Oncological Emergencies Dr. Gary Harding md, frcpc

Investigations

• CBC normal

• Mildly elevated BUN and Cr

• Normal LFTs

• Standard electrolytes normal

• Concern of pneumonia

• Chest x-ray ordered……

• Calcium checked

• 4.5

Hypercalcemia

Symptoms

• Usually nonspecific

• Many times patients present with very high calcium level

• Most research done in hyperparathyroidism

Gastrointestinal

• Constipation is most common15

• Exacerbated or confused with narcotic effects
• Related to autonomic dysfunction

• Anorexia

• Vague abdominal pain

• Rarely can lead to pancreatitis

Renal Dysfunction

• Nephrolithiasis

• More common in hyperparathyroidism

• Nephrogenic diabetes insipidus

• Defect in concentrating ability
• Polyuria and polydipsia

• Chronic renal failure

• Longstanding high calcium
• Calcifcation, degeneration, and necrosis of tubules

Neuropsychiatirc

• Anxiety

• Depression

• Cognitive dysfunction

• Delerium
• Psychosis
• Hallucinations
• Somnolence
• Coma

Cardiovascular

• Short QT interval

• Supraventricualr arrhythmias

• Ventricular arrhythmias

Physical Findings

• Usually not specific

• Dehydration secondary to diuresis caused by the hypercalcemia

• Corneal deposition of calcium

• “band keratopathy” on slit lamp exam

Epidemiology

• Occurs in about 10 to 20% of patients with cancer

• Both solid tumors and leukemias

• Most common

• Breast
• Lung
• Multiple myeloma

Pathogenesis

Three mechanisms

• Osteolytic metastases with local cytokine release

• Tumor secretion of parathyroid hormone-related protein (PTHrP)

• Tumor production of calcitriol

Osteolytic Metastases

Breast cancer

• Breast cancer

• Non-small cell lung cancer

• Cytokines released

• Tumor necrosis factor
• Interleukin-1
• Stimulate osteoclast precursor differentiation into mature osteoclasts
• Leading to more bone breakdown and release of calcium

PTH-Related Protein

• Most common in patients with non-metastatic tumors

• Called humoral hypercalcemia of malignancy

• Secretion of PTH itself is a rare event

• PTHrP binds to same receptor as PTH and stimulates adeynylate cyclase activity

• Increased bone resorption
• Increases kidney calcium reabsorption and phosphate excretion

Calcitriol

• Hodgkin’s disease (mechanism in majority)

• Non-Hodgkin’s (mechanism in 1/3)

• Usually responds to glucocorticoid therapy

Diagnosis

Clinical symptomology with

• Clinical symptomology with

• History of cancer
• Risk factors for cancer
• Suppressed PTH

• Some centers can test for PTHrP to confirm Dx of humoral hypercalcemia

• High PTHrP may predict response to pamidronate16

• Less of a response

• Malignancy must be ruled out in patients that present with a very high calcium and no other obvious cause

Treatment

Aims

• Lower serum calcium concentration

• Treat complications if present

• Treat underlying disease

Volume

• Large volume of normal Saline administration

• Expands intravascular volume

• Increases calcium excretion

• Inhibition of proximal tubule and loop reabosrption
• Reduces passive reabsorption of calicum

• Follow fluid status b/c of danger of fluid overload

Inhibition of Bone Resorption

• Three therapies

• Calcitonin
• Bisphosphonates
• Gallium nitrate

• Historical therapy

• Antitumor antibiotic plicamycin (mithramycin)
• Multiple serious side effects
• No longer manufactured

Calcitonin

• Salmon calcitonin

• Increases renal excretion of calcium

• Decreases bone reabsorption by interfering with osteoclast maturation

• Weak agent

• Works the fastest

Bisphosphonates

• Adsorb to the surface of bone hyroxyapatite

• Interfere with osteoclast activity

• Cytotoxic to osteoclasts

• Inhibit calcium release from bone

• Three commonly used

• Pamidronate
• Zoledronic acid
• Etidronate (1st generation, weaker)

Bisphosphonates

• More potent than calcitonin

• Maxium effect occurs in 2 to 4 days

• Trend to use of IV zoledronic acid in the acute situation

• Both are can be renal toxic

• More potent than pamidronate
• Administered over a shorter period of time (15 minutes vs. 2 hours)

Prophylactic Bisphosphonates

• Pamidronate use in patients with known lytic lesions17

• Less episodes of hypercalcemia
• Less pathologic fractures
• Less pain
• Less spinal cord compression
• Less need for radiation or surgery

Newly discovered side effect…

• Osteonecrosis of the jaw

• Recent case reports of jaw bone necrosis in patients on pamidronate

• EDUCATION needed

Gallium Nitrate

• Effective

• More potential for nephrotoxicity

• Rarely used

Dialysis

• Last resort

• Dialysis fluid with little or no calcium is effective

• Useful when patients can’t tolerate large volume resuscitation

• If calcium needs to be correct emergently

Recommendations in symptomatic situation

• Volume expansion

• Salmon calcitonin

• IV zoledronic acid or pamidronate

• Close follow up of calcium level and symptoms

Transitions in Treatment

Chemotherapy

• Two roles

• Direct treatment of cancer

• Palliation of symptoms

Palliative Chemotherapy

• Goal is not cure

• Goals

• Control of tumor
• Preservation of function
• Help tumor symptoms
• Pain
• Dsypnea
• Pruritis
• Poor appetite
• Weight loss

Fine Balance

• Chemotherapy can be very toxic

• Ratio: benefit vs. toxicity

• Host factors and tumor factors

• Delicate balance in palliative situation

• Want medications that affect tumor but do not heavily affect host

Psychology of Cancer

• Psychological evolution during cancer treatment

• Many people have fought very hard with their disease

• Chemotherapy for “relief” not “cure” can be difficult concept for patients

• ART of medicine

Evolution

• Chemotherapeutic protocols that have less side effects

• molecular targeted therapies

• Attack tumor specifically
• Less effect on host

Breast cancer

• Breast cancer

• Colon Cancer

• Prostate cancer

• Lung cancer

Breast Cancer

• Aromatase inhibitors for ER positive tumors

• Anastrozole, Letrozole, Exemestane

• Trastuzumab (Herceptin)

• Humanized monoclonal antibody targeting Her-2/neu protein on breast cancer cells
• Inhibits growth factor signal transduction
• Tolerated quite well

Colon Cancer

• Capecitabine (Xeloda)

• Oral drug that is transformed into 5-FU with three enzymatic reactions

• Final enzyme is at higher levels in tumor cells
• Contributes to drug’s less toxic side effect profile
• Less stomatitis, less myelosupression

Targeted GI Therapies

• Bevacizumab

• Monoclonal antibody to vascular endotheial growth factor receptor
• Some cardiac toxicity

• Cetuximab

• Monoclonal antibody to human epidermal growth factor receptor
• Skin toxicity

Prostate Cancer

• LHRH analogues

• Leuprolide (Lupron)

• Goserelin (Zoladex)

• Stop testosterone production with limited side effects

Lung Cancer

• In stage IV disease patients who receive Cisplatin based doublet chemotherapy live longer and feel better than best supportive care

• Hard to balance side effects

Gefitinib (Iressa)

• Targets epidermal growth factor receptor (tyrosine kinase small molecule inhibitor)

• May have a role in the palliation of advanced non small cell lung cancer patients

Palliative Care Debate

• Do not accept any patient on “active” therapy

• This needs to be further elucidated

• Patients being palliated with chemotherapy or targeted therapies still have other palliative care issues and needs

• Should a patient still on Xeloda for breast or colon cancer not be admitted to St. Boniface 8A?

Thank you

Any questions?