9.29.04 colon ca teaching conference - dartmouth … effective for sporadic colon ca actually can...

Colon CancerColon Cancer

Resident Teaching ConferenceSeptember 29, 2004

Hank Kutz / Dr. Colacchio

Malignant Colonic Malignant Colonic NeoplasmsNeoplasms

• Adenocarcinoma (90-95%)

• Carcinoid

• Lymphoma

• Squamous Cell Carcinoma

• Plasmacytoma

• Melanoma

Colorectal Colorectal AdenocarcinomaAdenocarcinoma

• Incidence: 155,000 cases/year (colorectal)• Deaths per Year: 60,000

2nd most common cause of cancer death in men3rd 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

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

AdenomaAdenoma--Carcinoma SequenceCarcinoma Sequence

• Accumulation of MutationsDCC, MCC, p53, K-ras, APC, MSH2, MLH1, etc.

AdenomaAdenoma--Carcinoma SequenceCarcinoma Sequence

• Incidence of dysplasia or cancer:Increases with polyp sizeIncreases with extent of villous component

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 hereditary non-polyposis colon cancer (HNPCC)?

• What genetic defects are involved in HNPCC?

• Can we chemoprevent colon cancer?

Screening Screening -- RecommendationsRecommendations

Screening Screening –– Risk FactorsRisk Factors

Start screening 5 years before age of youngest 1st degree

relative with colon CA if known

ScreeningScreening

• Fecal Occult Blood Testing

• Barium Enema

• Sigmoidoscopy

• Colonoscopy

• Virtual Colonoscopy

Fecal Occult Blood TestingFecal Occult Blood Testing

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

• ONLY screening test shown by RCT’s to reduce the risk of death from Colon CA

15-33% risk reduction

• 40% sensitivity / 96-98% specificity

• If positive, w/u with colonoscopy17-46% with positive FOBT will have Carcinoma or large adenoma

SigmoidoscopySigmoidoscopy

• Can examine about half of the colon• Less incidence perforations

1-2/1000 Colonoscopy1/10,000 Sigmoidoscopy

• Misses proximal lesions, usually used in conjunction with FOBT or BE

• 90% sensitivity / 99% specificityFor areas examined by scope

ColonoscopyColonoscopy

• Can be used to remove polyps• Negative colonoscopy obviates the need

for screening for 5 years if no other risk factors

• No RCT’s looking at effectiveness of colonscopy to reduce mortality from CA

• > 90% sensitivity / 99% specificity

Other Screening ModalitiesOther Screening Modalities

• Barium EnemaUsed in past for screeningLow sensitivity – 48% for lesions > 1 cm!

• Digital Rectal ExaminationNot shown to be effective in trials, even with FOBT

• Virtual Colonoscopy91% sensitivity for > 1 cm lesions17% False Positives – then requiring colonoscopy

Screening and MortalityScreening and Mortality

• 80-85% of colorectal cancers are sporadiceven 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 lower incidence of colorectal cancer and decreased mortality than a similar unscreened population

Screening PointsScreening Points

• FBOT only method with evidence supporting decreased mortality from CA

• Sigmoidoscopy – controversialCheaper, safer25% will have at least 1 polyp – only 1 in 5 of these will have a high-risk adenoma, can’t biopsyWho of these to send for colonoscopy?

• Patients should be offered a choice based onLevel of risk for colorectal CAWhat they’ll comply with

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

• Accounts for 5-10% of colorectal cancersIncidence 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

HNPCC HNPCC –– Amsterdam CriteriaAmsterdam Criteria

• 3 or more relatives with colorectal cancerOne must be 1st-degree relative to 2 others with colon cancer

• 2 successive generations must be affected

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

HNPCC HNPCC –– Clinical CharacteristicsClinical Characteristics

• Early age of onset of colorectal cancer

• More proximal lesions60-70% proximal to splenic flexure

• Increased % metachronous lesions

• Improved Survival

HNPCC HNPCC –– 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

HNPCC HNPCC –– Genetic CharacteristicsGenetic Characteristics

• Increased frequency of microsatelliteinstability (MSI)

DNA repair mechanism defectGenes: MSH2, MLH1

• MSI > in proximal colon

• Tend to have diploid DNA

• TGF-β and BAX gene mutations common

• More indolent

ChemopreventionChemoprevention

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

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

• Generally performed by RCT’s in patients with prior colorectal CA followed for recurrence of adenomas

• Diet, fiber, and antioxidant vitamins have not been shown by RCT’s to decrease risk of recurrent adenomas

• COX-2i’s and Sulindac have been shown to reduce the number of adenomas found in FAP alone

Not effective for sporadic colon CAActually can cause regression of adenomas

Case #2Case #2

A 63 y.o. man underwent complete resection of T3N0M0, Stage II adenocarcinoma of the ascending colon. No adjuvant therapy is planned. There is no family history of colorectal cancer. How should he be followed?

Screening for RecurrenceScreening for Recurrence

• 70-80% of patients have tumors that can be resected 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

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 scanPET ScanCEARadioimmuno detection (mAb to tumor Ag)


• History / Physical Exam• Labs (CEA, LFT’s, CBC, FOBT’s)• Radiology: CXR, CT Scan, U/S, BE• Colonoscopy, Sigmoidoscopy

What is optimal surveillance to improve outcomes without over-screening?


• Practice patterns vary considerably• Not much evidence for optimal

surveillance strategies in patients without localized symptoms

• Meta-analyses suggest more intensive surveillance carries slight improvement in survival (20% relative risk reduction)

Recurrences typically picked up earlier


• High-yield: Onset of new symptomsAbdominal PainChange in Bowel habitsBlood in stool

• Low Yield:Physical ExaminationRoutine Labs (LFT’s, CBC, FOBT)


• CXR – ControversialSurvival after lung met resection similar to that after liver met resectionRare that CXR is first test detecting recurrence

• CEACommonly first test to identify recurrenceUseful even for those with normal level at first resectionCost-effective, Safe


• CT-Scan, Liver imaging1 out of 6 studies demonstrated survival benefit with routine CT-scans (Q3-12 months)2 out of 6 studies demonstrated survival benefit with liver imaging alone, although detection did not increase number of curative hepatectomiesUnlikely to detect curable local or pelvic recurrence, esp. in setting of prior XRT


• Patients with prior colorectal CA 1.5 - 3 times more likely than general population to develop a second colorectal CA

Should continue serial screening colonscopyevery 3-5 yearsHowever CEA more likely to detect localrecurrence when compared to colonoscopy


• Key is routine follow-up and early detection of new symptoms:

Abdominal Pain, Change in bowel habits, or blood in stoolPatient 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 resection

because doubling time of microadenoma is 1 year and will 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

Case #3Case #3

An 80 y.o. woman had an endoscopicpolypectomy of a mass in her transverse colon. Path demonstrates an invasive cancer extending through the muscularismucosa into the stalk of the polyp. The polyp margin was negative for cancer. Does she need further surgery?

AdenomatousAdenomatous PolypPolyp

• Characterized By:Physical Features

• Pedunculated, sessile, ulcerated…etc.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


• ManagementAdenomas should be completely removed

• Sessile ≥ 2 cm should receive segmental resection

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

Recurrence rate of adenomas estimated as 32-42% by 3 years (National Polyp Study)

Malignant PolypsMalignant Polyps

• ManagementEndoscopic polypectomy is adequate if CA confined to head of polypControversial when invades stalk:

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

• If adequate margin but unfavorable histology, or family history of colon CA, segmental resection would be indicated

Colon Cancer Colon 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 rateAbsence of lymphocyte response to tumor

• ? Blood transfusion• ? Method (Laparoscopic vs. Open)

Staging: Standard Staging: Standard PreopPreop EvaluationEvaluation

• Full colonic evaluation

• CXR

• CT Abd/Pelvis or U/S of Liver

• Routine blood tests:LFT’s, Coags, CBC

• ? CEA – not for diagnosis but surveillance

StagingStaging

• 3 Systems:Dukes Classification

• Depth of invasion for rectal tumors beneath peritoneal 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)

Changes to TNM Staging SystemChanges to TNM Staging System

Case #4Case #4

A 70 y.o. man had guiac positive stools. Colonoscopy showed a 2 cm sessile mass in the cecum, biopsy positive for 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 no imageable disease?

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

Adjuvant TherapyAdjuvant Therapy

Update: Adjuvant TherapyUpdate: Adjuvant Therapy

• 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 features of the tumor or presentation

• Grade 3-4 histology, Mucinous/colloid, Lymph or vascular invasion

• Bowel obstructionWithout these, chemotherapy not indicated

• Minimum of 6 nodes must be examined in order to establish Stage II disease, if less then assume more advanced disease


• Stage III/IVCombinations of irinotecan, oxaliplatin, or capecitabine are NOT recommended for adjuvant chemotherapy at this time, pending results of ongoing trials

• PET scanning is indicated to determine if patients with potentially resectable recurrences are free of disseminated disease

ONLY time PET scanning currently recommended in treatment of colorectal cancer.


• Chemotherapy for Metastatic Disease (Figure 1)

Sentinel Node BiopsySentinel Node Biopsy

• Value of SLN biopsy for CRC is upstaging node-negative patients to node positive

i.e. Detecting more Stage III disease that would otherwise be pathologically staged as Stage I or II

• Helps identify small pericolic nodes that are otherwise overlooked on gross examination


• Need 12 nodes with resection specimen to be considered adequate for staging

• Koren, et al –30 node-negative CRC cases with < 10 nodes from mesentary were reprocessed to identify more lymph nodes8 of 30 (27%) were upstaged to stage III disease


• Typically nodes from CRC specimen thinly sectioned and only 1 or 2 slides examined

• SLN can be serially sectioned and examined or ultrastaging on SLN can be used

RT-PCRIHC

• Remaining nodes can be examined in usual fashion

Sentinel Node Biopsy Sentinel Node Biopsy -- StepsSteps

• Mobilize colon and mesentary

• Inject 1 ml isosulfan blue around region of tumor

• Blue nodes visible

• Proceed with resection as usual, incorporating SLN

• RCT needed to further assess efficacy

Sentinel Node Biopsy Sentinel Node Biopsy -- StepsSteps

• Important because:Chemo in stage 3 disease saves 33% of lives

If can upgrade 18 patients from stage 1-2 to stage 3 then will save 6 lives…because they will then get chemo.

• 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 metastasesIn 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-SLN’s 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?

• How?

Rising CEA after resectionRising CEA after resection

• CEA elevated in > 90% of patients with disseminated colorectal CA and in 20% of patients with localized disease

• Serum levels generally elevated in proportion with tumor burden and often correlate with response to therapy

• 2/3 of patients with recurrence will have elevated CEA level

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

• Covered 2 weeks ago…

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

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

• 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

The COST Trial: Recovery and QOL

Results • For Laparoscopic Colectomy:

– symptom distress, pain, QOL scores generally lower, but not significant statistically

– LOS shorter (5 vs. 6 days, p<.001)– IV narcotic shorter (3 vs. 4 days, p<.001)– Oral analgesic shorter (1.9 vs. 2.2 d, p<.001)

The COST Trial

Criticisms:• QOL scales insensitive (e.g. scores scaled

from 1-3, nearly all results were 1’s)• If pain is similar, why are the lap colectomy

patients taking less narcotic and leaving the hospital sooner?

• Conflict of interest reflected in the “spin” –dampen enthusiasm for lap colectomy prior to trial completion

The COST Trial

How about cancer survival?

May, 2004

COST TrialCOST Trial

• 48 Institutions

• 872 patients with adenocarcinoma of the colon to undergo open or laparoscopicallyassisted colectomy

• Median follow-up 4.4 years


• Rates of intraoperative complications, 30-day postop mortality, complications at discharge and 60 days, hospital readmission, and reoperationwere very similar between the groups

• Lap assisted group hadShorter 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)


• Recurrence rates similar16% Recurrence in Lap assisted18% Open Colectomy

• Wound site recurrence< 1% in both groups

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

What about port site recurrences?

LAPAROSCOPIC COLECTOMY

• 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

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

LAPAROSCOPIC COLECTOMY

LAP COLECTOMY: ARE THERE BENEFITS?

• Anecdotes may affect what you want to do in your practice, but they should not guide policy.

• Published single-surgeon case series aren’t much better

• As usual we must turn for guidance to – Randomized trials– Surgical science

LAP COLECTOMY: TWO QUESTIONS

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

• Should the procedure be used to treat cancer of the colon?– port site recurrence, survival

LAP COLECTOMY: RANDOMIZED TRIALS

• 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

• A lot of early attention spurred by anecdotal reports of port site metastases

• A rush to the bench ensued: some animal models suggested tumor cell proclivity for implantation 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% and 0.7% -- in two case series of >1000 patients

As a result …

• Seeing less research on port site recurrence

• Seeing more research on immuno-oncologic response to surgical trauma

Tumor Implant Study

• 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)

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

Summary: QOL

• Virtually all studies find at least some benefit from laparoscopic colectomy, some more than others

• Debate persists regarding whether this benefit is large or small, and whether this benefit is worth pursuing

• My take: when it’s great, it’s great. When it’s not, it’s like open surgery.

Summary: Cancer

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

• Nature of the dialogue has changed from “is 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: it’s the same operation, so the cancer result is likely similar

“The Barcelona Trial”


• Subject recruitment from 1993 to 1998• 219 patients randomized from 1 hospital

– 111 lap– 108 open

• Post-operative follow-up and adjuvant protocols same in each arm

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

Perioperative Outcomes


Conclusion #1Laparoscopic colectomy is associated with

- quicker recovery- fewer perioperative complications

(they expected that)

What about Cancer Outcomes?

Cancer Outcomes

Most of the difference is in Stage III disease

Stage I

Stage II


Conclusion #1Laparoscopic colectomy is associated with

- quicker recovery- fewer perioperative complications

Conclusion #2Laparoscopic colectomy is more effective

than open surgery in terms of cancer-related survival (largely due to stage III dz)


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

• Barcelona and COST trials suggest modest benefit to laparoscopic colectomy in terms of LOS, analgesic use, and peri-operative morbidity

• Only one RCT (Barcelona) has published survival results, suggests survival benefit associated with lap colectomy

9.29.04 colon ca teaching conference - dartmouth … effective for sporadic colon ca actually can...

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