Case 8: Philippe LaCologne - Colorectal Cancer + Metastasis

Cancer Metastasis

Malignant cells spreading to organs + tissues

Cancer Metastasis: Pathophysiology

2 stages

1. Invasion of extracellular tissue

2. Dissemination + colonization

Cancer Metastasis 1: Invasion of Extracellular Tissue

1. Tumor cells produce proteases = Degrade basement membrane

2. Tumor cells invade past basement membrane → Extracellular tissue

3. Tumor produces cytokines + extracellular growth factors = Stimulate tumor cell tropism/growth towards vasculature + lymphatics

• Tropism

Cancer Metastasis 2: Dissemination + Colonization

1. Tumor cells enter vasculature + lymphatic vessles

• Host defences destroy most circulating cancer cells

2. Tumor cells evade host defenses = Implant in distant tissue

3. Produce angiogenic factors = Promote angiogenesis = Supply O2 + nutrients to neoplastic cells

• Vasculogenesis: New blood vessel formation

• Neoangiogenesis: Form from existing blood vessels + capillaries

Organ Tropism

Preferential metastsis locations

Target Organ = First capillary bed encountered during spread

• Usually regional lymph nodes

Organ Tropism: Liver

2nd most common metastasis site

Primary Cancer:

• Lung

• Breast

• Colorectal

• Cervical

Organ Tropism: Bone

Usually axial skeleton

Lesion Types:

• Lytic: NSCLC, kidney, thyroid, multiple myeloma

• Blastic: Prostate, SCLC

• Mixed: Breast

Primary Cancer:

• Lung

• Breast

• Prostate

• Cervical

• Skin

Organ Tropism: Brain

Primary Cancer:

• Lung

• Breast

• Colorectal

• Skin

Organ Tropism: Lungs

Primary Cancer:

• Breast

• Colorectal

• Prostate

• Cervical

• Skin

Cancer Metastasis: Treatment/Management

Combined

• Local therapy

• Systemic therapy

Cancer Metastasis Management: Local Therapy

Decrease tumor size

• Surgery

• Radiation

Cancer Metastasis Treatment: Systemic Therapy

Treat metastasize tumors + prevent further spread

• Cytotoxic chemotherapy

• Targeted therapy against oncoproteins

• Immunotherapy

Cancer Metastasis: Staging Importance

Treatment selection

• Lower stage = Surgery/radiation alone

• Higher stage = Systemic or combined

Prognosis

Surveillance

Tumor Biomarkers: Use

Screening

Predictive/prognostic

Monitor treatment effectiveness

Detect recurrence

Tumor Biomarkers: Prostate-Specific Antigen

Enzyme produced by prostate

Cancer: Prostate

Uses:

• Screening: Elevated

• Prognostic

• Monitoring

Tumor Biomarkers: Alpha Fetoprotein (AFP)

Produced in fetus

• Transient maternal elevation

Cancers:

• Hepatocellular carcinoma

• Germ cell tumors

Uses:

• Screening: Elevated

• Prognostic

• Monitoring

Tumor Biomarkers: Beta-hCG

Cancers:

• Testicular

• Ovarian

Uses:

• Prognostic

• Monitoring

Tumor Biomarkers: Carcinoembryonic Antigen (CEA)

Cancers: Nonspecific

• Colorectal

• Lung

• Gastric

• Pancreatic

• Breast

• Thyroid

• Ovarian

Uses:

• Prognostic: Elevated = Poor

• Monitoring

Tumor Biomarkers: Thyroglobulin

Cancer: Thyroid

Uses:

• Monitoring

Tumor Biomarkers: Calcitonin

Cancer: Thyroid

Uses:

• Prognostic

• Monitoring

Tumor Biomarkers: Chromogranin A

Protein stored in neural cells

Cancers:

• Neuroendocrine tumors

• Neuroblastoma

• SCLC

Uses:

• Prognostic: Elevated = Poor prognosis

• Monitoring

Tumor Biomarkers: Neuron Specific Enolase (NSE)

Released during brain injury

Cancers:

• Neuroendocrine tumors

• Neuroblastoma

• SCLC

Uses:

• Prognostic: Elevated = Poor prognosis

• Monitoring

Tumor Biomarkers: Beta-2 Microglobulin (B2M)

Part of MHC-1

Cancers:

• Multiple myeloma

• Lymphoma

• CLL

Uses:

• Prognostic

• Monitoring

Tumor Biomarkers: CA 19-9

Cancers:

• Pancreatic

• Biliary tract

• Upper GI

Uses:

• Prognostic

• Monitoring

Tumor Biomarkers: CA 125

Cancer: Ovarian

Uses:

• Prognostic

• Monitoring

Tumor Biomarkers: CA 15-3 + CA 27-29

Cancer: Breast

Uses:

• Prognostic: Elevated = Poor prognosis

• Monitoring

Colorectal Cancer: Description

Malignant neoplasm in colon or rectum

Colorectal Cancer: Epidemiology

Risk factors…

• Male

• Older age

• Genetics

• Sedentary lifestyle

• Smoking

• GI conditions (IBD)

• Colon polyps

Colorectal Cancer: Etiology

Gene mutations

Hereditary syndromes

Colorectal Cancer Etiology: Gene Mutations

Oncogenes (KRAS)

Tumor suppressor genes (APC, TP53)

Mismatch repair genes

• MMR genes: MLH1, MSH2

Colorectal Cancer Etiology: Hereditary Syndromes

Familial Adenomatous Polyposis; APC tumor suppressor mutation

• Autosomal dominant

• Ex:

  • Gardner syndrome

  • Turcot syndrome

  • Peutz-Jeghers syndrome

  • Juvenile polyposis syndrome

Lynch Syndrome: Hereditary Nonpolyposis Colorectal Cancer

• Mismatch repair gene mutation

Colorectal Cancer: Pathophysiology

1. Sporadic: 2-hit hypothesis from epigenetic changes = Gene mutations
   Hereditary: Inherited gene mutations

2. Mutations in oncogenes, tumor suppressor genes, mismatch repair genes = Increased cell proliferation

3. Over time = Adenomas → Carcinomas

Colorectal Cancer: Clinical Presentation

Asymptomatic

• Early

Constitutional symptoms

Abdo discomfort

Right-Sided:

• Melena

• IDA

• Diarrhea

Left-Sided:

• Bowel changes

• Blood-streaked stool

• Colicky abdo pain

Rectal:

• Hematochezia (bright red blood)

• Pencil-shaped stool

• Rectal pain

• Flatulence

• Fecal incontinence

• Tenesmus: Increased urgency

Colorectal Cancer: Investigations

DRE

Blood test

Genetic testing

Imaging

Colorectal Cancer Investigations: DRE

Palpable rectal cancers

Blood

Colorectal Cancer Investigations: Blood Test

CEA

• Baseline

• Follow treatment response

CBC

• Microcytic anemia (IDA)

LFTs

Coagulation panel

Colorectal Cancer Investigations: Genetic Testing

Indications:

• < 50 years

• Family history

Colorectal Cancer Investigations: Imaging

Flexible sigmoidoscopy

Colonoscopy + biopsy

CT

Colorectal Cancer Imaging: Flexible Sigmoidoscopy

Indications:

• < 40 years

• No other red flags + risk factors

Colorectal Cancer Imaging: Colonoscopy + Biopsy

Gold standard

Confirm diagnosis

Finding: Ulceroproliferative friable mass

Colorectal Cancer Imaging: CT

Indications:

• Staging

• Determine metastasis

• Colonoscopy contraindications

Findings:

• Endoluminal filling defect

  • Irregular margins

• Apple core lesion

  • Bowel narrowing from cancer stenosis

Colorectal Cancer: Treatment/Management

Genetic counselling

Surgical

Radiation

Systemic therapy

Multidisciplinary cancer care model

Surveillance

Colorectal Cancer Treatment: Surgical

Tumor resection + regional lymph node dissection

• Colon: Colectomy

• Rectal

Palliative: Intestinal Bypass

• Cancer obstructing bowels

  • Ileocolonic anastomosis

  • Colostomy

Colorectal Cancer Management: Radiation

Rectal

NOT colon unless palliative

• Radiate small intestines → Enteritis + Strictures

Colorectal Cancer Treatment: Systemic Therapy

Chemotherapy

Biologics

Colorectal Cancer Systemic Therapy: Chemotherapy

FOLFOX: Folinic acid (Leucovorin) + 5-fluorouracil (5-FU) + Oxaliplatin

FOLFIRI: Leucovorin + 5-FU + Irinotecan

CAPOX: Capecitabine + Oxaliplatin

Adverse Effects:

• Myelosuppression

• GI

• Fatigue

• FOLFOX: Peripheral neuropathy

• FOLFIRI: Alopecia

• CAPOX: Hand-food syndrome, peripheral neuropathy

Colorectal Cancer Systemic Therapy: Biologics

Anti-VEGF antibodies

• Ex: Bevacizumab

EGFR antibodies

• Ex: Cetuximab

Colorectal Cancer Management: Multidisciplinary Cancer Care Model

Improve quality of life + survival + patient experiences

Include…

• Oncologists

• GI

• Allied health

Colorectal Cancer Management: Surveillance

CEA

CT

Colonoscopy

Colorectal Cancer: Complications

Bowel obstruction

Bowel perforation

Peritoneal carcinomatosis

Peritoneal Carcinomatosis

Description: Tumor metastasis to peritoneum

Clinical Presentation:

• Ascites

• Fistulas

• Fatigue

• Abdo pain

Treatment:

• Surgery

• Chemotherapy