Supportive Care of Cancer
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Supportive Care of Cancer -- Part 2 Chirag Dave, Pharm. D. Candidate Class of 2012 Systems Pharmacology V
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Transcript of Supportive Care of Cancer
Supportive Care of Cancer -- Part 2
Chirag Dave, Pharm. D. Candidate Class of 2012
Systems Pharmacology V
Learning Objectives
1. Explain the pathophysiology of chemotherapy induced nausea and vomiting (CINV).
2. Describe the classes of medications used to treat CINV; specifically where they act, when they should be used, and their major side effects.
3. Recognize Oral Cavity/GI tract complications associated with chemotherapy and how they can be prevented and treated.
4. Explore the concept of “Cancer-‐Related Fatigue”
Side effects are what kill you!
The Back Story
Nausea and Vomiting
Overview
• Estimated that 70-‐80% cancer patients experience chemotherapy induced nausea and vomiting, despite being treated for it.
• Prophylaxis is the most effective method of managing CINV.
• N/V can significantly affect quality of life (fatigue, treatment adherence, days off work, etc…) • What else? (Think physical implications)
• Dehydration, electrolyte imbalances, malnutrition, aspiration pneumonia, and esophageal tears.
Definitions
• Nausea: the subjective feeling of the need to vomit.
• Vomiting: forceful expulsion of the stomach contents.
• Retching: rhythmic contraction of the abdominal muscles without actual emesis.
Pathophysiology of NV
Pathophysiology of NV Areas involved in N/V Location Important
Receptors
Vomiting Center (VC) CNS H1 M1 NK1 5-‐HT3
Chemoreceptor Trigger Zone (CTZ) CNS 5-‐HT3 D2 NK1 Chemoreceptors
GI System Periphery 5-‐HT3 Mechanoreceptors Chemoreceptors
Vestibular System Periphery H1 M1
Cerebral cortex, Limbic system, Meninges, Thalamus & Hypothalamus
CNS Complex
Vomiting Center
• Located in the Medulla Oblongata.
• Acts as the coordinator of the emetic response.
• Receives afferent signals from CTZ, GI system, Vestibular system, and other areas of the brain.
• Sends signals to effector organs (salivary glands, abdominal muscles, & cranial nerves)
CTZ
• Chemoreceptors sense toxins and noxious substances (in blood & CSF).
• This is where D2 receptors are located and where D2 antagonists act.
• Also has mu-‐opioid receptors present.
GI System
• GI mucosa contains enterochromaffin cells. • Contain large amount of body’s serotonin stores.
• When chemically or physically stimulated/irritated, they release 5-‐HT.
• This stimulates Cranial nerves IX, X (afferent nerves).
• As well as VC & CTZ via 5-‐HT3 receptor activation.
Vestibular System
• Implicated in motion sickness & vertigo. • Patients who are predisposed to motion
sickness will have a harder time with chemotherapy.
• Stimulate the VC through ACh and Histamine.
Cerebral Cortex & Limbic System
• Implicated in anticipatory nausea/vomiting due to anxiety.
• Which class of medications is often used to treat anxiety?
• “Place & Taste” association is important to consider in treatment, especially with children • Can’t change the place. • Taste management.
CINV Classification • Acute Onset:
• Occurs minutes-‐hours after drug administration. • Peaks after 5-‐6h • Commonly resolves within 24h.
• Delayed-‐Onset: • Occurs >24h after CTX. • Commonly implicated agents: cisplatin, carboplatin,
cyclophosphamide, doxorubicin.
• Anticipatory: Incidence is 18-‐57%, and is more common in younger patients.
• Breakthrough: vomiting that occurs despite Px that requires rescue antiemetic use.
• Refractory: emesis that occurs despite Px and rescue antiemetic use.
Relevant Causes of NV
• CNS disorders: brain metastases, anxiety.
• Metabolic disorders: hyponatremia, uremia.
• GI disorders: bowel obstructions, gastroparesis, distention
• Medications: chemotherapy agents, antibiotics, antifungals, opiates, and irradiation. • Radiation can cause N/V, particularly when patients
receive whole body or upper abdominal radiation.
Incidence & Severity of CINV
1. Agents used (refer to “Emetogenic Potential”).
2. Dosage of agents/duration of infusion
3. Schedule and Route of Administration
4. Concurrent radiation therapy
5. Patient factors: 1. Age: Younger (<50y/o) = More NV 2. Sex: Female 3. Prior CTX 4. Alcoholism: IMPROVES ability to tolerate NV 5. Previous history: motion sickness, other N/V
Emetogenic Potential
Category Frequency in patients
High emetic risk >90% frequency of emesis
Moderate emetic risk 30-‐90% frequency of emesis
Low emetic risk 10-‐30% frequency of emesis
Minimal emetic risk <10% frequency of emesis
• Antineoplastic agents’ emetogenic potential is established by the % of patients that experience emesis on the agent WITHOUT any anti-‐emetic therapy.
• The risk of CINV is present for at least 3 days for “HIGH” risk CTX and 2 days for “MEDIUM” Risk CTX.
IV Agents (FYI)
IV Agents (FYI)
PO Agents (FYI)
Treatment of CINV
• Various combinations of the following classes of medications are used, according to NCCN guidelines. 1. Serotonin Receptor Antagonists (5-‐HT3) 2. Dopamine Antagonists (D2) 3. NK-‐1 Receptor Antagonists 4. Systemic Corticosteroids (SCS) 5. Benzodiazepines (Bzd) 6. H2 blockers/PPIs
Recommended Prophylactic Combinations (IV Agents) Category Combination
High (>90%) Day 1: 5-‐HT3 + SCS+ NK-‐1 Day 2-‐3: 5-‐HT3 (per institution) (+/-‐) H2/PPI (+/-‐) Bzd
Moderate (30-‐90%) Day 1: 5-‐HT3 + SCS (+/-‐) NK-‐1 Day 2-‐3: 5-‐HT3 or SCS or NK-‐1 (+/-‐) H2/PPI (+/-‐) Bzd
Low (10-‐30%) SCS or D2 (Metoclopramide or Prochlorperazine) (+/-‐) H2/PPI (+/-‐) Bzd
Minimal (<10%) No routine prophylaxis
All agents on Day 1 are started before chemotherapy (morning)
Breakthrough Emesis Management
• The principle is to add an agent from a different drug class than the routine anti-‐emetics.
Recommended Classes:
Used often Not used often
Benzodiazepines Cannabinoids
Dopamine Antagonists Scopolamine
5-‐HT3
SCS
1. Serotonin Receptor Antagonists
• Mechanism of Action: • Blocks 5-‐HT3 receptors, preventing Serotonin binding, thereby
inhibiting afferent nerve transmission to VC.
• PK/PD: • All agents are equally effective at equal doses. • Dose response curve is flat • Not more effective than other classes for delayed CINV (other than
palonosetron). • Give 30 minutes prior to CTX.
• Side effects: • *CONSTIPATION*…Treat with what? • QT Prolongation • Headache • Transient elevation of LFTs
1. Serotonin Receptor Antagonists 4Half-‐life Metabolism Dose Cost
Ondansetron 3-‐6h 3A4 substrate
16-‐24mg PO 8-‐24mg IV (MDD = 32mg)
30 tab x 4mg = $70.99
Granisetron (Patch too!)
6h PO 9h IV
-‐ 2mg PO 0.01mg/kg IV (MDD = 1mg)
2 tab x 1mg = $45.99 1 patch = $359.98
Dolasetron (PO for CTX)
6-‐8h -‐ 100mg PO 5 tab x 100mg = $355.96
Palonosetron ~40h
-‐ 0.25mg IV 1 vial = $406.98
2. NK-‐1 Receptor Antagonists
• Mechanism of Action: • Blocks NK-‐1 receptors, preventing Substance P from binding in the CNS.
• PK/PD: • Watch for drug interactions: with CTX and other medications (e.g.
Warfarin , OC) • 3A4 substrate, Inhibits 3A4, Induces 3A4 & 2C9
• Can be used for acute and delayed CINV, in combination with a 5-‐HT3 & SCS.
• Give PO 1 hour prior to CTX, give IV 30 min prior TO CTX.
• Side Effects: mild • Fatigue
• Headache
• Diarrhea
2. NK-‐1 Receptor Antagonists
Half-‐life
Metabolism Dose Cost
Aprepitant (PO) 9-‐13h 3A4 substrate Inhibits 3A4 Induces 3A4 & 2C9
-‐125mg Day 1 -‐80mg on Day 2 & Day 3
3 day regimen = $383.99
Fosaprepitant (IV)
2min Rapidly converted to Aprepitant
115mg over 30 minutes, then 80mg on Day 2 & Day 3
1 vial (115mg) = $223.79
• +Warfarin (2c9): Monitor INR during the 7-‐10d period after administration.
• +Oral Contraceptives: Decreases AUC for OCs, therefore use alternative method of contraceptive 1 month after administration.
3. Dopamine Antagonists
• Mechanism of Action: • Block D2 receptors, preventing Dopamine from
binding in the CNS.
• PK/PD: • Agent specific • Best used for breakthrough CINV, as PRN.
• Side Effects: • *Somnolence* • Monitor for EPS symptoms (i.e. dystonia). • Pay attention to BBWs (i.e. with Olanzapine).
3. Dopamine Antagonists Dose Cost
Haloperidol 0.5-‐2mg PO/IV q4-‐6h PRN 90 tab x 1mg = $19.99
Metoclopramide 10-‐40mg PO/IV q4h or q6h PRN
30 tab x 5mg = $12.99
Olanzapine 2.5mg-‐5mg PO BID 30 tab x 10mg = ~$500
Prochlorperazine 25mg suppository q12h OR 10mg PO/IV q4h or q6h
12 Supp x 25mg = $33.99 30 tab x 5mg = $13.99
Promethazine 12.5-‐25mg PO or IV (via central line) q4h
30 tab x 12.5mg = $15.99
Misc. Agents
4. Systemic Corticosteroids: Main agent used is Dexamethasone
• Exact MoA in CINV is unknown, but enhances efficacy of 5-‐HT3s (~20%)
• Have anti-‐tumor properties (used in some regimens, i.e. CHOP)
• Useful for acute and delayed CINV.
5. Benzodiazepines: Main agent used is Lorazepam
• Used for anticipatory CINV due to anxiety.
• Take night before/morning of.
6. H2s & PPIs: Used for dyspepsia.
Misc. Agents 7. Cannabinoids: Dronabinol, Nabilone
• Used in refractory cases.
• Exact mechanism is not known, but there are cannabinoid receptors in the CTZ and VC.
8. Scopolamine:
• Antagonizes serotonin and histamine.
• Used in motion sickness.
• Patch is applied behind the ear.
Oral cavity & GI Complications
Overview
• Approximately 40% of CTX patients have oral cavity complications, and almost 100% with head/neck radiation.
• GI tract complications are also an issue as chemotherapy and radiation affects gut flora and may cause structural alterations.
• Some of the issues that result are mucositis, xerostomia, infection, bowel movement changes, and intestinal malabsorption.
Mucositis
• It is the inflammation and ulceration of affected mucosal membranes.
• Most often, non-‐keratinized mucosa is affected @ basal layers.
• VERY PAINFUL…It feels like you’re swallowing razors.
• Occur about 5-‐7d after CTX (cell turnover is 7-‐14d), and resolves completely in 1-‐3 weeks.
• Happens most often with antimetabolites (i.e. methotrexate, cytarabine) and antitumor antibiotics
Mucositis Presentation:
• Severe pain, often requiring systemic opioids.
• Decreased ability to eat, speak, swallow.
• Infection (viral, bacterial, or fungal), most often local.
Treatment: Palliative and Preventative
• Prevention: • Time between CTX and Radiation. • Chlorhexidine rinses…AVOID ALCOHOL rinses (i.e. Listerine). • Cryotherapy: Ice chips in the mouth during treatment. • Palifermin:
• A keratinocyte growth factor, resulting in proliferation of epithelial tissue. • Give IV 3 consecutive days before myelotoxic therapy. • Side effect: rash, edema.
Mucositis
Palliation:
• Magic mouthwash, BMX or its variants • Benadryl -‐ Inflammation • Maalox – Acid indigestion • Xylocaine – Topical anesthetic • Nystatin -‐-‐ ___________ • Swish, gargle, & spit 3-‐6x/day
• Gelclair – Bioadherent gel barrier
• Opioids
Xerostomia • Damage to salivary glands leads to “dry mouth”
• Other effects: • Lower salivary pH • Decrease salivary IgA • *Altered sense of taste
Xerostomia
Treatment:
• Amifostine: • Preventative therapy • Not for everyone due to Cost & SEs (N/V, hypotension).
• Pilocarpine: • Stimulates salivary flow. • Cholinergic side effects.
• Any other agents that stimulate salivation (sugar free candy/gum). • Why sugar free?
• Salivary substitutes (MANY…but Biotene may be familiar).
Oral Complications
• Because of all this, we see increased infection (aided by neutropenia), dental caries (tooth decay), and decalcification.
• Prevention of caries is done through fluoride rinses and good dental hygiene.
• What about…Osteonecrosis of the jaw?
Lower GI Complications • Microvilli on intestinal cells atrophy and function is
affected. • Decreased medication absorption.
Constipation:
• Vinca alkaloids are known offenders (cause autonomic nerve dysfunction)
• Also a troubling side effect of 5-‐HT3 antagonists.
Lower GI Complications Diarrhea:
• Sometimes due to the cancer itself, often due to medications (i.e. 5-‐FU, cytarabine)
• Irinotecan: SEVERE diarrhea & other cholinergic symptoms • Early (within 24h, linked to PSNS stimulation) and DELAYED diarrhea • Issues: dehydration, F&E imbalances, other cholinergic symptoms • Treatment:
• F&E Management • Early: Atropine @ time of treatment. • Delayed: Loperamide @ promptly after first episode.
• Octreotide: somatostatin analog which has many effects but reduction in GI motility + F&E retention is what we’re interested in.
Cancer-related Fatigue
Overview
• Cancer-‐ related fatigue (CRF) is rarely an isolated symptom and occurs with pain, distress, anemia, and sleep disturbances.
• CRF can severely affect QoL, which is most of the battle, and activities of daily living (ADLs)
Causes
• Anemia • Decreased RBC production & increased RBC
destruction à net negative blood volume. • Managed acutely with blood transfusions and
chronically with epoetin/darbopoetin alpha.
• Pain
• Nutritional deficits
• Emotional distress
Management
• Screening should be systematic and at the start of every visit (using a standardized assessment scale).
• Nutritional consults
• Exercise!
• Limit naps to <1h to not interfere with night-‐time sleep.
• Cognitive behavioral therapy.
Pharmacologic Treatment?
• Psychostimulants can be considered, but use remains investigational.
• Methylphenidate has more evidence of benefit than modafinil.
• Caffeine?
Questions?
Additional Resources Lohr L. Nausea and Vomiting. In: Koda-‐Kimble MA, Young LY, Alldredge BK et al.,
eds. Applied Therapeutics: The Clinical Use of Drugs. 9th ed. Baltimore: Lippincott Williams & Wilkins; 2009: 1-‐12.
Falla, L. Implications of recent guideline updates on the management of chemotherapy induced nausea and vomiting. The Oncology Pharmacist. 2o1o; 3(6): 4-‐10.
Ettinger DS, Armstrong DK, Barbour S et al. Antiemesis (Version 1.2012). NCCN Guidelines. 2011.
Berger AM, Abernethy PA, Atkinson A et al. Cancer-‐Related Fatigue (Version 1.2011). NCCN Guidelines. 2010.
Worthington HV, Clarkson JE, Bryan G et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane database of systematic reviews. 2011; 4: 1-‐275
