Pharm Flashcards
1
Q
What are the common sites for metastasis growth for renal cancer?
A
- Lymph nodes (most common)
- Lung, liver, bone (destructive lesions)
- Adrenal gland, brain
- Opposite kidney
- Subcu skin nodules
2
Q
What is the principal means of curing renal cancer? Alternatives?
A
- Principal means of producing a cure -> sx excision
- More advanced stage/grade, or if metastasis, chemo, targeted tx, immunotx, radiotx employed
- Drugs are also employed as adjunctive therapy with surgery/radiation
- Drugs employed as primary therapy where medical circumstances preclude surgery
3
Q
What is the main renal childhood tumor?
A
- Nephroblastoma (Wilm’s tumor): most common renal tumor in children (usually kids 3-4 y/o)
- Curable in majority of affected children: 5 year survival rate consistently above 90%
4
Q
What is the standard tx for nephroblastoma? Recurrent disease?
A
-
Standard chemo post nephrectomy:
1. Vincristine, dactinomycin x 18 weeks
2. Vincristine, dactinomycin, doxorubicin 24 wks
3. Vincristine, doxorubicin, cyclophosphamide, etoposide x 24 weeks -
Recurrent disease involves alternating courses of:
1. Vincristine, Doxorubicin, Cyclophosphamide
2. Etoposide and Cyclophosphamide
5
Q
What is the standard chemo for childhood clear cell sarcoma? Recurrent disease?
A
-
Standard chemo involves one of the following:
1. Vincristine, dactinomycin and doxorubicin for 15 months and radiation therapy
2. Vincristine, doxorubicin, cyclophosphamide and etoposide and radiation therapy -
Recurrent disease
1. Cyclophosphamide and carboplatin should be considered if not used initially
2. If involving the brain, kids have responded to tx with ifosfamide carboplatin and etoposide (ICE) coupled with local control consisting of either surgical resection and/or radiation
6
Q
What is the therapy for childhood rhabdoid and neuroepithelial tumors?
A
No satisfactory therapy has been discovered
7
Q
Carboplatin toxicity
A
Myelosuppression, infection susceptibility
8
Q
Cyclophosphamide toxicity
A
Myelosuppression, hemorrhagic cystitis (MESNA antidote)
9
Q
Doxorubicin toxicity
A
Bone marrow suppression, acute and chronic cardiotoxicity
10
Q
Dactinomycin toxicity
A
- Myelosuppression
- Hepatic dysdunction
- Infection susceptibility
11
Q
Etoposide toxicity
A
- Hematologic toxicity
- BP instability
12
Q
Ifosfamide toxicity
A
- Bone marrow suppression
- Hemorrhagic cystitis (MESNA antidote)
13
Q
Vincristine toxicity
A
- Neurotoxicity
- Bilateral sensory stocking-glove pattern
14
Q
What genetic alteration is associated with clear cell renal cell carcinoma? Describe the pathway.
A
- Von Hippel Lindau (VHL)
- VHL-HIF-EPO pathway
1. Functional VHL gene produces pVHL, which forms a pVHL-E3 ligase complex and mediates poly ubiquitination (Ub) and proteasomal degradation (PD) of HIF. As a result, the translocation (TR) of HIF to the nucleus and the subsequent transactivation of HIF regulated molecules, including EPO is prevented
2. When VHL gene mutated, pVHL and formation of the pVHL-E3 ligase are impaired -> HIF stabilized, up-regulated, and translocated to nucleus, where it dimerizes with o/HIF subunits, transactivates HIF responsive genes incl EPO -> EPO binds to its receptor EPOR and mediates some of the bio aspects of cancer progression, like INC in angiogenesis, inflammation and DEC in intrinsic and drug-induced apoptosis - Apart from VHL mutations, hypoxia is the major factor regulating production of EPO. In normoxic conditions, HIF is degraded, whereas in hypoxia, HIF is stabilized and lead leads to the activation of EPO
15
Q
What are the primary molecular targets in the tx of metastatic clear cell renal cell carcinoma? Via which drugs?
A
- VEGF, VEGF receptor, mTOR
1. Bevacizumab: anti-VEGF Ab
2. Axitinib: blocks VEGFR, PDGFR tyrosine kin
a. Pazopanib: blocks VEGFR, PDGFR, FFGFR, c-kit, others
b. Sunitinib: blocks VEGFR tyrosine kinase
3. Sorafenib: blocks VEGFR, PDGFR, KIT, and RAF tyrosine kinases
4. Everolimus, Temsorolimus: block mTOR - These rx primarily inhibit angiogenesis and tumor growth; cytotoxic therapy ineffective (<10% response)
- Aldesleukin (IL-2), IFN-alpha also used
16
Q
Clear cell renal carcinoma sequence of tx. Are these txs curative?
A
- Common clinical practice: TKI first, then mTOR agent gives rise to better outcome that administering the mTOR inhibitor as first-line therapy
- Recently approved Axitinib only approved as follow up therapy, after failure of the initial drug
- None of the treatments is curative -> typically they produce a median progression-free survival in the order of 9-12 months
17
Q
Rapamycins summary
A
-
Bind to FKBP12 and inhibit mTORC1
1. Immunosuppressant effects
2. INH cell-cycle progression, angiogenesis
3. Promotion of apoptosis - Resistance incompletely understood, but may arise through action of a 2nd (unaffected) mTOR complex, which regulates AKT kinase
1. May be responsible for incomplete responses or resistance of rapamycins -> dual mTORC1 and mTORC2 inhibitors are in clinical development
18
Q
What is the activity of the rapamycins?
A
- Temsirolimus prolongs survival and delays disease progression in pts w/adv and poor, intermediate-risk renal cancer, as compared to standard interferon-alpha treatment
- Everolimus, as compared to placebo, prolongs survival in patients who had failed initial treatment with anti-angiogenic drugs
23
Q
What two immunotherapeutic drugs are used to treat renal cell carcinoma? Are they efficacious?
A
- INF-alpha, IL-2: more durable response in some pts and in a small number, a clinical cure
- Pt performance, # of metastatic sites and where (liver), prior nephrectomy, time from nephrectomy to systemic tx some factors that may impact outcome
- Overall chance of partial or complete remission with immunotherapy is 12.9%, compared to 2.5% for non-immunotherapy, and 4.3% with no treatment
1. Median survival averaged 13.3 months - Reduced dose IV or SC interleukin-2 provides equivalent survival to high dose with less toxicity
- Optimal dose, duration of INF-alfa unclear; modest survival benefit compared to o/commonly used txs and should be considered for control arm of future studies of systemic agents. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies
24
Q
IL-2 summary and AE’s
A
- T-cell growth factor: involved in imm system control
- Admin of high dose IL- 2 akin to the induction of controlled state of septic shock
- Administered IV to hospitalized pts 3 x weekly; max # of doses usually tolerated is 14
- IL-2 produces CAPILLARY LEAK SYNDROME:
1. Hypotension
2. Low systemic vascular resistance
3. Tachycardia
4. Heme toxicity (grade 3⁄4)
5. Pulmonary edema
6. Renal toxicity - 126 AE’s listed
26
Q
INF-alpha-2b summary and AE’s
A
- MOA: binding of endogenous Type I: IFN-α, β, and ω to cell surface IFNAR1/IFNAR2 receptors activates cyto JAK/STAT to produce ISGF3 complex (IFN- stimulated gene factor 3 complex of STAT1, STAT2, and IRF-9) that translocates to nucleus & binds IFN-stimulated response element (ISRE) -> transcriptional up-regulation of genes responsible for antiviral, anti-proliferative, antitumor activities
- Used off label in tx of clear cell renal carcinoma, and also used for other medical conditions including malignant melanoma and hepatitis B & C
- Administration is SC 3 x weekly
- Black box warnings: neuropsychiatric, autoimmune, ischemic, and infectious disorders
-
Most common AE’s:
1. ≤ 95% fatigue, fever, flu-like symptoms
2. Leukopenia (72%), neutropenia (92%) -
Less common AE’s:
1. Xerostomia, dysguesia (distortion of taste)
2. Diaphoresis, dizziness, cough, somnolence
33
Q
How does Amphotericin-B damage the kidney?
A
- Can create pores in cell membrane -> allows back flux of H+ into cell, inhibiting urinary H+ excretion and, therefore, results in distal RTA, urinary conc defects and electrolyte disturbances
- Also produces renal vasoconstriction
- Volume expansion is standard of care
38
Q
How does Cisplatin damage the kidneys?
A
- Extraordinary accumulation in renal tubular cells
- Ototoxic agent because copper transporter (Ctr1) in the inner ear. Not based on concentration gradient
- Exposure of tubular cells to cisplatin activates signaling pathways that are cell death promoting; also induces TNF-alpha production in tubular cells, triggering a robust inflammatory response, further contributing to tubular cell injury and death
- May induce injury in renal vasculature, and ischemic tubular cell death + DEC GFR -> acute renal failure
- OCT2: organic cation transporter protein
39
Q
For which drugs are you concerned about potassium?
A
- ACEI’s, ARB’s
- Diuretics
