Pharm Flashcards
What are the common sites for metastasis growth for renal cancer?
- Lymph nodes (most common)
- Lung, liver, bone (destructive lesions)
- Adrenal gland, brain
- Opposite kidney
- Subcu skin nodules
What is the principal means of curing renal cancer? Alternatives?
- 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
What is the main renal childhood tumor?
- 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%
What is the standard tx for nephroblastoma? Recurrent disease?
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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
What is the standard chemo for childhood clear cell sarcoma? Recurrent disease?
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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
What is the therapy for childhood rhabdoid and neuroepithelial tumors?
No satisfactory therapy has been discovered
Carboplatin toxicity
Myelosuppression, infection susceptibility
Cyclophosphamide toxicity
Myelosuppression, hemorrhagic cystitis (MESNA antidote)
Doxorubicin toxicity
Bone marrow suppression, acute and chronic cardiotoxicity
Dactinomycin toxicity
- Myelosuppression
- Hepatic dysdunction
- Infection susceptibility
Etoposide toxicity
- Hematologic toxicity
- BP instability
Ifosfamide toxicity
- Bone marrow suppression
- Hemorrhagic cystitis (MESNA antidote)
Vincristine toxicity
- Neurotoxicity
- Bilateral sensory stocking-glove pattern
What genetic alteration is associated with clear cell renal cell carcinoma? Describe the pathway.
- 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

What are the primary molecular targets in the tx of metastatic clear cell renal cell carcinoma? Via which drugs?
- 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

Clear cell renal carcinoma sequence of tx. Are these txs curative?
- 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
Rapamycins summary
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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
What is the activity of the rapamycins?
- 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
Rapamycin important issues
- Temsirolimus: weekly IV (metabolized to sirolimus, likely the more important agent)
- Everolimus: daily oral drug
- Both CYP 3A4 substrates: drug-drug interactions
- Prominent side effects: mild maculopapular rash, mucositis, anemia, and fatigue -> 30-50% of pts
- Reversible leukopenia, thrombocytopenia with progressive drug cycles (minority)
-
Pulmonary infiltrates in 8% of patients receiving everolimus and in a smaller percentage of those treated with temsirolimus
1. If cough or shortness of breath sxs devo or radiological changes progress, drug should be discontinued -> prednisone may hasten the resolution of radiological changes and sxs
TKI’s summary
- Primarily INH VEGFR tyrosine kinases, although some have activity at o/receptor systems that contributes to clinical activity and AE’s
- Small molecular weight orally administered drugs metabolized in liver by CYPs incl, CYP3A4 (potential for drug-drug interactions -> diminished bioavail and clinical effectiveness)
- Common but non life-threatening adverse effects, including N/V, fatigue, weakness, rash, etc.
- Several SIGNIFICANT adverse effects common to these drugs. CV problems are predictable, given the action of these drugs on VEGFR, and its involvement in vascular form and function
TKI adverse effects
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CV: thromboembolism, hemorrhagic events
1. HTN: rapid onset -> mgmt. For pts already receiving rx tx for this condition, need for dose adjustment when starting/stopping TKI tx
2. QT prolongation: most prominently with pazopanib and sorafenib
3. Blood dyscrasias: lympho-, neutro-, leuko- & thromobocytopenias - Hepatic (elevated enzymes): hepatic failure (black box warning for pazopanib and sunitinib)
- Renal: proteinuria
- Endocrine: monitor thyroid, adrenal func, blood glu
- Hypersensitivity: Stevens Johnson syndrome (sorafenib, sunitinib)
Bevacizumab summary and AE’s
- Monoclonal Ab: IV infusion (no CYP3A4 interactions)
- Pattern of AE”s mirrors that of TKIs -> in addition to N/V, fatigue, weakness, dizziness, also assoc with:
1. Thromboembolic events
2. Hypertension
3. CHF
4. Proteinuria
5. Blood dyscrasias - Black box warnings: hemorrhage, GI perforation, wound healing complications
- Usually admin on 2-wk cycle, alone, or in combo w/INF -> combo has been shown to be superior to INF alone, but even the combo provides only a limited duration of clinical effect
1. Significant improvement in progression-free survival (10.2 months), compared with interferon alfa alone (5.4 months)
What two immunotherapeutic drugs are used to treat renal cell carcinoma? Are they efficacious?
- 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

IL-2 summary and AE’s
- 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




