoCA


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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 rapidlyproliferating neoplasm may force malignant cells

along tissue planes of least resistance 2) increased cell motility can contribute to malignantinvasion

3) malignant cells may secrete enzymes capable ofdegrading the basement membrane, breaking down

cellular barriers


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Modes of Spread

Transperitoneal Spread Transmural extension, peritoneal penetration Peritoneal implants, omental implants

Lymphatic Spread Stepwise spread: sentinel lymph node mapping

Hematogenous Spread Cascade Hypothesis: liver to lungs to other sites Circulating malignant cells: (no adverse effect)

28% pts during induction; 50% pts during laparotomy

Implantation

Concerning reports of implantation of exfoliated malignant cells On raw surfaces: hemorrhoidectomy, fistula, fissure surfaces;

suture lines; abdominal scars; mucocutaneous junction ofostomies


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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

Organs most frequently involved: Liver: 77%

Lungs: 15% Bones: 5%

Brain: 5%


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T Categories

Tx: no description of the tumor's extent is possible because of incompleteinformation

Tis: involves only the mucosa, it has not grown beyond the muscularismucosa (inner muscle layer) of the colon or rectum

this stage is also known as carcinoma in situ or intramucosal carcinoma

T1: through the muscularis mucosa and extends into the submucosa T2: through the the submucosa, and extends into the muscularis propria T3: completely through the muscularis propria into the subserosa

T4: spread completely through the wall into nearby tissues or organs


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N&M Categories for ColorectalCancer

Nx: no description of lymph node involvementis 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 possiblebecause of incomplete information

M0: no distant spread is seen M1: distant spread is present


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Submucosal InvasionClassification

sm 1 = invasion limited to the upper 1/3 of the mucosa

sm 1 a = horizontal invasion limited to less than of thewidth 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


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Residual Tumor (R)

R0: Complete resection, margins histologically negative

No residual tumor left after resection

R1: Incomplete resection, margins histologically involved Microscopic tumor remains after resection of gross

disease

R2: Incomplete resection, margins involved Gross disease remains after resection


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Colon Cancer Staging

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

T2 N0 M0

Stage II T3 N0 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


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Stage Grouping

Stage 0: Tis, N0, M0: It has not grown beyond the inner layer (mucosa) of the colon or rectum, akacarcinoma in situ or

intramucosal carcinoma

Stage I: T1, N0, M0, or T2, N0, M0: Through the muscularis mucosa into the submucosa or it may also have grown into the muscularis propria

Stage IIA: T3, N0, M0: Through the wall of the colon or rectum into the outermost layers

Stage IIB: T4, N0, M0: Through the wall of the colon or rectum into other nearby tissues or organs

Stage IIIA: T1-2, 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

Stage IIIB: T3-4, N1, M0: 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

Stage IIIC: Any T, N2, M0: Any T but has spread to 4 or more nearby lymph nodes but not distant sites

Stage IV: Any T, Any N, M1: Any T, any N, but has spread to distant sites such as the liver, lung, peritoneum, or ovary


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Colorectal Cancer Staging


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Colon Cancer Staging

T1: submucosa

T2: into muscularis

T3: through muscularis

T4: adjacent invasion

N1: 1-3 nodes

N2: 4+ nodes

N3: nodes along namedvascular trunk

M0: no evidence

M1: metastatic spread

TNM STAGING 5 yr I T1,2 N0 M0 >90%

II T3,4 N0 M0 40-85%

III any T N1 M0 30-65%

IV any T any N M1


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Synchronous Carcinoma

Incidence ranges from 2-8%

Preoperative total colon evaluation

Colonoscopy is optimal method


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Diagnosis

History may not be helpful

Early diagnosis may depend on screening


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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


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Colonoscopy


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Radiology

Barium Enema Ultrasound

Intra-op liver ultrasound, 93.3% sensitivity

CT Scan

Evaluation of primary malignancy and liver Extent of disease, adjacent organ relationships

MRI Generally not as sensitive as CT Increased sensitivity with endoanal coil

PET Scan More accurate than CT in identifying malignancy Especially useful in follow-up, hepatic evaluation


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Air Contrast Barium Enema


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CT Scan Reconstruction


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Virtual Colonoscopy


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Carcinoembryonic Antigen

Field Effect CEA expressed by normal mucosa adjacent to carcinomas Gradient effect, falling off by 5cm

Normal levels depend on specific assay, but in general


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Surgical Principles

Resection based on lymphatic drainage,blood supply

Suture ligate named or large vessels

Go to root of mesentery to get lymphaticdrainage

En bloc resection of involved structures

Remember intra-op US for liver lesions


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Segmental Resection


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Anastomosis or Not?


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Complicated Carcinomas

Obstruction

Stenting

Perforation

Bleeding

Invasion of Adjacent Viscera


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Obstruction

Right-sided lesions: TOC is resection with primary anastomosis Removal of right and proximal transverse colon

Left-sided lesions:

Three-stage procedure Hartmanns procedure Two-stage procedure Subtotal colectomy

On-table lavage Primary resection

Stenting


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Colonic Stenting

Dohmoto, 1991: Used for palliation

Tejero et al, 1994:

Used prior to surgery

Can be used to relieve acute obstruction Permits elective oral preparation, +/- colonoscopy

May allow subsequent resection with primaryanastomosis Multiple randomized, non-randomized, non-

controlled trials show it is safe and allows single stagesurgery


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Colonic Stenting


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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


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Invasion of Adjacent Viscera

Resection en bloc all or part of the attachedviscus

Exceptions: Duodenum or base of bladder

Remove primary lesion and mark structures at riskwith metal clips

M&M related to anterior exenteration or Whippleprobably greater than possible benefit


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Palliative Resection

Resection performed to eliminatesymptoms 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 mayoutweigh any temporary symptomaticrelief

S h M t h


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Synchronous, MetachronousCarcinomas

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%


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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, extrahepaticinvolvement (except lung)

Anatomic, nonanatomic, enucleation resections


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Liver Metastasis


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Pulmonary Metastasis

Resectability:

1) Ideally solitary, possibly solitary in each

lung 2) Primary should be controlled locally

3) No other evidence of metastasis Except concomitant hepatic metastatectomy

4) Medical condition should allow forthoracotomy and pulmonary resection


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Adjuvant Therapy

Five general underlying principles:

1) there may be occult, viable malignant cells in circulation and/orestablished, microscopic foci of malignant cells locally or at distantsites

Intravascular, intralymphatic, or intraperitoneal

2) therapy is most effective when the burden of malignancy isminimal

3) agents with reported effectiveness against the carcinoma areeffective

4) Cytotoxic therapy shows a dose-response relationship andtherefore must be administered in maximally tolerated doses, andthe duration of therapy must be sufficient to eradicate all malignantcells

5) The risk-to-benefit ratio for therapy must be favorable toindividuals who may remain asymptomatic for their natural lifeexpectancy after resection of their malignancy


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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, orpelvic sidewalls

4) transmural penetration to a macroscopic degree

5) extensive microscopic penetration with thepresence of positive lymph nodes

5 Year Relative Survival


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5-Year Relative Survivalfor Colon Cancer by AJCC Stage

Percent alive 5 years or more after being diagnosed with coloncancer

depending on their stage of disease at diagnosis.

Derived from people who have had colorectal cancer in the past 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 yearsafter their cancer is diagnosed

Used to produce a standard way of discussing prognosis

Relative survival rates dont include patients dying of otherdiseases

Five-year relative survival rates are considered to be a moreaccurate way to describe the prognosis for patients with a particulartype and stage of cancer

These 5-year rates are based on patients diagnosed and initiallytreated more than 5 years ago

May no longer be accurate because improvements in treatment may

result in a better outlook for recently diagnosed patients JNCI2004;96:1420

5 Year Relative Survival


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5-Year Relative Survivalfor Colon Cancer by AJCC Stage

Stage I 93%

Stage IIA 85%

Stage IIB 72%Stage IIIA 83%

Stage IIIB 64%

Stage IIIC 44%

Stage IV 8%


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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 isacidic get fewer mets cannot compete with bacteria no perforation has higher chance for carcinomatosis


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colon cancer vail 2008

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