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Co lo n Ca n cer Co lo n Ca n cer

Resident Teaching Conference

September 29, 2004

Hank Kutz / Dr. Colacchio

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Malignant ColonicMalignant Colonic NeoplasmsNeoplasms

Adenocarcinoma (90-95%)

Carcinoid

Lymphoma

Squamous Cell Carcinoma

Plasmacytoma

Melanoma

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ColorectalColorectalAdenocarcinomaAdenocarcinoma

Incidence: 155,000 cases/year (colorectal)

Deaths per Year: 60,000 2nd most common cause of cancer death in

men

3rd most common cause of death in women

Overall 5 year survival: about 50%

Male:Female ratio 1:1

7-8% of cases in those < 50 years of age

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Colorectal Cancer DistributionColorectal Cancer Distribution

Ascending Colon: 18%

Transverse Colon: 9% Descending Colon: 5%

Sigmoid Colon: 25%

Rectum: 43%

Now higher incidence of right-sided cancers: Rule of thumb: 50% proximal to splenic flexure, 50%

distal to splenic flexure

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AdenomaAdenoma--Carcinoma SequenceCarcinoma Sequence

Accumulation of Mutations

DCC, MCC, p53, K-ras, APC, MSH2, MLH1, etc.

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AdenomaAdenoma--Carcinoma SequenceCarcinoma Sequence

Incidence of dysplasia or cancer:

Increases with polyp size Increases with extent of villous component

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Case #1Case #1

What are the recommendations for colorectal

cancer screening? Have screening tests been shown to reduce the

mortality from colon cancer?

What are the Amsterdam criteria for hereditarynon-polyposis colon cancer (HNPCC)?

What genetic defects are involved in HNPCC?

Can we chemoprevent colon cancer?

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ScreeningScreening -- RecommendationsRecommendations

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ScreeningScreening Risk FactorsRisk Factors

Start screening 5 years beforeage of youngest 1st degree

relative with colon CA if known

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ScreeningScreening

Fecal Occult Blood Testing

Barium Enema

Sigmoidoscopy

Colonoscopy Virtual Colonoscopy

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Fecal Occult Blood TestingFecal Occult Blood Testing

Most common screening test in U.S. 3 serially obtained samples

ONLY screening test shown by RCTs to reducethe risk of death from Colon CA

15-33% risk reduction

40% sensitivity / 96-98% specificity

If positive, w/u with colonoscopy 17-46% with positive FOBT will have

Carcinoma or large adenoma

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SigmoidoscopySigmoidoscopy

Can examine about half of the colon

Less incidence perforations 1-2/1000 Colonoscopy

1/10,000 Sigmoidoscopy Misses proximal lesions, usually used in

conjunction with FOBT or BE

90% sensitivity / 99% specificity

For areas examined by scope

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ColonoscopyColonoscopy

Can be used to remove polyps

Negative colonoscopy obviates the needfor screening for 5 years if no other riskfactors

No RCTs looking at effectiveness ofcolonscopy to reduce mortality from CA

> 90% sensitivity / 99% specificity

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Other Screening ModalitiesOther Screening Modalities

Barium Enema Used in past for screening

Low sensitivity 48% for lesions > 1 cm!

Digital Rectal Examination Not shown to be effective in trials, even with FOBT

Virtual Colonoscopy 91% sensitivity for > 1 cm lesions 17% False Positives then requiring colonoscopy

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Screening and MortalityScreening and Mortality

80-85% of colorectal cancers are sporadic

even in those younger than 50 years of age

Removal of adenomas lowers the incidence of

cancer

Population that undergoes regular colonic

surveillance and polypectomy has a lowerincidence of colorectal cancer and decreasedmortality than a similar unscreened population

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Screening PointsScreening Points

FBOT only method with evidence supportingdecreased mortality from CA

Sigmoidoscopy controversial Cheaper, safer

25% will have at least 1 polyp only 1 in 5 of thesewill have a high-risk adenoma, cant biopsy

Who of these to send for colonoscopy?

Patients should be offered a choice based on Level of risk for colorectal CA

What theyll comply with

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Hereditary NonHereditary Non--polyposispolyposis Colorectal Cancer (HNPCC)Colorectal Cancer (HNPCC)

Accounts for 5-10% of colorectal cancers

Incidence 1/200 1/1000 Autosomal Dominant (80-95% gene penetrance)

Combination of: Cancer Family Syndrome (Lynch Syndrome II)

Hereditary Site-specific Colon Cancer Syndrome

(Lynch Syndrome I)

Incidence of adenomas same as general

population, just occur earlier in life

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HNPCCHNPCC Amsterdam CriteriaAmsterdam Criteria

3 or more relatives with colorectal cancer

One must be 1st-degree relative to 2 otherswith colon cancer

2 successive generations must be affected

At least 1 patient must be less than 50 y.o.

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HNPCCHNPCC Clinical CharacteristicsClinical Characteristics

Early age of onset of colorectal cancer

More proximal lesions

60-70% proximal to splenic flexure

Increased % metachronous lesions

Improved Survival

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HNPCCHNPCC Colonic AdenomasColonic Adenomas

Develop sooner and are larger

Have more villous features

Greater % have high grade dysplasia

Colonoscopy Q1-2 years starting at age 25

Associated Extracolonic Tumors (Lynch II)- Ovarian - Uterine

- Breast - Stomach

- Pancreas - Small Bowel

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HNPCCHNPCC Genetic CharacteristicsGenetic Characteristics

Increased frequency of microsatellite

instability (MSI) DNA repair mechanism defect

Genes:MSH2, MLH1

MSI > in proximal colon

Tend to have diploid DNA

TGF- and BAX gene mutations common

More indolent

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ChemopreventionChemoprevention

Evidence that ASA, NSAIDs, Calcium, and COX-2inhibitors may reduce incidence of CA by reducing # of

adenomas 40-50% risk reduction for developing colorectal CA regardless oflocation in colon, age, gender, and race

Generally performed by RCTs in patients with prior

colorectal CA followed for recurrence of adenomas Diet, fiber, and antioxidant vitamins have not been

shown by RCTs to decrease risk of recurrent adenomas

COX-2is and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone Not effective for sporadic colon CA

Actually can cause regression of adenomas

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Case #2Case #2

A 63 y.o. man underwent completeresection of T3N0M0, Stage IIadenocarcinoma of the ascending colon.

No adjuvant therapy is planned. There isno family history of colorectal cancer.

How should he be followed?

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Screening for RecurrenceScreening for Recurrence

70-80% of patients have tumors that can beresected with curative intent

5-yr survival for localized Dz = 90%

5-yr survival with regional nodes = 65%

More than 90% of relapses occur by 5 yrs

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Recurrent Colorectal CA: Role of Radical SurgeryRecurrent Colorectal CA: Role of Radical Surgery

Will only save patient if obtain negative

microscopic margins Only small proportion are candidates

Thorough search for other mets: Chest and abdominal CT scan

PET Scan

CEA

Radioimmuno detection (mAb to tumor Ag)

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History / Physical Exam

Labs (CEA, LFTs, CBC, FOBTs) Radiology: CXR, CT Scan, U/S, BE

Colonoscopy, Sigmoidoscopy

What is optimal surveillance to improveoutcomes without over-screening?

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Practice patterns vary considerably

Not much evidence for optimalsurveillance strategies in patients withoutlocalized symptoms

Meta-analyses suggest more intensivesurveillance carries slight improvement in

survival (20% relative risk reduction) Recurrences typically picked up earlier

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High-yield: Onset of new symptoms

Abdominal Pain Change in Bowel habits

Blood in stool

Low Yield:

Physical Examination Routine Labs (LFTs, CBC, FOBT)

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CXR Controversial

Survival after lung met resection similar to that afterliver met resection

Rare that CXR is first test detecting recurrence

CEA

Commonly first test to identify recurrence

Useful even for those with normal level at firstresection

Cost-effective, Safe

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CT-Scan, Liver imaging

1 out of 6 studies demonstrated survivalbenefit with routine CT-scans (Q3-12 months)

2 out of 6 studies demonstrated survival

benefit with liver imaging alone, althoughdetection did not increase number of curativehepatectomies

Unlikely to detect curable local or pelvicrecurrence, esp. in setting of prior XRT

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Patients with prior colorectal CA 1.5 - 3

times more likely than general populationto develop a second colorectal CA

Should continue serial screening colonscopy

every 3-5 years However CEA more likely to detect local

recurrence when compared to colonoscopy

f

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Key is routine follow-up and early detection of newsymptoms:

Abdominal Pain, Change in bowel habits, or blood in stool Patient should know to call for any of these

Routine CEA levels Q3-6 months x 5 years CXR Q 1 year x 5 years

Colonoscopy routinely 1 year after initial resectionbecause doubling time of microadenoma is 1 year andwill then be visible on colonoscopy

Routine screening colonoscopy Q3-5 years after initial 5

year close followup PET scanning, EUS not recommended for screening at

present

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Case #3Case #3

An 80 y.o. woman had an endoscopicpolypectomy of a mass in her transversecolon. Path demonstrates an invasivecancer extending through the muscularismucosa into the stalk of the polyp. The

polyp margin was negative for cancer.Does she need further surgery?

dAd lP l

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AdenomatousAdenomatous PolypPolyp

Characterized By:

Physical Features Pedunculated, sessile, ulceratedetc.

Size (2 cm = 40% risk for dysplasia)

Glandular Structure Tubular, Villous, Tubulovillous

Mucinous or Colloid

Degree of dysplasia high grade = carcinoma in situ not through Basement

membrane

Invasive carcinoma = into muscularis mucosae

AdAd lP l

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AdAd t P lP l

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Management

Adenomas should be completely removed Sessile 2 cm should receive segmental resection

30-50% of pts. with 1 adenoma will have asynchronous adenoma

Recurrence rate of adenomas estimated as32-42% by 3 years (National Polyp Study)

M li P lM li t P l

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Malignant PolypsMalignant Polyps

Management

Endoscopic polypectomy is adequate if CAconfined to head of polyp

Controversial when invades stalk:

Polypectomy probably adequate if 2 mm margin,cancer not poorly differentiated, and no vascularor lymphatic invasion seen

If adequate margin but unfavorable histology, orfamily history of colon CA, segmental resectionwould be indicated

C l CC l C P ti I di tP ti I di t

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Colon CancerColon Cancer Prognostic IndicatorsPrognostic Indicators

Lymph node status # of positive nodes (> 3 = worse prognosis)

Presence of obstruction

Depth of invasion

Invasion: microvascular, lymphatic, serosa Histology: Mucinous/Colloid Carcinomas with poorer 5 year

survival rate Absence of lymphocyte response to tumor

? Blood transfusion

? Method (Laparoscopic vs. Open)

St i St d dSt i St d d PP E l tiE l ti

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Staging: StandardStaging: Standard PreopPreop EvaluationEvaluation

Full colonic evaluation

CXR

CT Abd/Pelvis or U/S of Liver

Routine blood tests:

LFTs, Coags, CBC

? CEA not for diagnosis but surveillance

St iSt i

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StagingStaging

3 Systems: Dukes Classification

Depth of invasion for rectal tumors beneathperitoneal reflection, hence modified

Classified A through C (D with Mets)

Modified Astler-Coller Staging System Depth of Invasion

Subdivisions for Dukes B and C tumors

TNM Classification System (AJCC/UICC)

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Changes to TNM Staging SystemChanges to TNM Staging System

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Changes to TNM Staging SystemChanges to TNM Staging System

Case #4Case #4

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Case #4Case #4

A 70 y.o. man had guiac positive stools. Colonoscopyshowed a 2 cm sessile mass in the cecum, biopsy positivefor colon cancer.

1. Should he have Lap or Open Surgery?2. Should you identify Sentinel Nodes?

3. Is there effective adjuvant therapy for Colon CA,and who should be treated?

4. Should you follow the pt. for recurrence? how?5. The CEA is rising. What studies would you get?

What would you do with a patient with noimageable disease?

6. A patient with a hepatic met? Pulmonary met?Local recurrence?

Adjuvant TherapyAdjuvant Therapy

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Update: Adjuvant TherapyUpdate: Adjuvant Therapy

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Stage II: To treat or not to treat? (T3/4 N0 M0) Consider adjuvant therapy for patients with high risk

for systemic recurrence based on histologic featuresof the tumor or presentation

Grade 3-4 histology, Mucinous/colloid, Lymph or vascularinvasion

Bowel obstruction

Without these, chemotherapy not indicated

Minimum of 6 nodes must be examined in orderto establish Stage II disease, if less then assumemore advanced disease


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Stage III/IV Combinations of irinotecan, oxaliplatin, or

capecitabine are NOT recommended for adjuvantchemotherapy at this time, pending results ofongoing trials

PET scanning is indicated to determine ifpatients with potentially resectable recurrencesare free of disseminated disease

ONLY time PET scanning currently recommended intreatment of colorectal cancer.


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Chemotherapy for Metastatic Disease (Figure 1)

Sentinel Node BiopsySentinel Node Biopsy

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Value of SLN biopsy forCRC is upstaging node-

negative patients to nodepositive i.e. Detecting more Stage III

disease that wouldotherwise be pathologicallystaged as Stage I or II

Helps identify smallpericolic nodes that areotherwise overlooked on

gross examination


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Need 12 nodes withresection specimen to be

considered adequate forstaging

Koren, et al 30 node-negative CRC cases

with < 10 nodes frommesentary were

reprocessed to identifymore lymph nodes

8 of 30 (27%) were upstagedto stage III disease


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Typically nodes fromCRC specimen thinly

sectioned and only 1 or 2slides examined

SLN can be seriallysectioned and examinedor ultrastaging on SLNcan be used

RT-PCR IHC

Remaining nodes can be

examined in usual fashion

Sentinel Node BiopsySentinel Node Biopsy -- StepsSteps

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Sentinel Node BiopsySentinel Node Biopsy StepsSteps

Mobilize colon andmesentary

Inject 1 ml isosulfan bluearound region of tumor

Blue nodes visible

Proceed with resection asusual, incorporating SLN

RCT needed to further

assess efficacy

Sentinel Node BiopsySentinel Node Biopsy -- StepsSteps

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Sentinel Node BiopsySentinel Node Biopsy StepsSteps

Important because: Chemo in stage 3

disease saves 33%of lives

If can upgrade 18patients from stage1-2 to stage 3 thenwill save 6livesbecause theywill then get chemo.

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SLN successfully identified in 85 of 86 pts (98.8%) 1.6 sentinel nodes per patient were identified

53 of 56 (95%) with negative SLN had no other

disease in other resected nodes 3 of 56 (5%) had disease in nodes other than the SLN

29 patients had SLN + for metastases

In 14 of 29, other non-SLN nodes were also + In 15 of 29 (18% of 85 pts) SLN was the only site of identified

metastasis and all other non-SLNs were negative In 7 of these micrometastases were identified on

only 1 or 2 of the 10 sections of a single SLN

Should you follow for recurrence?Should you follow for recurrence?

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Should you follow for recurrence?Should you follow for recurrence?

How?

Rising CEA after resectionRising CEA after resection

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Rising CEA after resectiong C

CEA elevated in > 90% of patients with

disseminated colorectal CA and in 20% ofpatients with localized disease

Serum levels generally elevated inproportion with tumor burden and oftencorrelate with response to therapy

2/3 of patients with recurrence will haveelevated CEA level

Hepatic, Pulmonary, and Local RecurrenceHepatic, Pulmonary, and Local Recurrence

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p , y,p y

Covered 2 weeks ago

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The COST Trial(a.k.a. NIH trial or US trial)

The COST Trial

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The COST Trial

Subject recruitment Aug 1994 Aug 2001

Funded by National Cancer Institute 48 participating centers

Endpoints: morbidity, QOL, survival Analysis based on intention-to-treat

Reported QOL recently More results anticipated in early 2004

The COST Trial: Recovery and QOL

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449 patients in COST trial

At 2 days, 2 weeks, 2 months Symptom Distress Scale

Quality of Life Index

Single Item Global Rating Scale

In-hospital analgesic use

Hospital length of stay


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Results

For Laparoscopic Colectomy: symptom distress, pain, QOL scores

generally lower, but not significant

statistically

LOS shorter (5 vs. 6 days, p

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The COST Trial

Criticisms:

QOL scales insensitive (e.g. scores scaledfrom 1-3, nearly all results were 1s)

If pain is similar, why are the lap colectomy

patients taking less narcotic and leavingthe hospital sooner?

Conflict of interest reflected in the spin dampen enthusiasm for lap colectomy priorto trial completion

The COST Trial

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The COST Trial

How about cancer survival?

May, 2004

COST TrialCOST Trial

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48 Institutions

872 patients with adenocarcinoma of thecolon to undergo open or laparoscopicallyassisted colectomy

Median follow-up 4.4 years


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Rates of intraoperative complications, 30-daypostop mortality, complications at discharge and

60 days, hospital readmission, and reoperationwere very similar between the groups

Lap assisted group had Shorter median hospital stay (5 vs 6 days p < 0.001)

Briefer use of IV narcotics (3 vs 4 days p < 0.001)

Shorter use of PO narcotics (1 vs 2 days p = 0.02)


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Recurrence rates similar

16% Recurrence in Lap assisted

18% Open Colectomy

Wound site recurrence

< 1% in both groups

Operative Factors: No difference in # of nodessampled, length of bowel and mesentaryresected, or margins between groups

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What about port siterecurrences?

LAPAROSCOPIC COLECTOMY

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Reported as early as 1991

Recent growth in interest and experience Feasibility (instruments, hand-assist)

Consumer demand

Surgeons interest

Alluring technical challenge

Market forces (remember cholecystectomy) Diminishing fears regarding safety in cancer

LAPAROSCOPIC COLECTOMY

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1. Are there benefits for the patient?

pain quality of life

2. Should we be doing this for cancer?

port-site recurrence

cancer-related survival

LAP COLECTOMY: ARE THERE BENEFITS?

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Anecdotesmay affect what you want to do

in your practice, but they should not guidepolicy.

Published single-surgeon case series

arent much better

As usual we must turn for guidance to

Randomized trials Surgical science

LAP COLECTOMY: TWO QUESTIONS

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Is the procedure any easier on patients? pain, periop morbidity, quality of life

Should the procedure be used to treatcancer of the colon?

port site recurrence, survival

LAP COLECTOMY: RANDOMIZED TRIALS

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Barcelona (PI:Lacy, 219 patients)

US (the COST Trial, ~1200 patients)

Australian (PI:Hewitt, 1200 patients)

European (the COLOR Trial, 1200 patients)

German (LAPCON Trial, 1200 patients)

Great Britain (CLASSIC Trial, 1000 patients)

PORT-SITE RECURRENCE

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A lot of early attention spurred by anecdotalreports of port site metastases

A rush to the bench ensued: some animalmodels suggested tumor cell proclivity forimplantation at port sites during

pneumoperitoneum However, in more recent large lap colectomy

series, rates are in the 0-1.3% range

Similar to open incision implant rates -- 0.6% and0.7% -- in two case series of >1000 patients

As a result

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Seeing less research on port site

recurrence Seeing more research on immuno-

oncologic response to surgical trauma

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Tumor Implant Study

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60 mice treated with

Anesthesia only (AC) Laparoscopic cecectomy (LC)

Open cecectomy (OC)

Injected tails with tumor cells

Counted lung and trachea metastases 14

days later (blind observer)

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Surgical trauma appears to promote implantation of tumor cells,More surgical trauma appears to promote more implantation.

Summary: QOL

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Virtually all studies find at least some

benefit from laparoscopic colectomy, somemore than others

Debate persists regarding whether this

benefit is large or small, and whether thisbenefit is worth pursuing

My take: when its great, its great. Whenits not, its like open surgery.

Summary: Cancer

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Fear of port site recurrence is going, going,almost gone

Nature of the dialogue has changed fromis it safe to is it a better treatment for

cancer? Are you doing it for cancer yet? The

Huns are at the gate ...

My take: its the same operation, so thecancer result is likely similar

The Barcelona Trial

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The Barcelona Trial

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Subject recruitment from 1993 to 1998

219 patients randomized from 1 hospital 111 lap

108 open

Post-operative follow-up and adjuvantprotocols same in each arm

Endpoints: morbidity, cancer survival Analysis based on intention-to-treat

Perioperative Outcomes

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The Barcelona Trial

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Conclusion #1

Laparoscopic colectomy is associated with- quicker recovery

- fewer perioperative complications

(they expected that)

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What about CancerOutcomes?

Cancer Outcomes

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Stage I

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Most of the difference is in Stage III disease

Stage IStage II

The Barcelona Trial

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Conclusion #1

Laparoscopic colectomy is associated with- quicker recovery

- fewer perioperative complications

Conclusion #2

Laparoscopic colectomy is more effectivethan open surgery in terms of cancer-related survival (largely due to stage III dz)

The Barcelona Trial

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Criticisms:

Small numbers of patients 36 open, 37 lap stage III cancers

Statistical analysis designed to test

equivalence, not superiority

Differences in proportions not receiving

chemotherapy

Summary of RCTs

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Barcelona and COST trials suggest modestbenefit to laparoscopic colectomy in termsof LOS, analgesic use, and peri-operativemorbidity

Only one RCT (Barcelona) has publishedsurvival results, suggests survival benefitassociated with lap colectomy

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