Case 9: Albert Johnson - Prostate Cancer

Hormone-Sensitive Cancer: Types

Estrogen-sensitive

• Breast

• Endometrial/uterine

• Ovarian

Androgen-sensitive

• Prostate

• Testicular

Thyroid

Hormone-Sensitive Cancer Therapies

Endocrine

Chemotherapy

Immunotherapy

Hormone-Sensitive Cancer: Endocrine Therapy

Determined by hormone-receptor status (immunohistochemistry)

MOA: Block hormone binding receptors = Decrease stimulus for cancer cell growth + proliferation

Endocrine Therapy: Estrogen-Sensitive Cancer

Increased…

• Estrogen receptors = Primary predictive marker

• Progesterone receptors = Supportive

Anti-estrogen therapy

Endocrine Therapy: Androgen-Sensitive Cancer

Increased androgen receptors

Androgen deprivation therapy

Hormone-Sensitive Cancer: Chemotherapy

Determined by stage + nodes affected

Hormone-Sensitive Cancer: Immunotherapy

Dtermined by molecular changes in cancer cells

Incurable Cancer: Description

Advanced late stage cancer + distant metastasis + life-limiting (6-24 months remaining)

Incurable Cancer: Treatments

Cancer-directed

• Systemic

• Locoregional

Non-cancer-directed

• Symptom management

• Psychosocial support

• Urgent treatment

Incurable Cancer: Cancer-Directed Treatments

Systemic: First-line

• Chemotherapy

• Targeted therapy

• Anti-angiogenic therapy (VEGF inhibitors)

• Immunotherapy

• Endocrine therapy

Locoregional: Palliative

• Radiation

• Surgery

• Ablation

Incurable Cancer: Non-Cancer-Directed Symptom Management

Continuous screening + reassessment

Pain:

• Non-opioids (acetaminophen, NSAIDs)

• Opioids

• SNRIs/TCAs

• Anticonvulsants (gabapentin/pregabalin)

• Corticosteroids

Dyspnea:

• Low-dose opioids

• O2

• Benzodiazepines

Nausea/Vomiting: Antiemetics

• Dopamine antagonists

• Serotonin antagonists

• Corticosteroids

• Anticholinergics

Anorexia: Appetite stimulants

• Olanzapine

• Dexamethasone

Incurable Cancer: Non-Cancer-Directed Psychosocial Support

CBT

• Spiritual care

Goals of care + advance care planning

Incurable Cancer: Non-Cancer-Directed Urgent Treatment

Improve quality of life

Prolong life + improve prognosis

Oncologic Emergencies: Types

Metabolic

Hematologic

Structural

Treatment-related

Metabolic Oncologic Emergencies

Electrolyte abnormalities

• Hypercalcemia

• Hyponatremia + SIADH

• Tumor lysis syndrome

• Hypoglycemia

Hematologic Oncologic Emergencies

Febrile neutropenia

Leukostasis

Hyperviscosity syndrome

VTE

Structural Oncologic Emergencies

Spinal cord compression

SVC syndrome

Pericardial effusion + cardiac tamponade

Pleural effusion

Malignant ascites

Bowel obstruction

Airway obstruction

Treatment-Related Oncologic Emergencies

Nausea/vomiting

Diarrhea

Cardiomyopathy

Immune-related (colitis, pneumonitis, hepatitis, myocarditis)

Prostate Cancer: Description

Malignancy in prostate gland

Prostate Cancer: Epidemiology

Risk factors…

• Older age (> 50)

• Family history

• African-American

• Smoking

• Genetics (BRCA2, Lynch syndrome)

• Diet

  • Saturated fat

  • Well-done meats

  • Ca2+

Prostate Cancer: Etiology

Lynch Syndrome: DNA mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2) = Increase risk

Hereditary Breast + Ovarian Cancer Syndrome: Recombination repair gene mutations (BRCA1/2, ATM, PALB2, CHECK2) = Increase risk

HOXB13 mutation: Tumor suppressor gene

Prostate Cancer: Pathophysiology

1. Tumor suppressor gene/oncogene mutation = Increased cell growth + proliferation

• Most Common: Erythroblast transformation specific (ETC) transcription factor fusion

2. Impaired gene transcription at androgen receptor binding sites = Androgen receptor-mediated DNA damage

3. Androgen receptor resensitization = Progress to castration-resistant prostate cancer

• After prolonged androgen deprivation therapy

Prostate Cancer: Clinical Presentation

Early:

• Usually asymptomatic

• Complicated lower urinary tract symptoms (LUTS)

  • Urinary retention

  • Hematuria

  • Incontinence

  • Flank pain

Advanced:

• Constitutional

• Bone pain (back)

• Neurological deficits (ED)

• Lymphadema

• GI symptoms

Prostate Cancer: Investigations

Blood tests

DRE

Imaging

Biopsy

Prostate Cancer Investigations: Blood Tests

PSA: Screening + monitoring

• Total: > 4 ng/mL

• Free/Unbound: Decreased (< 25%)

Alkaline phosphatase

• Elevated = Bone metastases

Prostate Cancer Investigations: DRE

Indications:

• Increased PSA

• LUTS

Findings:

• Localized nodules

  • Hard

  • Nontender

• Prostatomegaly + no sulcus

• Asymmetry

Prostate Cancer Investigations: Imaging

Multiparametric MRI (mpMRI)

• First0line

Transrectal US

• Guide biopsy

Cross-sectional imaging

• CT, MRI, PET-CT

• Determine metastasis

Prostate Cancer Investigations: Biopsy

Prophylactic antibiotics

• Prevent prostatitis

Finding: Adenocarcinoma

• Gleason Grade: Depend on tumor differentiation + stromal invasion (1 to 5) → Prognostic

Prostate Cancer: Treatment/Management

Nonpharmacological

Systemic therapy

Radiation therapy

Surgical

Prostate Cancer Treatment: Nonpharmacological

Watchful waiting

Active surveillance

Follow-up surveillance

Prostate Cancer Treatment: Watchful Waiting

Indications:

• Limited life expectancy (≤ 5 years)

• Slow-growing tumor

• Asymptomatic/minimal symptoms

Monitor with DRE + PSA

Prostate Cancer Treatment: Active Surveillance

Indications:

• Low-risk

• Life expectancy > 5 years

Monitor with DRE, PSA, biopsies, + mpMRI

Prostate Cancer Treatment: Follow-Up Surveillance

PSA (3-6 months)

DRE (annual)

Prostate Cancer Treatment: Systemic Therapy

Endocrine therapy

• Androgen deprivation therapy

• Androgen synthesis inhibitors

• Androgen receptor antagonists (antiandrogen therapy)

Chemotherapy

Prostate Cancer Treatment: Androgen Deprivation Therapy (ADT)

Medical Castration:

• GnRH Agonists: Leuprolide

• Gonadotropin-Releasing Antagonists: Degarelix

• GnRH Receptor Antagonists: Relugolix

MOA: Decrease pituitary stimulation on testes = Decrease testosterone production

Indications:

• Locally advanced

• Metastatic prostate cancer

Adverse Effects:

• Osteoporosis + fractures

• Sexual dysfunction

• Gynecomastia

• CVD + metabolic risk

Prostate Cancer Treatment: Androgen Synthesis Inhibitors

Ex: Abiraterone

MOA: Inhibit 17a-hydroxylase = Inhibit androgen synthesis

Indication: Adjunct to ADT

Adverse Effects:

• Increase mineralocorticoids → HTN, hypokalemia, arrhythmias

• Inhibit glucocorticoid production = Adrenal insufficiency

Prostate Cancer Treatment: Androgen Receptor Antagonists (Antiandrogen Therapy)

First-Generation: Flutamide, bicalutamide (short-term management)

Second-Generation: Apalutamide, enzalutamide

MOA: Displace androgens from androgen receptors

Indication: Adjunct to ADT

Prostate Cancer Treatment: Chemotherapy

Ex: Docetazel (cytotoxic)

Indication:

• Adjunct to ADT

• Metastatic

Prostate Cancer Treatment: Radiation Therapy

External beam radiation therapy

Brachytherapy

Indications:

• Localized

• Metastatic

• Adjuvant with surgery

Prostate Cancer Treatment: Surgical

Castration: Bilateral orchiectomy

Prostatectomy: Remove prostate gland + pelvic lymph nodes

Indications:

• Localized

• Unsuccessful radiation

Prostate Cancer: Complications

Decreased bone health

• Osteoporosis → Fractures + spinal cord compression

• Bone metastasis: Osteoblastic

Osteoporosis: Clinical Presentation

Neck/back pain

Bilateral paralysis

• Below affected level

Decreased sensation

• Below affected level

Urinary/bowel sphincter dysfunction

• Incontinence

• Decreased rectal tone

• ED

Osteoporosis: Investigations

Bone scintigraphy: Bone metastases

Bone mineral density scan (DEXA)

10-year fracture risk (FRAX)

Osteoporosis: Treatment

Osteoclast inhibitors

• Bisphosphonates

  • Bind hydroxyapatite binding sites = Prevent osteoclast function + increase apoptosis = Decrease bone resorption

  • Inhibit mineralization

• Denosumab

  • Monoclonal antibody against RANKL = Prevent osteoclast maturation = Decrease bone resorption