CES 2016 02 - Colorectal cancer

CES 2016.02: Lower Gastrointestinal Cancers

Mauricio Lema Medina MD

Mauricio Luján Piedrahíta, MD

Acknowledgments

Second cause of cancer death in the USThe incidence has decreased recently (in the US) due to screening

Mortality has decreased by about 25%

POLYPSGrossly visible protrusion fro the mucosal surface

Nonneoplastic hamartomaHyperplastic mucosal proliferation (hyperplastic polyp)

Adenomatous polypsClearly preneoplastic

Only a minority of polyps progress to cancerHigh prevalence: 30% and 50% in middle-aged and elderly adults

Only 1% become malignant

Multistep molecular evolution through cancerColon cancer is thought to arise from sequential DNA derrangements in a polyp

These may include: Point mutations in the K-ras (KRAS) oncogeneHypomethylation of DNA

Allelic loss of a TSG like 5q (APC), 18q (DCC), 17p (p53)

Oncogene activationLoss of tumor suppression activity

Multi-stage carcinogenesis in colon cancer

Inspired on: Vogelstein B, 1990

MAPK pathway (activating) mutations occur in about 60% CRC

KRAS: 40-50%NRAS: 10%

BRAF: 8%

POLYPS

PedunculatedFlat-based: sessileHigher risk of cancer development

TubularVillous

TubulovillousHigher risk of cancer development (3x)

Small (1.5 cm, or less)Intermediate (1.5-2.5 cm)

Substantial (2.5 cm, or more)(2-10% cancer risk)

(10% cancer risk or more)

The entire bowel should be visualized (1-3 risk of synchronous polyps).Follow-up with colonoscopies: 30-50% risk of another adenoma

Adenomas become cancer in about 5 yearsColonoscopy need not be more frequent than every 3 years

Once a poly is found

Risk factors for the development of colorectal cancer

Diet: animal fat Hereditary syndromes

Inflammatory bowel diseaseStreptococcus bovis bacteremia

Upper socioeconomic populations

Correlates with per capita consumption of calories,meat protein, dietary fat and oil, high cholesterol,

high coronary artery disease

Dietary fats change in the microbiome (anaerobes), converting bile-acids into carcinogens

High-calorie intake / inactivity cause obesity: insulin resistance, increase in IGF-1, more

polyps (and cancer)

Fibers and vegetable intake have no been proven to prevent CRC development

Up to 25% have a family historyPolyposis coli

MYH-associated polyposisNonpolyposis syndromes (Lynch)

More with ulcerative colitisRare during first 10 years

Thereafter: 1%/yr incidenceProphylactic colectomy for long active IBD

For unknown reasonConsider upper and lower GI endoscopies

Hereditary syndromesPolyposis coli

Thousands of adenomatous polyps through the large bowelAutosomal dominant

Deletion of 5qLoss of the APC gene (a TSG)

Gardner’s syndromeSoft-tissue and bony tumors

Congenital hypertrophy of the retinal epitheliumMesenteric desmoid tumors

Ampullary carcinomasPolyposis coli

Turcot’s syndromeMalignant tumors of the Central Nervous system

Polyposis coli

Polyps are rare before pubertyBut are detectable in most by age 25

Cancer will develop in (almost) all by 40

Once multiple polyps develop, total colectomy must be performedOffspring of affected patients have 50% risk of disease

Flexible sigmoidoscopy until 35 should be performedGerm-line APC mutation detection should be considered

Hereditary syndromes

Hereditary nonpolyposis colon cancer (HNPCC) - Lynch’s syndrome

Three or more relatives with documented colorectal cancer;one who is a first-degree relative of the other two;

CRC before 50 in at least one;Spanning at least 2 generations.

Autosomal dominantMedian-age at CRC diagnosis: less than 50

Screening colonoscopy starting on age 25 (q1 to 2 years), with pelvic US/endometrial biopsy for women

Poorly-differentiatedMucinous histologies

Right-sided preferenceBETER PROGNOSIS

Association with other malignancies (in the family)Ovarian or endometrial carcinomas in women

Gastric, small-bowel, pancreaticobiliary, genitourinary cancerssebaceus skin tumors

Lynch’s syndrome is associated with mutations of several geneshMSH2 (chromosome 2)

hMLH1 (chromosome 3), and others

Unable to repair DNA mismatches (MMR)High frequency of microsatellite instability

Colorectal cancer: presenting symptoms

Right-sided colon tumors May be very large without symptomsIron-deficiency anemia is characteristic

Left-sided tumorsAbdominal crampingIntestinal obstructionIntestinal perforation

Rectosigmoid tumorsHematochezia

tenesmusnarrowing of the caliber of stool

(similar to hemorrhoids)Anemia is rare

CRC: Staging, prognostic factors, and pattern of spread

Harrison’s, 19th Ed.

Predictors of poor outcome following total surgical resection in CRC

Tumor spread to regional lymph nodes

Number of lymph nodes involved

Tumor penetration to through the bowel wall

Poorly differentiated histology

Perforation

Tumor adherence to adjacent organs

Venous invasion

Preoperative CEA elevation

AneuploidySpecific chromosomal deletion (BRAF mutation, absence of MSI)



Adenocarcinoma

CRC: Staging

AJCC TNM, 7th Ed, 2010

CRC: Staging

AJCC TNM, 7th Ed, 2010



High-risk stage II

T4

Perforation

Obstruction

Lymphovascular invasion

non-R0 resection

Less than 12 lymph nodes evaluated

High-risk recurrence score (in MSS)

CRC: pattern of spread


Most recurrences occur within 4 years of surgery

At least 12 lymph nodes need to be evaluated to establish prognosis

TNM/Stage is prognostic

Regionallymph nodes

Supraclavicular

lymph nodesVia the portal venous

system

Liver metastasesInitial site of spread in 1/3Involved at death in 2/3

Distal rectum:

paravertebral venous

plexus

Median survival of metastatic CRC is improving: about 2-3 years (2016)

CRC: Treatment


Pre-surgical work-up

H&P

Basic labs, including LFTs, CEA

Thorax, abdomen and pelvis contrast-enhanced CT

Full-length colonoscopy

Surgery

Colectomy with regional lymph-node dissectionTotal mesorectal excision for rectal cancer with regional lymph-node

dissectionAt least 12 lymph-nodes need to be assessed

Surgery in symptomatic patients, regardless of metastasesAdequate surgical margins needed to avoid recurrence in the

anastomotic site

CRC: Treatment


Colon cancer (non-rectal)

Surgery

Stage I

Follow-up

Low-Risk Stage II

Follow-up

High-Risk Stage II/Stage III

Stage IVaResectable

Stage IVaConvertible

Stage IVb

Surgery

ChemoT PalliativeCT

Follow-up Follow-up Follow-up

AdjChemoT

Surgery

AdjChemoT

Surgery Surgery

CRC: Treatment


Adjuvant chemotherapy in colon cancer

Ideally, start within 1 month of surgery, for 6 months

Improves survival by 30% in stage III CRC patients

May improve survival in high-risk stage II colon cancer patients

Based on Fluorouracil (5-FU)

Infusional 5-FU both more effective, and less toxic, than bolus

Modulation with Folinate (Leucovorin, LV) improves outcomes

Addition of Oxaliplatin improves DFS and OS in stage III patients (ie, FOLFOX)

Unclear benefit of Oxaliplatin in stage II and older than 70

No benefit of adjuvant 5-FU alone in stage II patients with microsatellite instability

CRC: Treatment


Rectal cancer

Surgery

Stage I

Follow-up

Low-Risk Stage II

Follow-up

High-Risk Stage II/Stage III

Stage IVaResectable

Stage IVaConvertible

Stage IVb

Surgery

ChemoT PalliativeCT

Follow-up Follow-up Follow-up

AdjChemoT

Surgery

AdjChemoT

Surgery Surgery

ChemoRT ChemoRT

ChemoRT

ChemoRT

Pelvic radiation (with radiosensitizing chemotherapy) decreases local-recurrence, but has no impact in overall survival in rectal cancer

AdjChemoT

CRC: Treatment


Adjuvant chemotherapy in rectal cancer

Ideally, start within 1 month of surgery, for 6 months

Improves survival in stage II-III CRC patients

Based on Fluorouracil (5-FU)

Infusional 5-FU both more effective, and less toxic, than bolus

Modulation with Folinate (Leucovorin, LV) improves outcomes

Unclear benefit of Oxaliplatin in stage II and older than 70

Oxaliplatin reasonable in high-risk stage II rectal cancer (ie, FOLFOX)

No benefit of adjuvant 5-FU alone in stage II patients with microsatellite instability

CRC: Treatment


Systemic therapy for metastatic CRC

5-FU-based (or Capecitabine)

Each, oxaliplatin and irinotecan improve overall survival

Bevacizumab increases overall survival in first- and second-line always with CT

Other antiangiogenic agents can be used in second-line (aflibercept, ramicirumab)

Anti-EGFR agents are active as single-agents and combination in unmutated RAS

Left-sided colon cancer appear to derive greater benefit from anti-EGFR therapy

Multikinase inhibitors may afford benefit after all other agents have been used

With current therapies, median overall survival for metastatic CRC is abotu 39 mo

CRC: Clinical pathway - stage III colon cancer

Screening

SymptomsColonoscopy / Biopsy Staging

CT/CEA/labs Surgery 6 months adjuvant CT (ie, FOLFOX)


Screening



CRC: Clinical pathway - Stage II/III rectal cancer

Surgery 4-6 months adjuvant CT (ie, 5-FULV/FOLFOX)

ChemoRT(ie, 5FU/LV)


Screening





ChemoRT(ie, 5FU/LV)

CRC: Clinical pathway - Stage IVb CRC mutated RAS

BevacizumabFOLFIRI

BevacizumabFOLFOX Regorafenib


Screening





ChemoRT(ie, 5FU/LV)


BevacizumabFOLFIRI



CetuximabFOLFIRI


CRC: Follow-up


Post-treatment follow-up

3-5% life-time risk of a second CRC, 15% risk of polyps

5-year follow-up

H&P q12w x2-3 years. Thereafter, semi-annually until year 5

Triennial colonoscopy

CEA q12w x2-3 years. Thereafter, semi-annually until year 5

Contrast-enhanced thorax, abdomen and pelvis CT q1yr until year 3

CRC: Prognosis

Health & Medicine

CES 2016 02 - Colorectal cancer