Colon CA Management

8/3/2019 Colon CA Management

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GS II Presentation

A report by Block 6


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General Information This is the case of a 58 year old female, presenting with

a chief complaint of epigastric pain


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History of Present Illness

10 months

PTC

Pt felt epigastric pain, VAS 3/10.Sought consult and was prescribedomeprazole which she took daily.

(+) vomiting, anorexia

5 monthsPTC

Pt felt a hard fixed mass on R flank

with pain upon movement (+) directtenderness


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Targeted Review of Systems (+) increased bowel movements, hematochezia,

mucus mixed with stool, stool more malodorous,watery stools, abdominal pain, anorexia, weight loss

(-) vomiting, fever, chills,


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Past Medical History (-) TB, BA, Hpn, DM, Blood dyscracias

Has had no previous operations


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Family Medical History (+) bukol sa bituka in the mother

(-) TB, BA, Hpn, DM, Blood dyscracias


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Personal/Social History (+) prior OCP use

(+) occasional alcoholic beverage drinker

(-) smoking, illicit drug use


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OB History G4P4 (4004)

All 4 kids born full term, at home via a midwife andencountered no fetomaternal complications


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Targeted Physical ExaminationFindings HEENT: Pink conjunctivae, anicteric sclerae, pink oral

mucosa, thyroid not enlarged, (-) ANM, NVE, CLAD,trachea midline

Chest and lungs: ECE, CBS, (-) crackles, wheezes

Cardiac: AP, DHS, NRRR, (-) murmurs


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Targeted Physical ExaminationFindings Abdomen: Flat, soft, HABS, (+) direct tenderness on R

waist, (+) firm, tender mass on R waist.

GU: IE deferred


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GU: IE deferred


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GU: IE deferred


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GU: IE deferred


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GU: IE deferred


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Differential Diagnoses


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Colorectal Cancer R/I

(+) change in bowel movements, hematochezia, waterystools, abdominal pain, anorexia, weight loss, FMH of

abdominal tumor

R/o

Cannot be ruled out


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Crohns Disease R/I

(+) increased bowel movements, hematochezia,watery stools, abdominal pain, anorexia, weight loss

R/o

Cannot be entirely ruled out

Diarrhea of patient is of acute onset


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Ulcerative Colitis R/I

(+) increased bowel movements, watery stools,abdominal pain, anorexia, weight loss

R/O

Incontinence, urgency

No specific trigger for diarrhea


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Colonic Diverticulitis R/I

(+) increased bowel movements, watery stools,abdominal pain, anorexia, weight loss

R/o

(-) fever, chills, nausea, vomiting,

constipation/diarrhea pattern, urinary symptoms


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Colonic Polyps R/I

(+) increased bowel movements, watery stools,decreased caliber of stools, abdominal pain, >50 yo,

R/o

(-) fever, chills, nausea, vomiting,

constipation/diarrhea pattern, urinary symptoms


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Colon Cancer

Pathophysiology

F d t


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From adenoma tocarcinoma

carcinomas evolve through a progression of benignpolyps to invasive carcinoma

the larger the polyp, the higher the risk for cancer

tubular adenoma 2 cm 35%

villous adenomas carry a higher risk

than tubular adenomas villous adenoma >2 cm 50%


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Hereditary

(+) family history young age at onset presence of other

specific tumors anddefects

genetic mutation/spresent in all cells ofthe affectedindividual.

Sporadic

(-)family history older population (60-

80 y.o.) usually presents as

an isolated colon orrectal lesion

genetic mutation/slimited to the tumoritself.

Familial

Higher risk for familymembers: index case is young

(


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Mutation

Activationof

oncogenes(K-RAS)

Inactivation oftumor-

suppressorgenes (APC,

DCC, p53)


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APCgene tumor suppressor gene

located on chromosome 5q21

regulates the intracytoplasmic pool of -catenin

-catenin is a multifunctional protein which activates

transcription of genes like c-myc and others that regulatecellular growth and proliferation.


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also influences cell cycleproliferation by regulatingWnt expression

As -catenin levels rise,Wnt is activated.

Overexpression of Wntleads to activation of Wnttarget genes such ascyclin D1 and Myc, whichdrive cell proliferationand tumor formation.

APCgene


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K-ras gene proto-oncogene

mutation of only one allele will perturb the cell cycle

The K-ras gene product is a G protein involved inintracellular signal transduction

mutation G protein remains

in active formuncontrolled cell division


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DCC gene tumor suppressor gene

loss of both alleles is required for malignantdegeneration

role is poorly understood

may be involved in differentiationand cellular adhesion incolorectal cancer

more than 70% of colorectal


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p53 gene most frequently mutated tumor suppressor gene

occur rather late in the adenoma-carcinoma sequence

induces apoptosis in response to cellular damage

causes G1

cell-cycle arrest, allowing DNA repairmechanisms to occur

75% of colorectal cancers

prognostic significance


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MYH gene

Recently, a number of families were characterized with aphenotype resembling that of FAP or AFAP, but without adiscoverable APCgene defect.

Autosomal recessive inheritance

mutations in the gene responsible for base excision-repair and used to repair oxidative DNA damage


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Genetic Pathways

Loss of heterozygosity (LOH)pathway

chromosomal deletions andtumor aneuploidy

80% of colon CA

microsatellite stable

tend to occur in the moredistal colon, often have

chromosomal aneuploidy,and are associated with apoorer prognosis

Replication error

(RER) pathway

errors in mismatch repair

during DNA replication 20% of colon CA

associated withmicrosatellite instability(MSI)

tumors with MSI are morelikely to be right sided,possess diploid DNA, andare associated with a betterprognosis


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Mismatch repair genes

hMSH2, hMLH1, hPMS1,hPMS2, and hMSH6/GTBP

caretaker genes

police the integrity of thegenome and correct DNAreplication errors

mutations result in in the

HNPCC syndrome

microsatellite instability


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Incidence & risk factors


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Incidence

Most common malignancy of the GI tract

In 2003, the World Health Organization estimatedthat approximately 940,000 individuals werediagnosed with colorectal cancer worldwide and492,000 died from it that year.

Colorectal cancer is the third leading cause of

cancer deaths in the Philippines. In 2005, there were2,657 deaths due to colorectal cancer.


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Risk Factors

Aging

dominant risk factor for colorectal cancer

>90% of cases diagnosed in people older than 50

years

Hereditary Risk Factors

~ 80% sporadic

~ 20% with (+) family history


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Risk Factors

Environmental and DietaryFactors

Risk

Saturated or polyunsaturated fats Increase

Oleic acid (olive oil, coconut oil, fishoil) No increaseVegetable fiber Appears to be

protective

Alcohol IncreaseCalcium, selenium, vitamins A, C,and E, carotenoids, and plantphenols

May decrease

Obesity and sedentary lifestyle Increase dramatically


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Risk Factors

Inflammatory bowel disease

increased risk for the development of colorectal cancer

Other factors thought to increase risk include the

presence of primary sclerosing cholangitis and familyhistory of colorectal cancer.


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Other Risk Factors

Cigarette smoking

increased risk especially after >35 years of use

Patients with ureterosigmoidostomy

Acromegaly increased human growth hormone and IGF-I

Pelvic irradiation

Obesity

F t With D d Ri k f C l


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Factors With Decreased Risk of ColonCancer

Physical activity

Relative reduction risk of 40-50% for people with highenergy expenditure

NSAIDS

Postmenopausal female supplement

Diet Modification

Dietary fat and meat intake

Dietary fiber, vegetables,fruit

Vitamin E, Calcium

Statins


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Screening


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Screening

Preferred CRC screening recommendations:

Cancer prevention tests should be offered first. The

preferred CRC prevention test is colonoscopy every 10

years, beginning at age 50. Screening should begin at age 45 years in African

American

Cancer detection test. This test should be offered topatients who decline colonoscopy or another cancer

prevention test. The preferred cancer detection test isannual FIT for blood.


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Screening

Alternative CRC prevention tests:

Flexible sigmoidoscopy every 5 10 years

CT colonography every 5 years

Alternative cancer detection tests:

Annual Hemoccult Sensa

Fecal DNA testing every 3 years


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Screening

Recommendations for screening when family history ispositive but evaluation for HNPCC considered not indicated

Single first-degree relative with CRC or advanced

adenoma diagnosed at age 60 years Recommended screening: same as average risk

(colonoscopy every 10 years beginning at age 50 years)

Single first-degree with CRC or advanced adenomadiagnosed at age


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Screening

FAP

Patients with classic FAP (>100 adenomas) shouldbe advised to pursue genetic counseling and genetic

testing, if they have siblings or children who couldpotentially benefit from this testing

Patients with known FAP or who are at risk of FAPbased on family history (and genetic testing has not

been performed)should undergo annual flexiblesigmoidoscopy or colonoscopy, as appropriate, untilsuch time as colectomy is deemed by physician andpatient as the best treatment


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Screening

FAP

Patients with retained rectum after subtotalcolectomy should undergo flexible sigmoidoscopy

every 6 12 months

Patients with classic FAP, in whom genetic testing isnegative, should undergo genetic testing for bi-allelic

MYH mutations. Patients with 10 100 adenomascan be considered for genetic testing for attenuatedFAP and if negative, MYH associated polyposis


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Screening

HNPCC

Patients who meet the Bethesda criteria shouldundergo microsatellite instability testing of their

tumor or a family members tumor and/or tumorimmunohistochemical staining for mismatch repairproteins

Patients with positive tests can be offered genetic

testing. Those with positive genetic testing, or thoseat risk when genetic testing is unsuccessful in anaffected proband, should undergo colonoscopyevery 2 years beginning at age 20 25 years, untilage 40 years, then annually thereafter


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Work-up


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Laboratory Studies

Goal of assessing patients organ function (liver,

kidneys) in anticipation of diagnostic and therapeuticprocedures

Estimate tumor burden (carcinoembryonic antigen[CEA] level)


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Laboratory Studies

Complete blood cell count

Chemistries and liver function tests

Serum CEA


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Imaging Studies

Adequate imaging of the chest and abdomen should

be obtained for the purpose of staging.

Chest radiograph or chest CT scan

Abdominal barium study Abdominal/pelvic computerized tomography (CT

scan)

Contrast ultrasound of the abdomen/liver

Abdominal/pelvic MRI Positron emission tomography (PET) scans


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Procedures

Rectal examination

Colonoscopy

Sigmoidoscopy

Double contrast barium enema


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Histologic Findings

Microscopic appearance of colon adenocarcinomas

well-differentiated or

poorly differentiated glandular structures

Normal topological architecture of colonicepithelium in terms of a crypt-villous axis is lost.

N l Hi l


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Normal Histology

P l Diff i d


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Poorly Differentiated


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Colon cancer staging

TNM S i


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TNM Staging

International standard for staging colorectal cancer

3 descriptors:

T for primary tumor

N for lymph nodal involvement

M for metastasis

P i T (T)


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Primary Tumor (T)

NCCN: Clinical Practice Guidelines in Oncology: Colon Cancer. 2011.

R i l L h N d (N)


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Regional Lymph Nodes (N)


Di t t M t t i (M)


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Distant Metastasis (M)


Anatomic Stage/Prognostic


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Anatomic Stage/PrognosticGroups



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Management of

Colorectal Cancers

A report by Block 6

References:

Sabiston, Textbook of Surgery 18th ed

Schwartz, Principles of Surgery, 9th ed

NCCN Guidelines for Colon Cancer

P i i l f R ti


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Principles of Resection

TumorRemoval

Identify FieldDefects

Lymph NodeResections

Lymphovascular supply

Vessels, omentum,adjacent organs

Strong family history ofcolonic neoplasms

Subtotal versusComplete colectomies

Oncologic adequacy ofresection

12-node minimum

St S ifi Th


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Stage Specific Therapy

No risk of lymph node metastasis

Excision with assuranceStage 0

Based upon the risk of local recurrence andthe risk of lymph node metastasis.

Depends primarily on depth of invasion

Stage 1Malignant

Polyp

Cured with surgical resection Up to 46% of patients cured, die of colon

cancer, hence neoadjuvant therapy is advised.

Stage 1Localized

Carcinoma

St S ifi Th


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Stage Specific Therapy

Neoadjuvant therapy based on 5-FU reducesrecurrence.

New chemotherapeutic agents, capecitabine,irinotecan, oxaliplatin, angiogenesis inhibitors, andimmunotherapy are promising

Stage III

Tany, N1,M0

All patients require neoadjuvant chemotherapy

Survival is extremely limited, but highly selectedpatients with isolated, resectable metastases (usuallyin the liver or lungs) may benefit from metastectomy.

In those who cannot be cured surgically, palliation isthe focus of therapy.

Stage IVTany, N1, M1

M li t P l


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Malignant Polyp

A malignant polyp is defined as one with cancerinvading the submucosa

Classified as carcinoma in-situ, and therefore they

have not penetrated the submucosa and do notmetastasize.

In patients with invasive cancer or adenoma(tubular, tubulovillous, or villous), no additionalsurgery is required if the polyp has been completelyresected and has favorable histological features.

Favorable features: grade 1 or 2 lesion, nolymphovascular space invasion, negative resection

margins


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Malignant Polyp

Colectomy with en bloc removal of lymph nodes is recommended if: The polyp is fragmented

The margins cannot be assessed

There is unfavorable histology

All patients who have resected polyps should undergo total colonoscopyto rule out other synchronous polyps, as well as appropriate follow-up

surveillance endoscopy.

Non-metastatic Invasive


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o etastat c as eCarcinoma

A complete staging workup is mandatory, including:

Pathologic tissue review

Total colonoscopy

CBC

Blood chemistry profile

Carcinoembryonic antigen (CEA) determination

Baseline computed tomographic (CT) scans of the

chest, abdomen, and pelvis.



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Carcinoma

Surgical procedure of choice (if resectable):

Colectomy with en bloc removal of the regional lymphnodes.

Extent should be based on the tumor location,resecting the portion of the bowel and arterial arcadecontaining the regional lymph nodes.

Other nodes, such as those at the origin of the vesselfeeding the tumor, as well as suspicious lymph nodesoutside the field of resection, should also be biopsiedor removed if possible.



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Carcinoma

For resectable colon cancer that is causing overtobstruction, resection with diversion, stent insertionfollowed by colectomy, or diversion followed bycolectomy are options.

If the cancer is locally unresectable or medicallyinoperable, chemotherapy is recommended with thegoal of converting the lesion to a resectable state.

Chemotherapy in Colon


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pyCancer

Choices for adjuvant therapy for patients with resectednonmetastatic colon cancer are dependent on the stage ofdisease:

Stage 2 (high risk) & Stage 3

6 mos. 5-FU/LV/oxaliplatin capecitabine

Stage 2 (low risk)

5-FU capecitabine

Stage 1

No need for adjuvant therapy



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Cancer Relapses occur within 2 years following surgery Relapse rates (


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Types of Chemotherapy

FOLFOX (infusional 5-fluorouracil (5-FU), leucovorin(LV), oxaliplatin)

Regimen of choice in both adjuvant and metastaticchemotherapy.

Complication: grade 3 peripheral sensory neuropathy

FLOX (bolus 5-FU/LV/oxaliplatin)

No statistically significant difference in over survival.

Grade 3 neurotoxicity, diarrhea, and dehydration were higherin FLOX than FOLFOX.

Capecitabine

Single agent, at least equivalent to bolus 5- FU/LV

Adjuvant Chemoradiation


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Adjuvant Chemoradiation

Radiation therapy delivered concurrently with 5-FU-based chemotherapy may be considered for veryselect patients with disease characterized as T4tumors penetrating to a fixed structure or for patientswith recurrent disease.

Radiation therapy fields should include the tumorbed as defined by preoperative radiological imaging

and/or surgical clips. Intraoperative radiotherapy(IORT), if available, should be considered for thesepatients as an additional boost.1

Invasive Metastatic Colon


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Cancer 50%-60% of patients diagnosed with colorectal cancer

will develop colorectal metastases

80%-90% of these have unresectable metastatic liverdisease

over one-half of patients who die of colorectal cancer have

liver metastases at autopsy and that metastatic liver diseaseis the cause of death in the majority of these patients.

The criteria for determining patient suitability for resectionof metastatic disease are

the likelihood of achieving complete resection of all evidentdisease with negative surgical margins

maintaining adequate liver reserve

Incomplete resection or debulking has not been shown tobe beneficial.



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Invasive Metastatic ColonCancer

Chemotherapy is recommended in conjunction withliver resection in those patients who arechemotherapy nave.

Potential advantages of preoperative chemotherapyinclude:

earlier treatment of micrometastatic disease

determination of responsiveness to chemotherapy(which can be prognostic and help in the planning of

postoperative therapy)

avoidance of local therapy for those patients with earlydisease progression.



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Invasive Metastatic ColonCancer

Potential disadvantages include: chemotherapy-induced liver injury

missing the window of opportunity for resection making itdifficult to identify areas for resection.

potential for development of liver steatohepatitis and sinusoidalliver injury when irinotecan- and oxaliplatin-basedchemotherapeutic regimens are administered.

The current management of disseminated metastatic colon

cancer uses various active drugs, either in combination oras single agents: 5-FU/ LV, capecitabine; irinotecan,oxaliplatin, bevacizumab, cetuximab, and panitumumab.

Nonresectable Invasive


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Metastatic Colon Cancer

Primary treatment of unresectable synchronous liveror lung metastases by palliative colon resectionshould be considered only if the patient has anunequivocal imminent risk of obstruction or acutesignificant bleeding.

Symptomatic improvement in the primary is oftenseen with systemic chemotherapy even within the

first 1 to 2 weeks, and routine palliative resection ofa synchronous primary lesion should not beroutinely done in the absence of overt obstruction.

Post-treatment


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Surveillance

Evaluate:

possible therapeutic complications

discover a recurrence that is potentially resectable for

cure to identify new metachronous neoplasms at a

preinvasive stage

Increased rates of resectability and survival in

patients treated for local recurrence and distantmetastases of colorectal cancer in more recentyears, thereby providing support for more intensivepost-treatment follow-up in these patients.

Post-treatment


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Surveillance

Colonoscopy is recommended at approximately 1 yearfollowing resection (or at approximately 3 to 6 monthspost resection if not performed preoperatively due to anobstructing lesion).

Repeat colonoscopy is typically recommended at 3years, and then every 5 years thereafter, unless follow-upcolonoscopy indicates advanced adenoma.

CT scan is recommended to monitor for the presence ofpotentially resectable metastatic lesions, primarily in the

lung and the liver. CT Scan and CEA monitoring should be done from the

1st to 5th years but are not recommended after 5 years.

Post-treatment


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Surveillance

Initial follow-up office visits at 3 month intervals forhistory and physical examination may be moreuseful for patients diagnosed with stage III disease,whereas patients with a diagnosis of stage I diseasemay not need to be seen as frequently.

Recommendation First 3 years Years 4 and 5


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RECOMMENDATIONS

Patients should undergo regular surveillance for at

least 5 years following resection.

PhysicalExamination

q 3-6 months q 6 months

Serum CEA q 3 months q 6 months

Chest andAbdominal CT Scan

Annually

Follow-up

Colonoscopy

3rd Year q 5 years

Documents

Colon CA Management