Oral Chemotherapy Flashcards
Thalidomide, Lenalidomide, and Pomalidomide are what kind of oral chemo agents?
Immunomodulators
Anti-angiogenics
IMiDs
Why would patients prefer oral chemo?
Convenience
Less invasive
Ease of administration
Sense of empowerment
Why oral over IV chemo?
Less invasive
Convenient
Self-administered
May be payable through Medicare Part D
Advantages of oral chemo from a healthcare professional standpoint
oral admin can provide prolonged drug exposure which may be important for drugs with schedule-dependent efficacy
potential to reduce the use of healthcare resources for inpatient and ambulatory patient care services
may provide better QOL
Challenges of oral chemo therapy
many drug-drug and drug-food interactions
patients with hx of dysphagia, odynophagia, severe n/v
patient adherence
less opportunity for healthcare professionals for pt interaction (pt edu, tox management, assessment on dz response)
shift of responsibility from provider to pt
drug cost ($$$)
How do IMiDs work?
Selectively inhibit secretion of pro-inflammatory cytokines
Stimulates anti-CD3 stimulated Tcells
Inhibits trophic signals to angiogenic factors in cells
Induces cell cycle arrest and cell death in myeloma cells
Which anti-angiogenic does not need renal adjustment?
Thalidomide
Which immunomodulator needs hepatic adjustment?
Pomalidomide
What are the 3 adverse effects to immunomodulators/anti-angiogenics/IMiDs?
Neuropathy, DVT/PE, Myelosuppression (neutropenia)
What is the major warning related to immunomodulators: Thaliodmide, Lenalidomide, Pomalidomide?
Pregnancy Category X - REMS needed
Everolimus blocks which important factor?
VEGF (vascular endothelial growth factor) and HIF-1 (hypoxia-inducible factor)
mTOR kinase inhibitor with antiproliferative and antiangiogenic properties
Adverse effects related to Everolimus
Metabolic Syndrome (hi-cholesterol, glucose, TG), Electrolyte abnormalities (decrease in K, Ca, Phos, Mg, HCO3), fatigue/malaise, edema
Major DDIs with Everolimus
CYP3A4 inducers/inhibitors
Which alkylating agent is available IV and PO?
Cyclophosphamide and Temozolomide
Cyclophosphamide has what adverse effects?
Hemorrhagic cystitis (dose-dependent), alopecia, N/V (dose-dependent), sterility
What patient education pts are important for cyclophosphamide?
Do not administer at bedtime to minimize risk of bladder irritation
Take during or after meals
INCREASE fluid INTAKE while on therapy to decrease risk of hemorrhagic cystitis
MOA of Temozolomide
A prodrug**: hydrolyzed to active form MTIC which exerts cytotoxic effects
Adverse Effects of Temozolomide
Non-specific: fatigue, N/V, constipation, lymphocytopenia
Patient education for Temozolomide
Absorption is affected by food, so consistently take with or without food
May take on empty stomach at bedtime to reduce N/V
Anti-emetics** are recommended that prevent N/V (for higher doses > 75 mg/m2/day)
PCP Prophylaxis** (in pts receiving concomitant radiotherapy, longer dosing regimens, or concomitant steroids)
Selective estrogen receptor modulator (SERM) oral chemotherapy agent
Tamoxifen
ADRs for Tamoxifen
Mood changes, vasodilation, edema, nausea, vasomotor (hot flashes), vaginal discharge - bone and tumor pain
BBW: VTE and increased risk of uterine malignancies
MOA for Abiraterone
Blocks CYP17 (involved in androgen synthesis) and inhibits cortisol production
ADRs for Abiraterone
(Since cortisol precursor is still available, it causes the following): hypokalemia, fluid retention, hypertension, vasomotor side-effects, increased LFTs, hypertriglyceridemia
PK/PD of Capecitabine
Prodrug that converted into active metabolite 5-FU**
ADRs of Capecitabine
HFS, diarrhea, mucositis/stomatitis
Patient education of Capecitabine
Usually administered in 2 divided doses taken 12 hours apart
Doses should be taken with water within 30 min after a meal
Avoid prolonged sun exposure (use sunscreen)
Largest group of oral chemotherapy agents
Tyrosine Kinase Inhibitors
What is the ending of Tyrosine Kinase Inhibitors?
“-nibs” small molecule: used in both solid tumors and heme cancers
Class side effects of Tyrosine Kinase Inhibitors from all inhibitions (VEGF, EGFR, BCR-ABL)
Diarrhea**, Fatigue, Rash
Class side effects with Tyrosine Kinase Inhibitors for VEGF inhibition
HFS**, HTN, hemorrhage
Class side effects with Tyrosine Kinase Inhibitors for EGFR inhibition
Acneiform rash**, nail changes, hair changes
Class side effects with Tyrosine Kinase Inhibitors for BCR-ABL inhibition
Fluid retention**
FLT-3 inhibitors
Midostaurin, Gilteritinib
Midostaurin ADR of FLT-3 Inhibitors
Nausea, Mucositis, Myelosuppression**, Diarrhea, Hyperglycemia, Edema, Fatigue, Headache
Gilteritinib ADR of FLT-3 Inhibitors
Hypertriglyceridemia, Increased LFTs, headache, fatigue, edema, hyperglycemia, nausea, mucositis, diarrhea, myelosuppression
CDK-4/6 Inhibitors (3): Cyclin-dependent Kinase inhibitors
Palbociclib, Abemaciclib, Ribociclib
MOA of CDK-4/6 Inhibitors
Interrupting hormone signals that stimulate proliferation (usually CDK-4/6 are up-regulated: they are associate with uncontrolled cell proliferation)
ADRs with Palbociclib, Abemaciclib, Ribociclib (CDK-4/6 Inhibitors)
Diarrhea (Abemaciclib), Neutropenia (Palbociclib), Fatigue, Nausea, Increased LFTs
PARP Inhibitors
Olaparib, Niraparib, Rucaparib, Talazoparib (-parib)
MOA of Olaparib, Niraparib, Rucaparib, Talazoparib (-parib)
PARP Inhibitor (Poly (ADP-ribose) polymerase enzyme inhibitor; PARP-1/2 are involved in detecting DNA damage, and promoting repair; therefore, inhibition results of apoptosis
PARP Inhibitors are not super well tolerated, and usually not the most effective dose. What are the ADRs of Olaparib, Niraparib, Rucaparib, Talazoparib (-parib)?
Myelosuppression (Olaparib), Nausea (Olaparib, Niraparib, Rucaparib), Headache, Fatigue
IDH-1/2 Inhibitors
Ivosidenib, Enasidenib
MOA for IDH-1/2 inhibitors: Ivosidenib, Enasidenib
Inhibitor of mutant isocitrate dehydrogenase 1/2 enzymes. Mutated IDH 1/2 leads to increased levels of 2-hydroxyglutarate, which is responsible for impaired hematopoietic differentiation, typically seen in leukemia cells. SO by blocking the mutant IDH-1/2, restore proper bone marrow differentiation
ADRs for IDH-1/2 Inhibitors: Ivosidenib, Enasidenib
Hyperbilirubinemia & Myelosuppression (Enasidenib**), Differentiation Syndrome (think MOA), N/D
Why is differentiation syndrome a side effect of IDH-1/2 Inhibitors?
MOA is to prevent impaired differentiation, so it restores proper differentiation. This can cause a hyper-proliferation of myeloid cells = excessive inflammatory response.
Causes “sepsis looking” response: hypotension, fever, dyspnea, hypoxia, peripheral edema, pleural or pericardial effusion, and multi-organ dysfunction
Management of Differentiation syndrome with Ivosidenib, Enasidenib
Hold therapy and initiate glucocorticoid therapy and monitor hemodynamics
Can resume when sxs done
PI3K inhibitors
Idelalisib, Duvelisib, Copanlisib (-lisib)
MOA of PI3K Inhibitors: Idelalisib, Duvelisib, Copanlisib (-lisib)
Inhibition of delta isoform of phosphatidylinositol-3 kinase will lead to apoptosis
PI3K-delta is highly expressed in malignant lymphoid B-cells, and when PI3K is activated, it will cause survival + proliferation + angiogenesis –> development of cancer when dysregulated
ADRs for Idelalisib, Duvelisib, Copanlisib (-lisib)
Fatigue, Diarrhea, Nausea, Myelosuppression
Proteasome inhibitors
Ixazomib
MOA for Ixazomib (Proteasome Inhibitors)
Reversible inhibition of chymotrypsin-like activity of beta-5 subunit of the 20s proteasome leading to cell cycle arrest and apoptosis
Proteasome are important for protein degradation and expression [—– Blocking proteasome will lead to accumulation of misfolded proteins to promote cell death
ADR for Proteasome Inhibitors (Ixazomib)
Peripheral neuropathy**, eye disease, peripheral edema, diarrhea, nausea, myelosuppression (thrombocytopenia, neutropenia)
BCL-2 Inhibitors
Venetoclax
MOA of Venetoclax (BCL-2 Inhibitor)
Selective inhibition of anti-apoptotic BCL-2 protein which is over-expressed in leukemic cells –> causes apoptosis of B cells
BCL-2 also mediates tumor cell survival and has been associated with tumor resistance to chemotherapy on the mitochondrial membrane
ADRs for Venetoclax (BCL-2 Inhibitor)
TLS**, fatigue, edema, diarrhea, AST elevation, myelosuppression, myalgia
Describe TLS associated with Venetoclax (BCL-2 Inhibitor)
Oncologic emergency characterized by metabolic disturbances that results from the massive lysis of tumor cells that release their contents into the bloodstream
Sxs: hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia
Prophylaxis required during venetoclax initiation/ramp-up phase
What is the prophylaxis for TLS during venetoclax initiation/ramp-up phase?
AML: If WBC >=25,000, adequate hydration + anti-hyperuricemic
CLL: all levels of tumor burden requires hydration (PO/IV) + anti-hyperuricemic
HDAC Inhibitors
Vorinostat, Panobinostat (-inostat)
MOA of Vorinostat, Panobinostat (-inostat) : HDAC Inhibitors
Histone deacetylase (HDAC) inhibition resulting in increased acetylation of histone proteins
Accumulation of acetylated histones and other proteins induces cell cycle arrest and apoptosis
Histones are structural support for DNA. Usually you need to deacetylase to remove the groups. But if it is blocked = cell death
ADR of HDAC Inhibitors: Vorinostat, Panobinostat (-inostat)
Fatigue, peripheral edema, nausea, diarrhea, muscle weakness, myelosuppression
Clinical Pearls to remember for HDAC Inhibitors: Vorinostat, Panobinostat (-inostat)
Obtain EKG prior to therapy initiation to verify that QTc <450 ms (for Panobinostat)
For Vorinostat, Panobinostat (-inostat) prior to treatment, start:
- baseline ANC >=1500
- platelet >= 100k
- *due to myelosuppression ADR**
Hedgehog Pathway inhibitors
Vismodegib, Sonidegib, Glasdegib (-degib)
MOA of Vismodegib, Sonidegib, Glasdegib (-degib): Hedgehog pathway inhibitors
Hedgehog pathway regulates cell growth and differentiation in embryogenesis
Mutation in the hedgehog pathway results to unrestricted proliferation of basal cells of the skin
Hedgehog inhibitors bind to Smoothened Homologue (SMO), which is the transmembrane protein involved in hedgehog-signal transduction –> cell death
ADR for Vismodegib, Sonidegib, Glasdegib (-degib): Hedgehog pathway inhibitors
Increased CPK, Fatigue, Nausea, Diarrhea, Decrease appetite
Which drug class is known for acneiform rash? (Think MOA)
EGFR Inhibitors (TKIs) - highest for all grades Afatinib
Describe acneiform rash cause by EGFR inhibitors
on face, back, chest
first 2-4 weeks: first presents with acne-like rash
peaks at weeks 4-6: post inflammatory effects, dry skin, fissure
decreases after 6-8 weeks: paronychia (a skin infection around the fingernails or toenails)
How to decrease incidence rate of acneiform rash with EGFR inhibition
Start one of these WITH therapy for total duration 6-8 weeks (also they are associated with treatment for grades of rash):
Topical [Grade 1]: Hydrocortisone 1% cream + moisturizing emollients + sunscreen (SPF 15+)
Systemic [Grade 2]: Doxycycline 100 mg PO BID or Minocycline 100 mg PO daily
[Grade 3/4]: Prednisone 0.5 mg/kg IV
Onset and symptoms of HFS from multi-targeted tyrosine kinase inhibitor
Onset: 2-4 weeks of therapy (1st month)
Symptoms: erythema, paresthesia, blisters in the palms and soles followed by thick hyperkeratotic, tender, lesions
Dose-dependent effect: Resolution if therapy is held
Pharmacologic/Non-Pharmacologic Management of HFS
Diarrhea is caused by which drugs?
Capecitabine + TKIs
Management for Diarrhea with Capecitabine and TKIs
Hold oral chemotherapy if increase of >= 4 stools/day over baseline
Increase fluid intake
Loperamide (Imodium): cancer treatment-induced 4mg followed by 2mg q4hrs or **after each loose stool (no maxdose) OR 4mg follow by 2mg every q2hrs
Diphenoxylate/Atropine 2.5/0.025 mg (Lomotil): when imodium fails, adjunct therapy 2.5-5mg PO QID until symptoms control
