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198 Cards in this Set
- Front
- Back
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Consequences of toxicities
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* Fear and anxiety
* Treatment refusal * Poor compliance * Impaired QOL * Financial cost * Morbidity * Treatment deaths |
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Side effects of chemotherapy
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* "Chemo brain"
* Alopecia * Ototoxicity * Mucositis * Fatigue * Pulmonary toxicity * Cardiotoxicity * Nausea/vomiting * Diarrhea * Extravasations * Organ failure * Cystitis * Sterility * Myelosuppression * 2nd Cancers * Neuropathy * Skin reactions |
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What kind of rating system is used to quantify toxicities?
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Common Terminology Criteria for Adverse Events [CTCAE]
Numerical scale from 1 to 5: 1 = Mild 2 = Moderate 3 = Severe 4 = Disabling / life-threatening 5 = Death Descriptive rubrics for each category |
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Describe a Grade 1 Chemotherapeutic toxicity
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A grade 1 toxicity is considered mild. Using diarrhea as an example, this would be an increase of <4 stools per day over baseline
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Describe a Grade 2 Chemotherapeutic toxicity
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A grade 2 toxicity is considered moderate. Using diarrhea as an example, this would be an increase of 4-6 stools per day; IV fluids < 24 hours; not interfering with ADL
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Describe a Grade 3 Chemotherapeutic toxicity
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A grade 3 toxicity is considered severe. Using diarrhea as an example, this would be an increase of 7 or more stollds per day; IV fluids > 24 hours; hospitalization required
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Describe a Grade 4 Chemotherapeutic toxicity
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A grade 4 toxicity is considered disabling. Using Diarrhea as an example, this would include life-threatening consequences like hemodynamic collaps
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Describe a Grade 5 Chemotherapeutic toxicity
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Grade 5 is death
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Remember the grading system
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MMSD: My mother said diss death : Mild Moderate Severe Disabling Death Not that you wouldn't remember
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T or F: Every patient on chemotherapy experiences some toxicity. Some patients may experience all toxicities of their chemo regimen.
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FALSE: While it is true that every patient has some toxicity, no one gets all toxicities.
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Which grades of toxicity are the most common?
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Grades 1 and 2 are the most common grades of toxicity. This is acceptable to healthcare providers. Dose reduction is not warranted.
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Which grades of toxicity are uncommon?
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Grade 5 = death is the most uncommon toxicity
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Which grades of toxicity require dose adjustments?
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Grades 3 and 4 are likely and require dose adjustments: Hold doses to permit recovery. Reduce subsequent doses. Prevention important if it is possible.
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Describe hematologic toxicities
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Myelosuppression = most common acute dose-limiting side effect (DLT). Neutropenia = decrease in neutrophils. Thrombocytopenia = decreased platelets. Anemia - due to reduced RBCs.
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Describe non-hematologic toxicities
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* Nausea and vomiting = most common non-hematologic side effects. Most dreaded by patients. Very good prevention and management. * Fatigue = pervasive chronic effect. * Bladder problems. * Cardiac toxicity. * GI toxic effects. * Hepatic impairment * Infertility. * Nephrotoxicity. * Neurotoxicity. * Pulmonary problems. * Skin toxicities. * 2nd Cancers. * Infusion rxns. * Vascular effects.
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Discuss Myelosuppression in general
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* Myelosuppression: White blood cells, Neutrophils (ANC), Platelets, Red blood cells. * Most common dose-limiting toxicity. * Onset depends on lifespan of blood cells. * Drug, dose, and regimen- specific. * Traditional cytotoxics > targeted therapies and hormones
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How is Myelosuppression managed?
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* Hold and/or reduce subsequent doses. * Hematopoietic growths factors. * Transfusions.
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What are the treatment parameters for Myelosuppression?
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ANC >= 1500/mm3, Platelets >= 100,000 mm3
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Discuss Neutropenia
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* Neutrophil lifespan ~ 6-12 hours. * Decrease leads to infection risk. * Most important myelosuppressive toxicity. * Usual onset 10-14 days. * Neutropenia vs febrile neutropenia. * Option of colony stimulating factors - Most effective for prevention.
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Discuss Thrombocytopenia
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* Platelet lifespan ~ 7 days; slower onset. * Bleeding precautions. * Beware of NSAIDs, anticoagulants. * Hematopoietic growth factors not very effective. * Platelet transfusions.
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Discuss Anemia
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* S/Sx = Fatigue and cardiac symptoms * RBC lifespan = around 120 days. * Onset usually over weeks to months. * RBC Transfusions * Erythropoietin Stimulating agents
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Discuss Erythropoietin Stimulating agents
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* Stimulate RBC production and increase Hgb. * Decrease transfusions requirements. * Associated with increased mortality and disease progression. * Indicated for chemotherapy-induced anemia only. * Only allowed in specific patient populations . * Treat to the lowest Hgb level required to avoid RBC transfusions
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Discuss bladder toxicity
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* AGENTS likely to cause: Cyclophosphamide and ifosfamide. * PATHOPHYSIOLOGY: - Toxic metabolite acrolein. - Binds to critical thiols in bladder mucosa. - Produces bladder wall damage (hemorrhagic cystitis). * RISK FACTORS: - Dose and cumulative lifetime dose. - Dehydration. - Pelvic XRT. * SYMPTOMS: - hematuria. - dysuria. - frequency * PREVENTION: - Hydration. - Mesna
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Discuss hydration as a prevention strategy for bladder toxicity
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"* Increase urine flow. * Reduces acrolein contact time with bladder wall. * Oral hydration for usual cyclophosphamide doses [500-1000 mg/m2] * IV hydration for high cyclophosphamide doses and ALL ifosfamide doses
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Counseling point to promote Oral Hydrtion
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* Drink 2-3 liters / day for the day of chemo plus 2 additional days. * Two large glasses before bed. * Repeat during night. * Choice of fluids. * Need for antiemetics.
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Discuss Mesna as a prevention strategy for bladder toxicity
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* Mercapto ethane sulfonate sodium. * Sulfhydryl compound. * Converted to dimesna then to mesna in renal tubules. * Complexes with acrolein. * Non-toxic complex is voided. * DOSING: - Intermittent dosing for short infusions. - Continuous dosing for CIV infusions. - Oral administration
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Discuss Cardiac Toxicity
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* AGENTS likely to cause: Anthracyclines: - Doxorubicin is the most common agent used and usually used chronically. Has the greastest risk of cardiac toxicity. - Epirubicin. - Idarubicin. - Daunorubicin. - Trastuzumab. - Cyclophosphamide. - 5-Flourouracil. - Interleukin-2. - Taxanes. - Sunitinib. * PATHOPHYSIOLOGY: - Anthracyclines reduced to free radicals. + Damage mitochondrial membranes. + Disrupt energy production. - Iron-anthracycline complexes initiate lipid peroxidation and cell destruction. - Injury is progressive with each dose. -
Heart susceptibility: + Many mitochondria. + Low levels of antioxidant enzymes * RISK FACTORS: - High cumulative doses > “Speed limit” of 550 mg/m2. + Safe dose in children is lower. + Safe dose with radiation is lower. - Bolus administration. - Very young or old. - Females > males. - Pre-existing cardiac disease. - Genetic predisposition. * PREVENTION: - Measure LVEF. + Hold drug for <45-50% at rest. + Hold if > 10% drop . - Limit cumulative doses. - Avoid high peaks. + Infusions or frequent small doses. + Other toxicities increased. - Use less toxic analogs or liposomal products. - May pretreat with dexrazoxane. |
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Discuss pretreatment with Dexrazoxane to prevent cardiac toxicity
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* Iron chelator. * Prevents formation of iron-drug complex. * Reduces risk by 50%. * Concerns: reduced antitumor effect. * Begin at 300 mg/m2. * Limited clinical use
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Discuss Cardiac Toxicity Management
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* Permanent damage. * Responsive to medical management. - Inotropes. - Afterload reducing agents. - Etc. * May be progressive. * Heart transplant.
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Discuss Cardiac Toxicity of Trastuzumab
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* Additive with anthracyclines. * ~3-4% increased risk. * Risk factors: - Radiation to left side. - DM. - CAD. - Valvular dysfunction. * MOA: related to HER-2 receptors in cardiac tissues. * Generally reversible
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What cardiotoxic manefestation is associated with Cyclophosphamide?
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hemorrhagic pancarditits
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What cardiotoxic manefestation is associated with 5-Fluorouracil?
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* ischemic changes. - Continuous infusions. - Capecitabine .
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What cardiotoxic manefestation is associated with Interleukin-2?
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myocardial depression
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What cardiotoxic manefestation is associated withTaxanes?
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sinus bracycardia
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What cardiotoxic manefestation is associated with Sunitinib?
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congestive failure
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Agents and Adjustments important in hepatic dysfunction
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What are the three main manifestations of GI toxicity?
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* Nausea/vomiting * Mucositis * Diarrhea
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What is Mucositis?
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Mucositis or stomatitis * Mucosa has a high cell turnover rate * Direct and indirect toxic effects on mucosa * Sx: tenderness, redness, burning, ulceration * Risk affected by drug, regimen, diagnosis
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Mucositis: Prevention and Management
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"* Risk assessment; dental evaluations * Strict oral hygiene * Symptomatic relief: - Local protective agents - Analgesics - Anti-infectives * Prevention – make mucosa more resistant: Palifermin [Kepivance™, rH keratinocyte growth factor]
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What are the most common chemotherapy agents that cause mucositis?
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5-Fluorouracil, Doxorubicin, and Methotrexate are the most common but really any cytotoxic agent can cause mucositis
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How does chemo toxicity cause diarrhea?
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* Mucosa has a high cell turnover rate * Direct and indirect toxic effects on mucosa
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What are the two types of diarrhea?
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* Acute and chronic * Acute diarrhea: - cholinergic sumptoms - prophylaxis and treatment with atropine * Chronic diarrhea: - aggressive loperamide dosing - octreotide for unresponsive diarrhea
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How is diarrhea managed?
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* Take diarrhea seriously!! * loperamide use: - DO NOT READ THE BOX - Treastment: + At the first loose stool, take 4 mg loperamide to start + then take 2 mg every 2 hours + stop if no BM in 12 hours + restart if diarrhea recurs * Maintain fluids * Contact HCP for uncontrolled diarrhea * May require dose reduction to minimize
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What are the risk factors for diarrhea?
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* Elderly patients >65, female, the following chemo agents: 5-Fluorouracil with leucovorin or 5-fluorouracil continuous infusion, Irinotecan
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Drug-induced hepatotoxicity
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* covalent binding between reactive metabolites and liver cell proteins or DNA * Calcium alterations may damage cell membranes
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Acute reaction hepatotoxicity
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* Increase in transaminases * Increase in bilirubin
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List the most common hepatotoxic agents
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* Cytarabine: reversible cholestasis with high dose (HDAC) regimens * Methotrexate: chronic low dose regimens; use ‘pulse’ dosing * Capecitabine: reversible increases in bilirubin * L-Asparaginase: interferes with protein synthesis (albumin , clotting and coagulation factors) * Antiandrogens: flutamide >> other agents; LFTs x 2 months
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What are the two main causes of hepatic dysfunction among cancer patients?
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Metastatic disease and drug induced. Chemo and other medications may need to be adjusted as a result.
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Chemo Agents associated with Renal Dysfunction and their Dose Adjustments
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What are the most common agents that cause infertility?
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Alkylating agents and hormonal agents
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How are male patients affected by drug-induced infertility?
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CHEMO: * affect develeoping spermatogonia * sperm counts drop at 2-3 months * this can become irreversable at 1-3 years * sperm cryopreservation is an option HORMONAL AGENTS: * androgen ablation * can also cause impotence and decreased libido - there are pharmacologic interventions qhich may help with this.
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How are female patients affected by drug-induced infertility?
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* Risk of infertility increases with age * Number of oocytes normally declines * Chemotherapy causes early menopause, hormonal preventions are unproven, Oocyte harvest and preservation is a solution * Avoid estrogens for menopausal SX in breast cancer patients * remember osteoporosis risk
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T or F: Only a few chemo agents put the kidneys at risk.
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FALSE: Many chemotherapy agents are excreted by the kidneys, putting the kidneys at risk.
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What are the three types of nephrotoxicity?
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Acute renal failure, Chronic renal failure, and renal dysfunction
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How does Cisplatin cause rephrotoxicity?
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* Renal tubule poison (proximal tubules >> other tubules >> glomeruli) * Cross-linking with DNA --proximal tubule necrosis * Acute -> increase in BUN and SCr * Chronic -> Permanent effects on GFR, Chronic magnesium loss
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How can Cisplantin nephrotoxicity be prevented?
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* Aggressive hydration - IV * Chloride containing vehicles * Mg and K+ supplementation * Diuretics if needed * Amifostine - rarely used * Carboplatin alternative - dosed using SCr
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How does Methotrexate cause nephrotoxicity?
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* Preceipitation of methotrexate crystals in the renal tubules. * High dose regimens - exceed drug solubility in acid urine
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How can Methotrexate nephrotoxicity be prevented?
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* Alkalinize urine * Hydrate * leucovorin NOT helpful
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What are the three main causes of renal dysfunction among cancer patients?
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* Drug induced * Aging * Comorbid condition The result is that chemo or other medications may need to be renally adjusted
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Is neurotoxicity a life threathetening toxicity associated with chemo agents?
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* Usually not life threatening but can be debilitating
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What systems can be damaged due to neurotoxicity?
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* CNS * PNS * Autonomic nerves * Sensory organs
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What SXs are characteristic of neurotoxicity?
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* CNS - confusion, ataxia, seizures, and somnolence * PNS - numbness and tingling * Autonomic - constipation, orthostatic instability * Sensory organs - hearing loss, blindness
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How is neurotoxicity treated?
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* Hold chemo dose * Dose reductions * Antiepileptic drugs
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What agents are associated with CNS neurotoxicities?
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* Cytarabine (HDAC) – cerebellar toxicity * Ifosfamide – lethargy, somnolence, encephalopathy * Methotrexate (high dose) - cerebellar toxicity, leukoencephalopathy
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What agents are associated with PNS neurotoxicities?
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* Cisplatin/Carboplatin - sensory; stocking-glove distribution; chronic and cumulative. * Vincas - sensory and motor; autonomic [avoid constipation]. * Taxanes – sensory and motor
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Discuss Oxalplatin Neurotoxicity
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* Acute reversible sensory syndrome > 90% * Rapid onset (hours to days) * Mouth, throat and hands * Numbness, tingling, electric-like sensations, foreign body sensation, "breathlessness" * Hyperexcitability from damage to sodium channels ["channelopathy"] * Oxalate may chelate Ca++ and Mg++; ??? give Ca++/Mg++ infusions???? * avaoid cold, ice
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Which agent is Ototoxic?
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Cisplatin
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Which agents are Ocular toxic?
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* Cisplatin * Vinca Alkaloids * Cytarabine * 5-Fluorouracil * Docetaxel
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What are the mechanisms of pulmonary toxicities?
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* Damage to small vessels and pneumocytes * Inflammation * Collagen deposits
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Snx of Pulmonary Toxicity?
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* Dyspnea, dry cough * Restrictive defect on PFT's
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What agents are known for causing pulmonary toxicities?
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Busulfan, bleomycin, targeted therapies If this occurs STOP THE DRUG!
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How does Bleomycin cause pulmonary toxicity?
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* Bleomycin-iron complex produces free radicals * Oxidize fatty acids; membrane damage and instability * Collagen production; lung fibrosis * Low hydrolase levels in lungs * Slow resolution * Cumulative doses > 450 units * Single dose > 30 units
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Which patients are at increased risk for developing pulmonary toxicities?
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* Elderly * Emphysema * XRT to lungs * High O2 * Renal failure * Lymphoma
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What are the three main manefestations of skin toxicities?
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* Alopecia * Rash and others * Extravasations
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What is Alopecia?
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* Common toxicity; affects decision-making * Scalp hair >> other body hair * Onset of hair-loss is 1-2 weeks; maximal around 3 weeks * reversible; regrowth 2-3 months
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What are the risk variation by class breakdown for alopecia?
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* Lowest: hormones, targeted agents * Low-Moderate: antimetabolites, heavy metals * High: classic alkylating agents * Very High: anthracyclines and taxanes
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What are some ways to prevent alopecia?
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* Scalp cooling - vasoconstriction limits drug delivery - moderately effective - uncomfortable * No effective pharmacologic interventions
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What patient support can be provided for alopecia?
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* acknowledgement of loss and grief * Expected reversibility * Regrowth may alter characteristics * Wigs, hats, turbans * Protect scalp from sunburn
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Discuss rashes as a chemo toxicity
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* Rahes may present in different forms * Rashes are not always representing hypersensitivity reactions
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What agents are known for causing rashes?
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* Gemcitabone * Small molecule tyrosine kinase inhibitors * EGFR inhibitors
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How are chemo rash toxicities treated?
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* Corticosteroids * Antihistamines * Topical or oral antibiotics
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What agents commonly cause photosensitivity reactions?
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* Flourouracil * Vinblastine * Dacarbazine * Methotrexate
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How can photosensitivity reactions be prevented/treated?
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* Take special care to avoid exposed scalp skin * Physical barriers; broad spectrum sun protection
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What is hand-foot syndrome?
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* Palmar-plantar erythrodysesthesia
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What agents commonly cause hand-foot syndrome?
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* Capecitabine * 5-Fluorouracil infusions * liposomal anthracyclines
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How is hand-foot syndrome managed?
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* emollients * analgesics * Dose reductions
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What is extravasation reaction?
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* occurs when drugs escape from the veins or intravenous catheters into subcutaneous tissues. * cutaneous manifestations of extravasation may range from discomfort and mild erythema to severely painful skin necrosis, ulcerations, and invasion and damage of deep tissue structures.
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What agents are known for causing extravasation reaction?
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* Vesicant drugs such as anthacyclines and Vincas * Irritant drugs * Drug administration techniques can have an effect
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How is extravasation managed?
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* Anthracyclines: ice +/- dexrazoxane (Totect) * Vinca: warm packs; hyaluronidase
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Discuss Fatigue as a chemo toxicity
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* Multifactorial * Impairs QOL, relashionships, mood, commitment to therapy * Lifestyle interventions can be helpful * CAUTIOUS use of erythropoiesis stimulating agents (ESAs) in anemic patients * CNS stimulants can also be helpful
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Discuss Neurocognitive dysfunction
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* "Chemo Brain" * found in 20-25% of patients * Subtle shifts in cognitive function * May be seen early or late in treatment * May improve over 6 months - 2 years following chemotherapy
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What are the main effects of Neurocognitive dysfunction?
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* Difficulty concentrating * Difficulty handling/performing multiple tasks * Difficulty with memory
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What is the mechanism for Neurocognitive dysfunction?
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Unknown mechanism. May be due to certain chemo agents, but this is unknown. May also have to do with Genetic or hormonal factors.
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T or F: "Chemo Brain" is not a result of anemia, fatigue or depression.
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TRUE
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What methods can be used to help patients with "Chemo Brain" function more effectively?
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* decrease work load * avoid multiple tasks * make lists * encourage more sleep
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What are the types of infusion reactions?
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Hypersensitivity: Type 1 reactions - Wheezing, dyspnea, rash, hypotension, bradycardia, pain * Immune related - (Mild) - fever, chills, rash - (Severe) – anaphylaxis
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How are infusion reactions treated?
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* Prevention – premedicate * Reaction – supportive care
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Discuss hypersensitivity reactions with taxanes
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* Type I reactions; usually with 2nd dose * Paclitaxel >>> docetaxel * Drug and vehicles implicated * Premedication regimens: - Diphenhydramine, Dexamethasone, H2 antagonist * Desensitization possible
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Discuss hypersensitivity reactions with platinum compounds
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* Most common with carboplatin * Risk increases with increasing number of doses * Most common after ~ 8 doses
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Discuss hypersensitivity reactions with L-asparaginase
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* Highly antigenic bacterial protein * Use test doses * “PEG-ylated” form decreases risk
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Discuss Infusion-related Reactions related to Monoclonal Antibodies
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* Risk depends on source of antibody: Murine >>> chimeric >> humanized >> human * Premedicate patients receiving murine or chimeric * Start infusion at slow rate; increase gradually * Stop or slow infusion rate if reaction occurs
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What agents commons cause joint and muscle aches?
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* Paclitaxel: Myalgias and Arthralgias - Onset 2-3 days after administration, Persists 2-4 days, Acetaminophen or NSAIDS, and Alternative therapies * Cytidine analogs and biologics: Flu-like syndrome * Vinblastine: Muscles aches * Colony stimulating factors: Bone pain
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Discuss teratogenicity
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* factors in fetal risk * highly ethical issue * precautions should be taken in women of child-bearing age
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What are the most common agents known to cause teratogenicity?
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* Thalidomide * Antimetabolites * Hormones agents
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What are risk factors for teratogenicity?
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* Risk depends on gestational age * Methotrexate produces greatest risk of fetal loss. * Avoid antiandrogens, antiestrogens * Other considerations: Supportive care agents, Maternal toxicity , altered kinetics, and risk of late effects
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Discuss vascular toxicities
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* Vasomotor flushes (“hot flashes”): -Hormonal suppression - Impact on quality of life - Pharmacologic management * Capillary leak syndrome - IL-2 * Docetaxel fluid retention and pulmonary edema: - Cumulative - Pretreat with corticosteroids
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Discuss Secondary Cancers
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* Best studied in Hodgkins Lymphoma survivors * Ionizing radiation +/- chemotherapy * Hematologic malignancies are most common * Causative agents: Alkylating agents, Topoisomerase-inhibitors
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What cancer has the highest number of new cases among men?
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Prostate cancer (25%)
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T or F: Prostate cancer is the number 1 cause of cancer related deaths among men?
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FALSE: Lung and Bronchus cancers (30%) are the leading cause. Prostate is second (9%)
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What is the risk of death from prostate cancer?
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about 3%
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What is the lifetime risk of contracting prostate cancer in older american men?
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* 1 in 6 (U.S. Caucasian) * 1 in 5 (U.S. African) over the age of 75
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What does autopsy evidence tell us about prostate cancer?
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* Foci may be present in as many as 1 in 4 men in their 30’s. * 44% of men in their 40’s have Prostatic Intraepithelial Neoplasia (PIN). (1 in 3 of these men have foci of invasive cancer) * >80% of men over age 80 have incidental prostate cancer at autopsy
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How is postate cancer staged?
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* Stage I: a single tumor is found in the prostate * Stage II: Multiple tumors in the prostate * Stage III: Tumor cells have left the prostate and has invaded nearby organ * Stage IV: Tumor cells are metastatic
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Prostate cancer presentation
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* Past - Abnormal digital rectal exam (DRE) - Urinary symptoms: Frequency, Hesitancy, Nocuria (awaking from sleep to urinate), Erectile dysfunction - Bone pain from metastatic disease * Currently – most new PCA patients have an elevated PSA in the current era
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How is postate cancer diagnosed?
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* Suspicion from elevated PSA or abnormal DRE * A transrectal ultrasound (TRUS) guided biopsy is an office-based procedure for tissue diagnosis of PCA: - Generally performed without sedation - Sextant (6) biopsy was standard, although more recent data show 10-12 biopsies has increased detection rate
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What trial looked at screenings for prevention of prostate cancer?
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Prostate Cancer Prevention Trial (PCPT)
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What were the findings of the Prostate Cancer Prevention Trial (PCPT)?
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* 25% relative reduction in PCA with finasteride (P < 0.001) from 24% to 18%. * High grade (Gleason 7-10) were increased with finasteride. * Finasteride is currently uncommonly used for prevention of PCA.
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What is the bottom line with prostate cancer screening?
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* Probably over-diagnoses cancer - Common disorder seen in 80% of 80 year olds at autopsy - 3% of men DIE from prostate cancer * Careful consideration of co-morbid conditions is highly recommended when considering starting or stopping a screening program * Ultimate decision is patient’s * Limited support for PSA screening in recent randomized trials
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What are the key concepts for Prostate Cancer?
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* The epidemiology -Common * Anatomy – staging * Presentation /diagnosis - Usually asymptomatic with PSA elevation * Pathology - Gleason score is key * Screening - Clear guidelines for using the PSA lacking * Prevention - Active area of research * Treatment - Still looking at the androgen receptor after all these years
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Discuss the concept of "hormone-refractory" prostate cancer
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* The definition of “hormone-refractory” remains difficult to precisely describe - After castration, low levels of androgen persist and PCA cells may also produce. * Adrenal also has a clear capacity to produce androgen (approximately 5-10% of the body’s testosterone production) - Ketoconazole and glucocorticoids * Abiraterone is a specific CYP17 inhibitor.
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T or F: Castration resistant prostate cancer has nothing to do with hormones?
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FALSE: Castration-resistant prostate cancer remains hormone driven
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How does the addition of Abiraterone acetate affect prostate cancer patients?
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* Deoxycorticosterone and corticosterone are increased leading to a decrease in aldosterone -> hypokalemia, hypertension, fluid overload, suppression of renin. * DHEA is decreased -> decrease in androstenedione -> decreases in testosterone and estradiol * 11-deoxycortisol is increased -> decrease in cortisol -> increased ACTH
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How does the addition of Abiraterone acetate and glucocorticoids affect prostate cancer patients?
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* Deoxycorticosterone and corticosterone are decreased so there is no decrease in aldosterone * DHEA is decreased -> decrease in androstenedione -> decreases in testosterone and estradiol * 11-deoxycortisol is decreased -> decrease in cortisol -> increased ACTH but since no increase in corticosterone ACTH is actually decreased
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Discuss bicalutamide used in addition to castration for PCA
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* An antiandrogen, such as bicalutamide, is used in addition to castration for PCA - Bicalutamide is much less potent than dihydrotestosterone for the androgen receptor
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Discuss MDV3100 used in addition to castration for PCA
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* MDV3100 is a second generation anti-androgen - Reduces nuclear localization of the androgen receptor - Impairs androgen receptor DNA binding
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Discuss Sipuleucel approach
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* Antigen presenting cells are removed and sent to a central lab * They are incubated with PA2024 – a fusion protein of PAP-GCSF * The cells are then re-infused into the patients * Ex-vivo loading
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What are the benefits and risks to Sipuleucel approach?
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BENEFITS: Some improvement in the time to disease progression (not significant). Significant increase in survival time RISKS: High incident of ADEs: Rigors, Pyrexia, Arthralgia, and Vomiting
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Is adjuvant chemo effective in prostate cancer?
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This is questionable… * Adjuvant chemotherapy, given after local therapy to improve the overall survival, is accepted in the major cancer types: Breast, Colon, Recently, in Lung, ?? Prostate
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What is a prostatectomy?
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Removal of the prostate gland
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What is Cryotherapy for prostate cancer?
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* Cryotherapy is an alternative to surgery or radiation for prostate cancer. * Cryotherapy kills prostate cancer by freezing prostate tissue. This method has been shown to effectively control cancer in men with early-stage prostate cancer. * Cryotherapy involves inserting several thin metal rods through the perineum (between the scrotum and the anus) and into the prostate. An ultrasound probe in the rectum helps guide your doctor to position the rods. Once the rod tips are in place, liquid nitrogen or argon gas is released into the rods, where it circulates and freezes the nearby tissue. This causes the cancerous cells to rupture and die.
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■Active surveillance (watchful waiting) ■External beam radiation therapy ■Radioactive seed implants (brachytherapy) ■Surgery to remove the prostate (radical prostatectomy) ■Cryosurgery ■Hormone therapy
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What is external beam radiation therapy for prostate cancer?
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* External beam radiation therapy (EBRT) is a standard treatment option for prostate cancer that has not spread beyond the prostate gland. * EBRT uses high-energy X-rays that are precisely focused on the prostate gland. The X-rays interfere with cancer cells' ability to reproduce and kill the cancer
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What is Radioactive seed implants (brachytherapy) for prostate cancer?
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Brachytherapy for prostate cancer delivers radiation directly into the prostate with radioactive pellets. This method delivers a higher dose of radiation to the prostate gland than does external beam radiation, while less surrounding tissue is damaged by radiation
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What is Hormone therapy for prostate cancer?
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* Male sex hormones (androgens) stimulate the growth of prostate cancer cells. The main type of androgen is testosterone. Hormone therapy may stop your body from producing testosterone or block testosterone from entering cancer cells. * Three methods of hormone therapy are: ■Luteinizing hormone-releasing hormone (LH-RH) agonists ■Anti-androgens ■Testicle removal (also called orchiectomy and castration)
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Gleason Pattern 2 pic
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Gleason pattern 3 pic
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Gleason pattern 4 pic
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Gleason pattern 5
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Is prostate cancer fast or slow growing?
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VERY slow growing
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How/where does prostate cancer spread?
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Spreads locally
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Where does prostate cancer usually metastasisze to?
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Bone, liver and lung
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How is prostate cancer screened for?
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* Prostate Specific Antigen (PSA) - No consistent screening guidelines - Normal range 0-4 ng/mL - Age adusted PSA values: older patient's PSA values may fall within the predictive range
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What is the Age Adjusted PSA for males ages 40-49?
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0-2.5 ng/mL
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What is the Age Adjusted PSA for males ages 50-59?
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0-3.5 ng/mL
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What is the Age Adjusted PSA for males ages 60-69?
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0-4.5 ng/mL
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What is the Age Adjusted PSA for males ages 70-79?
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0-6.5 ng/mL
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What is the clinical presentation of prostate cancer?
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* Early stage: Asymptomatic * Advanced stage disease: - Alteration in urination (frequency, flow, hesitancy, or pain) - Lower extremity edema - Pain
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What are the staging systems for prostate cancer?
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* TNM - stage I-IV * Jewett staging - Stage A-D
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What stage of prostate cancer is characterized by confignment to the prostate
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Localized disease - Stage 1 & 2 (A & B)
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What stage of prostate cancers characterized by some spread to the immediate surroundings?
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Stage 3 ( C ) and some stage 4 ( D )
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What stage of prostate cancers characterized by lymph node involvement or outside prostate invading surrounding tissues or distant organs?
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Stage 4 (D)
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What stage is prostate cancer most diagnosed at?
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60% diagnosed at stages 1-2 localized disease (followed by stage 3-4 Locally advanced and lastly stage 4 distant or metastatic disease)
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List the prognostic factors for prostate cancer?
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* PSA level * Stage * Gleason Score (categories <5, 6-7, 8-10 and calculation 3+5 = 8) * Age * performance status
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What is Gleason 2?
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* Gleason pattern 2 should staisfy the 3 "R's": 1) Round 2) Regularly spaced 3) Relatively uniform in size. * Gleason pettern 2 cancer consists of predominantly round acini without sharp angulation or distorted shapes.
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What is Gleason 3?
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"If there is a twofold or greater variation in acinar size, it's probably Gleason pattern 3 rather than pattern 2: When malignant acini are uniformly separated from one another, a twofold variation in acinar size distinguishes Gleason pattern 3.
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What is Gleason 4?
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Fusion is Fusion is Fusion (Gleason pattern 4): Acinar fusion separates most cases of Gleason pattern 4 and 3. This is a critical cut-point in grading prostate cancer, as pattern 4 indicates poorly differentiated cancer
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What is Gleason 5?
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The loss of most acinar lumens within fused acini indicates Gleason pattern 5: Most acinar lumens must be absent in order to separate Gleason pattern 5 from pattern 4. Tangential cutting and crush artifact may obscure or hide lumens. However, it most acini lack lumens, it constitutes pattern 5
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Choose a therapy regiment to treat PC's prostate cancer and list the side effects of this regimen."
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* LHRH agonists: Hot flashes, decreased libido, Impotence, gynecomastia, Tumor flare * Antiandrogen: Hot flashes, gynecomastia, LFT abnormalities, Diarrhea, Agent specific toxicity
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How do you deal with the side effect profile of PC's meds?
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* Hot flashes – Supportive care, SSRI’s, Venlafaxine * decreased libido – counsel patient * Impotence – Erectile dysfunction medications * gynecomastia – Counsel patient * Tumor flare – antiandrogen * LFT abnormalities – monitor labs * Diarrhea – monitor and treat with antidiarrheal
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What are the Goals of Treatment for prostate cancer?
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* decrease testosterone production * inhibit testosterone effects
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What is an important factor in making treatment decisions for prostate cancer?
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Life expectancy
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What are the treatment options for prostate cancer?
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* Surgery * Radiation * Hormone therapy * Chemotherapy
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Discuss surgery as a treatment option for prostate cancer
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* Curative * Radical prostatectomy - High risk patient may have LN dissection at time of surgery - Used to treat localized and locally advanced disease * Side effects: incontinence, erectile dysfunction, and morbidity
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Discuss radiation as a treatment option for prostate cancer
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* Curative * Localized and locally advanced disease * Some metastatic disease * Types: External beam, and Brachytherapy * Side effects: incontinence, ureteral inflammation, bowel dysfunction, erectile dysfunction
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Discuss Hormone therapy as a treatment option for prostate cancer
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* Hormone Therapy: - Androgen Deprivation (ADT) - Decrease testosterone or inhibit effects: Surgical castration, or medical castration * Goal – Testosterone level < 50 ng/mL * Used in some localized and locally advanced disease and all metastatic disease * Continuous vs. intermittent treatment * Risk of metabolic syndrome and osteoporosis
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Discuss Chemotherapy as a treatment option for prostate cancer
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For hormone refractory disease
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If a patient has <= 5 year life expectancy and is asymptomatic, what do you do next?
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No furthur work up is done for this patient
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If a patient has > 5 year life expectancy or is symptomatic, what happens next?
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Furthur work up and staging
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When is active surveillance appropriate?
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* Very low risk of recurrence: T1a, Gleason Score < 6, PSA <10 ng/mL, fewer than 3 biopsies +, PSA density <0.15 ng/mL/g * < 20 year survival
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What is active surveillance?
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* Aka: Watchful waiting or observation. * Monitoring : - PSA every 3- 6 months and DRE every 6-12 months for life expectancy > 10 y - Life expectancy < 10 y – PSA and DRE less frequently * Needle biopsy: Within 6 months or 18 months depending on type of biopsy * Treat at signs of progression: - Gleason grade 4-5 on repeat biopsies. - > # of positive biopsies. - PSA doubling time , 3 y or PSA velocity >0.75
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What are the advantages of active surveillance?
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* Avoid side effects of treatment * Maintain QOL * Decrease risk of unnecessary treatment
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What are the disadvantages of active surveillance?
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* Risk of missing the chance for a cure * Risk of progression * Treatment maybe have more side effects * increased medical care and costs * Uncertain of long term natural history with cancer
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What are acceptable treatment options for the treatment of localized prostate cancer with a low risk of recurrence?
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* Low risk of recurrence: - t1-T2a - Gleason score 2-6 - PSA <10 ng/mL: <10 year survival: active surveillance - > 10 year survival: active surveillance, radiation, or radical protatectomy plus or minus LN dissection
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What are acceptable treatment options for the treatment of localized prostate cancer with a intermediate risk of recurrence?
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"* Intermediate risk of recurrence: T2b-T2c or Gleason Score 7 or PSA 10-20 ng/mL - With <10 year survival: active surveillance or radiation or radical prstatectomy plus or minus LN dissection - With > 10 year survival: Radiation plus or minus ADT or radical prostatectomy with LN dissection
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What are acceptable treatment options for the treatment of localized prostate cancer with a high risk of recurrence?
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"* High risk of recurrence: T3a or Gleason Score 8-10 or PSA >20 ng/mL : ADT + Radiation or Radical prostatectomy + LN dissection
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What are acceptable treatment options for the treatment of locally advanced prostate cancer with a very high risk of recurrence?
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* Very high risk of recurrence: T3b-T4 : ADT + Radiation or ADT or Radical prostatectomy + dissection
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What adjucant treatements are appropriate for a patient treated with radical prostatectomy with positive margins?
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Add radiation
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What adjucant treatements are appropriate for a patient treated with radical prostatectomy with positive lymph nodes?
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Add ADT
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What is an appropriate treatment for metastatic prostate cancer with Any T, N1?
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* ADT plus radiation or * ADT
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What is an appropriate treatment for metastatic prostate cancer with Any T, any N, and M1?
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ADT
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Discuss ADT (Androgen Deprivation Therapy)
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* medical castration = surgical castration * Medications: - LHRH agonist - GnRH antagonist - Antiadrogens * Combined adrogen blockade = LHRH or GnRH plus antiandrogen * Need to meet testosterone suppression goal * If not controlled then add other agents
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Are antidrogens effective monotherapy?
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No
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What are antiandrogens used for?
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tumor flare
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AHA/NHLBI Scientific Statement Metabolic Syndrome Diagnostic Criteria
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LHRH
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* Chronic administration suppresses endogenous gonadotropin synthesis * transient stimulation period – TUMOR FLARE * Drugs: Abarelix and Degarelix
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Antiandrogens
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* Inhibits testosterone binding to androgen receptor * Flutamide(Eulixin®) * Bicalutamide (Casodex®) * Nilutamide (Nilandron®) * Effective in preventing tumor flare * Start before LHRH and continue for 1 month
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What are the second line treatment options for prostate cancer?
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* Antiandrogen withdrawl: - stop all hormonal therapy - 20-40% respond * time to response based ont eh half-life of the drugs * Ketoconazole: inhibits androgen synthesis, raised LFTs, P450 reachions * Estrogens: inhibits LH release * corticosteroids: suppresion of ACTH, any-inflammatory supress
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Treatment of hormone refractory prostate cancer
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* Androgen Independent Prostate Cancer or Castration Recurrent Metastatic Prostate Cancer * Eventually prostate cancer becomes hormone refractory * QOL commonly used to assess clinical benefit * Chemotherapy: Docetaxel based regiments are the stadard of care - regimend (Q3 weeks) - Docetaxel plus prednisone, Docetaxel plus estramustine - mitoxentrone plus prednisone
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Chemo toxicities associated with Mitoxantrone?
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* Anthracycline analogue - lower risk of cardiac toxicity * S/E: Alopecia, cardiac, myelosuppression, N/V, urine discoloration
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Chemo toxicities associated with Estamustine
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"* Combination of estradiol and nitrogen mustard. * Inhibits mitotic spindle formation * Oral formulation * S/E: N/V, gynecomastia, CHF, skin rash, thromboembolic events
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What are the three main supportive care issues with prostate cancer treatments?
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* Osteoporosis * Metabolic syndrome * Come metastasis
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Osteoporosis
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* Screening and treatment similar to general population - For men > 50 yo + Ca 1200 mg and Vit D 800-1000 IU * Additional treatment when risk for hip fracture or osteoporosis-related fracture + Bisphosphonates + Zolendronic acid 4 mg IV annually + Alendronate 70 mg orally weekly
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Bisphosphonates
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* Inhibit osteoclast activity of bone and reduce bone resorption 1) Direct inhibition of osteoclasts when they take up bisphosphonate present on the bones 2) Indirect inhibition of osteoclasts - stimulating activity of osteoblasts 3) Reduction in the number of osteoclasts by influence on their recuitment or life span
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Metabolic Syndrome
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* Made up of several conditions: Obesity, Insulin resistance, Dyslipidemia, Diabetes, Cardiovascular disease * No clear screening and intervention strategy
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Bone metastasis
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* detected using a bone scan * common sites: - pelvis - spine - femur * pain issues
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What are the goals of treatment for bone metastasis?
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* Decrease pain * Decreased skeletal-related complications: fractures and spinal cord compression
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How is Bone metastasis treated?
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* radiation - pallative: for localized bone disease, impending fracture, spinal cord compression * Radiopharmaceuticals: IV formulations that bind to bone and release local radiation - Samarium (Quadramet®) - Strontium (Metastron®) - S/E: Flushing, myelosuppression, bone pain * Bisphosphonates: Q3-4 weeks - Zolendronic acid 4 mg IV over 15 minutes (Reduce dose for CrCl 30-60mL/min or Contraindicated for CrCL < 30 mL/min) * Toxicities: Renal dysfunction, Osteonecrosis of the jaw, Electrolyte abnormities, Anemia
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What are other supportice care issues with prostate caner?
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* Erectile dysfunction * Incontinence * Pain management * Hot flashes * Anemia
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